WO2013143700A2 - Artificial nucleic acid molecules comprising a 5'top utr - Google Patents

Artificial nucleic acid molecules comprising a 5'top utr Download PDF

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Publication number
WO2013143700A2
WO2013143700A2 PCT/EP2013/000938 EP2013000938W WO2013143700A2 WO 2013143700 A2 WO2013143700 A2 WO 2013143700A2 EP 2013000938 W EP2013000938 W EP 2013000938W WO 2013143700 A2 WO2013143700 A2 WO 2013143700A2
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Prior art keywords
gene
utr
nucleic acid
sequence
acid molecule
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PCT/EP2013/000938
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French (fr)
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WO2013143700A3 (en
Inventor
Andreas Thess
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Curevac Gmbh
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Priority to ES13713359.1T priority Critical patent/ES2660129T3/en
Priority to US14/388,224 priority patent/US10080809B2/en
Priority to RU2014142881A priority patent/RU2660565C2/en
Priority to JP2015502143A priority patent/JP6301906B2/en
Priority to KR1020147030143A priority patent/KR20140139101A/en
Priority to BR112014023898A priority patent/BR112014023898A2/en
Priority to CN201380016968.7A priority patent/CN104321432B/en
Priority to SG11201405545XA priority patent/SG11201405545XA/en
Priority to MX2014011625A priority patent/MX358706B/en
Priority to EP13713359.1A priority patent/EP2831240B1/en
Priority to CA2866945A priority patent/CA2866945C/en
Priority to AU2013242405A priority patent/AU2013242405B2/en
Publication of WO2013143700A2 publication Critical patent/WO2013143700A2/en
Publication of WO2013143700A3 publication Critical patent/WO2013143700A3/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A61K48/0066Manipulation of the nucleic acid to modify its expression pattern, e.g. enhance its duration of expression, achieved by the presence of particular introns in the delivered nucleic acid
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/04Immunostimulants
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09Recombinant DNA-technology
    • C12N15/63Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/67General methods for enhancing the expression
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09Recombinant DNA-technology
    • C12N15/63Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/85Vectors or expression systems specially adapted for eukaryotic hosts for animal cells
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2830/00Vector systems having a special element relevant for transcription
    • C12N2830/50Vector systems having a special element relevant for transcription regulating RNA stability, not being an intron, e.g. poly A signal
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2830/00Vector systems having a special element relevant for transcription
    • C12N2830/80Vector systems having a special element relevant for transcription from vertebrates
    • C12N2830/85Vector systems having a special element relevant for transcription from vertebrates mammalian
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2840/00Vectors comprising a special translation-regulating system
    • C12N2840/10Vectors comprising a special translation-regulating system regulates levels of translation
    • C12N2840/105Vectors comprising a special translation-regulating system regulates levels of translation enhancing translation

Definitions

  • the invention relates to artificial nucleic acid molecules comprising a 5'UTR element derived from the 5'UTR of a TOP gene, an open reading frame, and optionally a 3'UTR element, a poly(A) sequence and/or a polyadenylation signal.
  • the invention relates further to a vector comprising a 5'UTR element derived from the 5'UTR of a TOP gene, to a pharmaceutical composition comprising the artificial nucleic acid molecule or the vector, and to a kit comprising the artificial nucleic acid molecule, the vector and/or the pharmaceutical composition, preferably for use in the field of gene therapy and/or genetic vaccination.
  • Gene therapy and genetic vaccination belong to the most promising and quickly developing methods of modern medicine.
  • Pathologically altered gene expression may result in lack or overproduction of essential gene products, for example, signalling factors such as hormones, housekeeping factors, metabolic enzymes, structural proteins or the like. Altered gene expression may not only be due to mis- regulation of transcription and/or translation, but also due to mutations within the ORF coding for a particular protein. Pathological mutations may be caused by e.g. chromosomal aberration, or by more specific mutations, such as point or frame-shift-mutations, all of them resulting in limited functionality and, potentially, total loss of function of the gene product.
  • misregulation of transcription or translation may also occur, if mutations affect genes encoding proteins which are involved in the transcriptional or translational machinery of the cell. Such mutations may lead to pathological up- or down-regulation of genes which are - as such - functional. Genes encoding gene products which exert such regulating functions, may be, e.g., transcription factors, signal receptors, messenger proteins or the like. However, loss of function of such genes encoding regulatory proteins may, under certain circumstances, be reversed by artificial introduction of other factors acting further downstream of the impaired gene product. Such gene defects may also be compensated by gene therapy via substitution of the affected gene itself.
  • vaccines may be subdivided into “first”, “second” and “third” generation vaccines.
  • First generation vaccines are, typically, whole-organism vaccines. They are based on either live and attenuated or killed pathogens, e.g. viruses, bacteria or the like. The major drawback of live and attenuated vaccines is the risk for a reversion to life- threatening variants. Thus, although attenuated, such pathogens may still intrinsically bear unpredictable risks. Killed pathogens may not be as effective as desired for generating a specific immune response. In order to minimize these risks, “second generation” vaccines were developed. These are, typically, subunit vaccines, consisting of defined antigens or recombinant protein components which are derived from pathogens.
  • Genetic vaccines i.e. vaccines for genetic vaccination, are usually understood as "third generation” vaccines. They are typically composed of genetically engineered nucleic acid molecules which allow expression of peptide or protein (antigen) fragments characteristic for a pathogen or a tumor antigen in vivo. Genetic vaccines are expressed upon administration to a patient and uptake by competent cells. Expression of the administered nucleic acids results in production of the encoded proteins. In the event these proteins are recognized as foreign by the patient's immune system, an immune response is triggered.
  • both methods, gene therapy and genetic vaccination are essentially based on the administration of nucleic acid molecules to a patient and subsequent transcription and/or translation of the encoded genetic information.
  • genetic vaccination or gene therapy may also comprise methods which include isolation of specific body cells from a patient to be treated, subsequent in vitro transfection of such cells, and re-administration of the treated cells to the patient.
  • DNA as well as RNA may be used as nucleic acid molecules for administration in the context of gene therapy or genetic vaccination.
  • DNA is known to be relatively stable and easy to handle.
  • the use of DNA bears the risk of undesired insertion of the administered DNA-fragments into the patient's genome potentially resulting in loss of function of the impaired genes.
  • the undesired generation of anti-DNA antibodies has emerged.
  • Another drawback is the limited expression level of the encoded peptide or protein that is achievable upon DNA administration and its transcription/translation.
  • the expression level of the administered DNA will be dependent on the presence of specific transcription factors which regulate DNA transcription. In the absence of such factors, DNA transcription will not yield satisfying amounts of RNA. As a result, the level of translated peptide or protein obtained is limited.
  • RNA is considered to be a rather unstable molecular species which may readily be degraded by ubiquitous RNAses.
  • RNA-degradation contributes to the regulation of the RNA half-life time. That effect was considered and proven to fine tune the regulation of eukaryotic gene expression (Friedel et a/., conserveed principles of mammalian transcriptional regulation revealed by RNA half-life, Nucleic Acid Research, 2009, 1 -12). Accordingly, each naturally occurring mRNA has its individual half-life depending on the gene from which the mRNA is derived. It contributes to the regulation of the expression level of this gene. Unstable RNAs are important to realize transient gene expression at distinct points in time. However, long-lived RNAs may be associated with accumulation of distinct proteins or continuous expression of genes.
  • mRNAs may also be dependent on environmental factors, such as hormonal treatment, as has been shown, e.g., for insulin-like growth factor I, actin, and albumin mRNA Gohnson et a/., Newly synthesized RNA: Simultaneous measurement in intact cells of transcription rates and RNA stability of insulin-like growth factor I, actin, and albumin in growth hormone-stimulated hepatocytes, Proc. Natl. Acad. Sci., Vol. 88, pp. 5287-5291 , 1991 ).
  • RNA For gene therapy and genetic vaccination, usually stable RNA is desired. This is, on the one hand, due to the fact that the product encoded by the RNA-sequence shall accumulate in vivo. On the other hand, the RNA has to maintain its structural and functional integrity when prepared for a suitable dosage form, in the course of its storage, and when administered. Thus, considerable attention was dedicated to provide stable RNA molecules for gene therapy or genetic vaccination in order to prevent them from being subject to early degradation or decay. It has been reported that the G/C-content of nucleic acid molecules may influence their stability.
  • nucleic acids comprising an increased amount of guanine (G) and/or cytosine (C) residues may be functionally more stable than nucleic acids containing a large amount of adenine (A) and thymine (T) or uracil (U) nucleotides.
  • WO02/098443 provides a pharmaceutical composition containing an mRNA that is stabilised by sequence modifications in the translated region. Such a sequence modification takes advantage of the degeneracy of the genetic code. Accordingly, codons which contain a less favourable combination of nucleotides (less favourable in terms of RNA stability) may be substituted by alternative codons without altering the encoded amino acid sequence.
  • This method of RNA stabilization is limited by the provisions of the specific nucleotide sequence of each single RNA molecule which is not allowed to leave the space of the desired amino acid sequence. Also, that approach is restricted to coding regions of the RNA.
  • mRNA stabilisation As an alternative option for mRNA stabilisation, it has been found that naturally occurring eukaryotic mRNA molecules contain characteristic stabilising elements. For example, they may comprise so-called untranslated regions (UTR) at their 5'-end (5'UTR) and/or at their 3'- end (3'UTR) as well as other structural features, such as a 5'-cap structure or a 3'- poly(A) tail. Both, 5'UTR and 3'UTR are typically transcribed from the genomic DNA and are, thus, an element of the premature mRNA.
  • UTR untranslated regions
  • Characteristic structural features of mature mRNA such as the 5'-cap and the 3'-poly(A) tail (also called poly(A) tail or poly(A) sequence) are usually added to the transcribed (premature) mRNA during mRNA processing.
  • a 3'-poly(A) tail is typically a monotonous sequence stretch of adenine nucleotides added to the 3 '-end of the transcribed mRNA. It may comprise up to about 400 adenine nucleotides. It was found that the length of such a 3'-poly(A) tail is a potentially critical element for the stability of the individual mRNA.
  • RNA, 8, pp. 1526-1537, 2002 may be an important factor for the well-known stability of ⁇ -globin mRNA (Rodgers et a/., Regulated ⁇ -globin mRNA decay is a cytoplasmic event proceeding through 3'-to-5' exosome-dependent decapping, RNA, 8, pp. 1526-1537, 2002).
  • ⁇ -globin mRNA The 3'UTR of ⁇ -globin mRNA is obviously involved in the formation of a specific ribonucleoprotein-complex, the a-complex, whose presence correlates with mRNA stability in vitro (Wang et a/., An mRNA stability complex functions with poly(A)-binding protein to stabilize mRNA in vitro, Molecular and Cellular biology, Vol 19, No. 7, July 1999, p. 4552-4560).
  • proteins belonging to the translational apparatus may be regulated not only at the transcriptional but also at the translational level.
  • translation of proteins encoded by so called 'TOP-genes' may be down-regulated by translational repression.
  • 'TOP-gene' relates to a gene corresponding to an mRNA that is characterized by the presence of a TOP sequence at the 5'end and in most cases by a growth-associated translation regulation (ladevaia et a/., All translation elongation factors and the e, f, and h subunits of translation initiation factor 3 are encoded by 5'-terminal oligopyrimidine (TOP) mRNAs; RNA, 2008, 14:1 730-1 736).
  • TOP 5'-terminal oligopyrimidine
  • a TOP sequence - also called the '5'-terminal oligopyrimidine tract' - typically consists of a C residue at the cap site, followed by an uninterrupted sequence of up to 13 or even more pyrimidines (Avni et a/., Vertebrate mRNAs with a 5'-terminal pyrimidine tract are Candidates for translational repression in quiescent cells: characterization of the translational cis-regulatory element, Molecular and Cellular Biology, 1994, p. 3822-3833).
  • TOP sequences are reported to be present in many mRNAs encoding components of the translational machinery and to be responsible for selective repression of the translation of these TOP containing mRNAs due to growth arrest (Meyuhas, eta/., Translational Control of Ribosomal Protein mRNAs in Eukaryotes, Translational Control. Cold Spring Harbor Monograph Archive. Cold Spring Harbor Laboratory Press, 1996, p. 363-388). These TOP sequences are thought to serve as a cis-regulatory element which inhibits the binding of translational regulatory proteins or the translational machinery itself. As a result, the translation of these genes is inhibited at the growth arrest of cells.
  • mRNAs of TOP genes which are normally associated with polysomes, change their status into the translational ly inactive 'sub-polysome' while most non-TOP mRNAs stay in the'polysome' state (Yamashita et a/., Comprehensive detection of human terminal oligo-pyrimidine (TOP) genes and analysis of their characteristics. Nucleic Acids Res. 2008 Jun;36(1 1 ):3707-15. doi: 10.1093/nar/gkn248. Epub 2008 May 14).
  • oligopyrimidine tract at the 5'end of the 5'UTR was required for translational repression of TOP genes.
  • the oligopyrimidine tract at the 5' end of mammalian ribosomal protein mRNAs is required for their translational control (Levy et a/., Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):331 9-23).
  • miRNA miR-10a positively controls the translation of ribosomal proteins by binding downstream of the TOP motif present in the 5'UTRs of TOP genes. Such an enhancement of translation was dependent on the presence of the TOP motif in the 5'UTR.
  • nucleic acid molecules which may be suitable for application in gene therapy and/or genetic vaccination.
  • Another object of the present invention is to provide nucleic acid molecules coding for such a superior mRNA species which may be amenable for use in gene therapy and/or genetic vaccination.
  • nucleic acid molecules coding for such a superior mRNA species which may be amenable for use in gene therapy and/or genetic vaccination.
  • it is the object of the present invention to provide improved nucleic acid species which overcome the above discussed disadvantages of the prior art by a cost-effective and straight-forward approach.
  • the object underlying the present invention is solved by the claimed subject-matter.
  • Adaptive immune response The adaptive immune response is typically understood to be an antigen-specific response of the immune system. Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is usually maintained in the body by "memory cells". Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it.
  • the first step of an adaptive immune response is the activation of naive antigen-specific T cells or different immune cells able to induce an antigen-specific immune response by antigen-presenting cells.
  • This occurs in the lymphoid tissues and organs through which naive T cells are constantly passing.
  • the three cell types that may serve as antigen-presenting cells are dendritic cells, macrophages, and B cells. Each of these cells has a distinct function in eliciting immune responses.
  • Dendritic cells may take up antigens by phagocytosis and macropinocytosis and may become stimulated by contact with e.g. a foreign antigen to migrate to the local lymphoid tissue, where they differentiate into mature dendritic cells.
  • Macrophages ingest particulate antigens such as bacteria and are induced by infectious agents or other appropriate stimuli to express MHC molecules.
  • the unique ability of B cells to bind and internalize soluble protein antigens via their receptors may also be important to induce T cells.
  • MHC-molecules are, typically, responsible for presentation of an antigen to T-cells. Therein, presenting the antigen on MHC molecules leads to activation of T cells which induces their proliferation and differentiation into armed effector T cells.
  • T cells recognize an antigen by their T cell receptors which do not recognize and bind the antigen directly, but instead recognize short peptide fragments e.g. of pathogen-derived protein antigens, e.g. so-called epitopes, which are bound to MHC molecules on the surfaces of other cells.
  • the adaptive immune system is essentially dedicated to eliminate or prevent pathogenic growth. It typically regulates the adaptive immune response by providing the vertebrate immune system with the ability to recognize and remember specific pathogens (to generate immunity), and to mount stronger attacks each time the pathogen is encountered.
  • the system is highly adaptable because of somatic hypermutation (a process of accelerated somatic mutations), and V(D)J recombination (an irreversible genetic recombination of antigen receptor gene segments). This mechanism allows a small number of genes to generate a vast number of different antigen receptors, which are then uniquely expressed on each individual lymphocyte.
  • Adjuvant/adjuvant component in the broadest sense is typically a pharmacological and/or immunological agent that may modify, e.g. enhance, the effect of other agents, such as a drug or vaccine. It is to be interpreted in a broad sense and refers to a broad spectrum of substances. Typically, these substances are able to increase the immunogenicity of antigens.
  • adjuvants may be recognized by the innate immune systems and, e.g., may elicit an innate immune response. "Adjuvants" typically do not elicit an adaptive immune response. Insofar, "adjuvants" do not qualify as antigens. Their mode of action is distinct from the effects triggered by antigens resulting in an adaptive immune response.
  • Antigen refers typically to a substance which may be recognized by the immune system, preferably by the adaptive immune system, and is capable of triggering an antigen-specific immune response, e.g. by formation of antibodies and/or antigen-specific T cells as part of an adaptive immune response.
  • an antigen may be or may comprise a peptide or protein which may be presented by the MHC to T-cells.
  • An artificial nucleic acid molecule may typically be understood to be a nucleic acid molecule, e.g. a DNA or an RNA, that does not occur naturally.
  • an artificial nucleic acid molecule may be understood as a non- natural nucleic acid molecule.
  • Such nucleic acid molecule may be non-natural due to its individual sequence (which does not occur naturally) and/or due to other modifications, e.g. structural modifications of nucleotides which do not occur naturally.
  • An artificial nucleic acid molecule may be a DNA molecule, an RNA molecule or a hybrid-molecule comprising DNA and RNA portions.
  • artificial nucleic acid molecules may be designed and/or generated by genetic engineering methods to correspond to a desired artificial sequence of nucleotides (heterologous sequence).
  • an artificial sequence is usually a sequence that may not occur naturally, i.e. it differs from the wild type sequence by at least one nucleotide.
  • the term 'wild type' may be understood as a sequence occurring in nature.
  • the term 'artificial nucleic acid molecule' is not restricted to mean 'one single molecule' but is, typically, understood to comprise an ensemble of identical molecules. Accordingly, it may relate to a plurality of identical molecules contained in an aliquot.
  • Bicistronic RNA, multicistronic RNA A bicistronic or multicistronic RNA is typically an RNA, preferably an mRNA, that typically may have two (bicistronic) or more (multicistronic) open reading frames (ORF).
  • An open reading frame in this context is a sequence of codons that is translatable into a peptide or protein.
  • Carrier / polymeric carrier A carrier in the context of the invention may typically be a compound that facilitates transport and/or complexation of another compound (cargo).
  • a polymeric carrier is typically a carrier that is formed of a polymer.
  • a carrier may be associated to its cargo by covalent or non-covalent interaction.
  • a carrier may transport nucleic acids, e.g. RNA or DNA, to the target cells.
  • the carrier may - for some embodiments - be a cationic component.
  • Cationic component typically refers to a charged molecule, which is positively charged (cation) at a pH value typically from 1 to 9, preferably at a pH value of or below 9 (e.g. from 5 to 9), of or below 8 (e.g. from 5 to 8), of or below 7 (e.g. from 5 to 7), most preferably at a physiological pH, e.g. from 7.3 to 7.4.
  • a cationic component may be any positively charged compound or polymer, preferably a cationic peptide or protein which is positively charged under physiological conditions, particularly under physiological conditions in vivo.
  • a 'cationic peptide or protein' may contain at least one positively charged amino acid, or more than one positively charged amino acid, e.g. selected from Arg, His, Lys or Orn. Accordingly, 'polycationic' components are also within the scope exhibiting more than one positive charge under the conditions given.
  • a 5'-cap is an entity, typically a modified nucleotide entity, which generally
  • a 5 '-cap may typically be formed by a modified nucleotide, particularly by a derivative of a guanine nucleotide.
  • the 5'-cap is linked to the 5'-terminus via a 5'-5'-triphosphate linkage.
  • a 5'-cap may be methylated, e.g. m7GpppN, wherein N is the terminal 5' nucleotide of the nucleic acid carrying the 5'-cap, typically the 5'-end of an RNA.
  • 5'cap structures include glyceryl, inverted deoxy abasic residue (moiety), 4', 5' methylene nucleotide, 1 -(beta-D- erythrofuranosyl) nucleotide, 4'-thio nucleotide, carbocyclic nucleotide, 1 ,5-anhydrohexitol nucleotide, L-nucleotides, alpha-nucleotide, modified base nucleotide, threo-pentofuranosyl nucleotide, acyclic 3',4'-seco nucleotide, acyclic 3,4-dihydroxybutyl nucleotide, acyclic 3,5 dihydroxypentyl nucleotide, 3 '-3 '-inverted nucleotide moiety, 3 '-3 '-inverted abasic moiety, 3'-2'-inverted nucleotide moiety, 3
  • Cellular immunity relates typically to the activation of macrophages, natural killer cells (NK), antigen-specific cytotoxic T- lymphocytes, and the release of various cytokines in response to an antigen.
  • cellular immunity is not based on antibodies, but on the activation of cells of the immune system.
  • a cellular immune response may be characterized e.g. by activating antigen-specific cytotoxic T-lymphocytes that are able to induce apoptosis in cells, e.g. specific immune cells like dendritic cells or other cells, displaying epitopes of foreign antigens on their surface.
  • Such cells may be virus-infected or infected with intracellular bacteria, or cancer cells displaying tumor antigens. Further characteristics may be activation of macrophages and natural killer cells, enabling them to destroy pathogens and stimulation of cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive immune responses and innate immune responses.
  • DNA is the usual abbreviation for deoxy-ribonucleic-acid. It is a nucleic acid molecule, i.e. a polymer consisting of nucleotides. These nucleotides are usually deoxy- adenosine-monophosphate, deoxy-thymidine-monophosphate, deoxy-guanosine- monophosphate and deoxy-cytidine-monophosphate monomers which are - by themselves - composed of a sugar moiety (deoxyribose), a base moiety and a phosphate moiety, and polymerize by a characteristic backbone structure.
  • the backbone structure is, typically, formed by phosphodiester bonds between the sugar moiety of the nucleotide, i.e. deoxyribose, of a first and a phosphate moiety of a second, adjacent monomer.
  • the specific order of the monomers i.e. the order of the bases linked to the sugar/phosphate-backbone, is called the DNA-sequence.
  • DNA may be single stranded or double stranded. In the double stranded form, the nucleotides of the first strand typically hybridize with the nucleotides of the second strand, e.g. by A/T-base-pairing and G/C-base-pairing.
  • Epitopes can be distinguished in T cell epitopes and B cell epitopes.
  • T cell epitopes or parts of the proteins in the context of the present invention may comprise fragments preferably having a length of about 6 to about 20 or even more amino acids, e.g. fragments as processed and presented by MHC class I molecules, preferably having a length of about 8 to about 10 amino acids, e.g. 8, 9, or 10, (or even 1 1 , or 12 amino acids), or fragments as processed and presented by MHC class II molecules, preferably having a length of about 13 or more amino acids, e.g.
  • B cell epitopes are typically fragments located on the outer surface of (native) protein or peptide antigens as defined herein, preferably having 5 to 15 amino acids, more preferably having 5 to 12 amino acids, even more preferably having 6 to 9 amino acids, which may be recognized by antibodies, i.e. in their native form.
  • Such epitopes of proteins or peptides may furthermore be selected from any of the herein mentioned variants of such proteins or peptides.
  • antigenic determinants can be conformational or discontinuous epitopes which are composed of segments of the proteins or peptides as defined herein that are discontinuous in the amino acid sequence of the proteins or peptides as defined herein but are brought together in the three-dimensional structure or continuous or linear epitopes which are composed of a single polypeptide chain.
  • Fragment of a sequence A fragment of a sequence may typically be a shorter portion of a full-length sequence of e.g. a nucleic acid molecule or an amino acid sequence.
  • a fragment typically, consists of a sequence that is identical to the corresponding stretch within the full-length sequence.
  • a preferred fragment of a sequence in the context of the present invention consists of a continuous stretch of entities, such as nucleotides or amino acids corresponding to a continuous stretch of entities in the molecule the fragment is derived from, which represents at least 20%, preferably at least 30%, more preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, and most preferably at least 80% of the total (i.e. full- length) molecule from which the fragment is derived.
  • a G/C-modified nucleic acid may typically be a nucleic acid, preferably an artificial nucleic acid molecule as defined herein, based on a modified wild- type sequence comprising a preferably increased number of guanosine and/or cytosine nucleotides as compared to the wild-type sequence. Such an increased number may be generated by substitution of codons containing adenosine or thymidine nucleotides by codons containing guanosine or cytosine nucleotides. If the enriched G/C content occurs in a coding region of DNA or RNA, it makes use of the degeneracy of the genetic code. Accordingly, the codon substitutions preferably do not alter the encoded amino acid residues, but exclusively increase the G/C content of the nucleic acid molecule.
  • Gene therapy may typically be understood to mean a treatment of a patient's body or isolated elements of a patient's body, for example isolated tissues/cells, by nucleic acids encoding a peptide or protein. It typically may comprise at least one of the steps of a) administration of a nucleic acid, preferably an artificial nucleic acid molecule as defined herein, directly to the patient - by whatever administration route - or in vitro to isolated cells/tissues of the patient, which results in transfection of the patient's cells either in vivo/ex vivo or in vitro, b) transcription and/or translation of the introduced nucleic acid molecule; and optionally c) re-administration of isolated, transfected cells to the patient, if the nucleic acid has not been administered directly to the patient.
  • a nucleic acid preferably an artificial nucleic acid molecule as defined herein
  • Genetic vaccination may typically be understood to be vaccination by administration of a nucleic acid molecule encoding an antigen or an immunogen or fragments thereof.
  • the nucleic acid molecule may be administered to a subject's body or to isolated cells of a subject. Upon transfection of certain cells of the body or upon transfection of the isolated cells, the antigen or immunogen may be expressed by those cells and subsequently presented to the immune system, eliciting an adaptive, i.e. antigen- specific immune response.
  • genetic vaccination typically comprises at least one of the steps of a) administration of a nucleic acid, preferably an artificial nucleic acid molecule as defined herein, to a subject, preferably a patient, or to isolated cells of a subject, preferably a patient, which usually results in transfection of the subject's cells either in vivo or in vitro, b) transcription and/or translation of the introduced nucleic acid molecule; and optionally c) re-administration of isolated, transfected cells to the subject, preferably the patient, if the nucleic acid has not been administered directly to the patient.
  • Heterologous sequence Two sequences are typically understood to be 'heterologous' if they are not derivable from the same gene. I.e., although heterologous sequences may be derivable from the same organism, they naturally (in nature) do not occur in the same nucleic acid molecule, such as in the same mRNA.
  • Humoral immunity refers typically to antibody production and optionally to accessory processes accompanying antibody production.
  • a humoral immune response may be typically characterized, e.g., by Th2 activation and cytokine production, germinal center formation and isotype switching, affinity maturation and memory cell generation.
  • Humoral immunity also typically may refer to the effector functions of antibodies, which include pathogen and toxin neutralization, classical complement activation, and opsonin promotion of phagocytosis and pathogen elimination.
  • an immunogen may be typically understood to be a compound that is able to stimulate an immune response.
  • an immunogen is a peptide, polypeptide, or protein.
  • an immunogen in the sense of the present invention is the product of translation of a provided nucleic acid molecule, preferably an artificial nucleic acid molecule as defined herein.
  • an immunogen elicits at least an adaptive immune response.
  • an immunostimulatory composition may be typically understood to be a composition containing at least one component which is able to induce an immune response or from which a component which is able to induce an immune response is derivable. Such immune response may be preferably an innate immune response or a combination of an adaptive and an innate immune response.
  • an immunostimulatory composition in the context of the invention contains at least one artificial nucleic acid molecule, more preferably an RNA, for example an mRNA molecule.
  • the immunostimulatory component, such as the mRNA may be complexed with a suitable carrier.
  • the immunostimulatory composition may comprise an mRNA/carrier-complex.
  • the immunostimulatory composition may comprise an adjuvant and/or a suitable vehicle for the immunostimulatory component, such as the mRNA.
  • Immune response An immune response may typically be a specific reaction of the adaptive immune system to a particular antigen (so called specific or adaptive immune response) or an unspecific reaction of the innate immune system (so called unspecific or innate immune response), or a combination thereof.
  • the immune system may protect organisms from infection. If a pathogen succeeds in passing a physical barrier of an organism and enters this organism, the innate immune system provides an immediate, but non-specific response. If pathogens evade this innate response, vertebrates possess a second layer of protection, the adaptive immune system.
  • the immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered.
  • the immune system comprises the innate and the adaptive immune system. Each of these two parts typically contains so called humoral and cellular components.
  • Immunostimulatory RNA in the context of the invention may typically be an RNA that is able to induce an innate immune response. It usually does not have an open reading frame and thus does not provide a peptide-antigen or immunogen but elicits an immune response e.g. by binding to a specific kind of Toll-like- receptor (TLR) or other suitable receptors.
  • TLR Toll-like- receptor
  • mRNAs having an open reading frame and coding for a peptide/protein may induce an innate immune response and, thus, may be immunostimulatory RNAs.
  • the innate immune system also known as non-specific (or unspecific) immune system, typically comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner. This means that the cells of the innate system may recognize and respond to pathogens in a generic way, but unlike the adaptive immune system, it does not confer long-lasting or protective immunity to the host.
  • the innate immune system may be, e.g., activated by ligands of Toll-like receptors (TLRs) or other auxiliary substances such as lipopolysaccharides, TNF-alpha, CD40 ligand, or cytokines, monokines, lymphokines, interleukins or chemokines, IL-1 , IL-2, IL-3, IL-4, IL- 5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-1 1 , IL-12, IL-13, IL-14, IL-15, IL-16, IL-1 7, IL-18, IL-19, IL- 20, IL-21 , IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31 , IL-32, IL-33, IFN- alpha, IFN-beta, IFN-gamma, GM-C
  • the pharmaceutical composition according to the present invention may comprise one or more such substances.
  • a response of the innate immune system includes recruiting immune cells to sites of infection, through the production of chemical factors, including specialized chemical mediators, called cytokines; activation of the complement cascade; identification and removal of foreign substances present in organs, tissues, the blood and lymph, by specialized white blood cells; activation of the adaptive immune system; and/or acting as a physical and chemical barrier to infectious agents.
  • a cloning site is typically understood to be a segment of a nucleic acid molecule, which is suitable for insertion of a nucleic acid sequence, e.g., a nucleic acid sequence comprising an open reading frame. Insertion may be performed by any molecular biological method known to the one skilled in the art, e.g. by restriction and ligation.
  • a cloning site typically comprises one or more restriction enzyme recognition sites (restriction sites). These one or more restrictions sites may be recognized by restriction enzymes which cleave the DNA at these sites.
  • a cloning site which comprises more than one restriction site may also be termed a multiple cloning site (MCS) or a polylinker.
  • MCS multiple cloning site
  • Nucleic acid molecule is a molecule comprising, preferably consisting of nucleic acid components.
  • the term nucleic acid molecule preferably refers to DNA or RNA molecules. It is preferably used synonymous with the term "polynucleotide".
  • a nucleic acid molecule is a polymer comprising or consisting of nucleotide monomers which are covalently linked to each other by phosphodiester-bonds of a sugar/phosphate-backbone.
  • the term "nucleic acid molecule” also encompasses modified nucleic acid molecules, such as base-modified, sugar-modified or backbone-modified etc. DNA or RNA molecules.
  • Open reading frame in the context of the invention may typically be a sequence of several nucleotide triplets which may be translated into a peptide or protein.
  • An open reading frame preferably contains a start codon, i.e. a combination of three subsequent nucleotides coding usually for the amino acid methionine (ATG or AUG), at its 5'-end and a subsequent region which usually exhibits a length which is a multiple of 3 nucleotides.
  • An ORF is preferably terminated by a stop-codon (e.g., TAA, TAG, TGA). Typically, this is the only stop-codon of the open reading frame.
  • an open reading frame in the context of the present invention is preferably a nucleotide sequence, consisting of a number of nucleotides that may be divided by three, which starts with a start codon (e.g. ATG or AUG) and which preferably terminates with a stop codon (e.g., TAA, TGA, or TAG or UAA, UAG, UGA, respectively).
  • the open reading frame may be isolated or it may be incorporated in a longer nucleic acid sequence, for example in a vector or an mRNA.
  • An open reading frame may also be termed 'protein coding region'.
  • a peptide or polypeptide is typically a polymer of amino acid monomers, linked by peptide bonds. It typically contains less than 50 monomer units. Nevertheless, the term peptide is not a disclaimer for molecules having more than 50 monomer units. Long peptides are also called polypeptides, typically having between 50 and 600 monomeric units.
  • a pharmaceutically effective amount in the context of the invention is typically understood to be an amount that is sufficient to induce a pharmaceutical effect, such as an immune response, altering a pathological level of an expressed peptide or protein, or substituting a lacking gene product, e.g., in case of a pathological situation.
  • Protein A protein typically comprises one or more peptides or polypeptides.
  • a protein is typically folded into 3-dimensional form, which may be required for to protein to exert its biological function.
  • a poly(A) sequence also called poly(A) tail or 3'-poly(A) tail, is typically understood to be a sequence of adenine nucleotides, e.g., of up to about 400 adenine nucleotides, e.g. from about 20 to about 400, preferably from about 50 to about 400, more preferably from about 50 to about 300, even more preferably from about 50 to about 250, most preferably from about 60 to about 250 adenine nucleotides.
  • a poly(A) sequence is typically located at the 3'end of an mRNA.
  • a poly(A) sequence may be located within an mRNA or any other nucleic acid molecule, such as, e.g., in a vector, for example, in a vector serving as template for the generation of an RNA, preferably an mRNA, e.g., by transcription of the vector.
  • Polyadenylation is typically understood to be the addition of a poly(A) sequence to a nucleic acid molecule, such as an RNA molecule, e.g. to a premature mRNA. Polyadenylation may be induced by a so called polyadenylation signal. This signal is preferably located within a stretch of nucleotides at the 3'-end of a nucleic acid molecule, such as an RNA molecule, to be polyadenylated.
  • a polyadenylation signal typically comprises a hexamer consisting of adenine and uracil/thymine nucleotides, preferably the hexamer sequence AAUAAA.
  • RNA maturation from pre-mRNA to mature mRNA comprises the step of polyadenylation.
  • a restriction site also termed 'restriction enzyme recognition site', is a nucleotide sequence recognized by a restriction enzyme.
  • a restriction site is typically a short, preferably palindromic nucleotide sequence, e.g. a sequence comprising 4 to 8 nucleotides.
  • a restriction site is preferably specifically recognized by a restriction enzyme.
  • the restriction enzyme typically cleaves a nucleotide sequence comprising a restriction site at this site. In a double-stranded nucleotide sequence, such as a double-stranded DNA sequence, the restriction enzyme typically cuts both strands of the nucleotide sequence.
  • RNA is the usual abbreviation for ribonucleic-acid. It is a nucleic acid molecule, i.e. a polymer consisting of nucleotides. These nucleotides are usually adenosine- monophosphate, uridine-monophosphate, guanosine-monophosphate and cytidine- monophosphate monomers which are connected to each other along a so-called backbone.
  • the backbone is formed by phosphodiester bonds between the sugar, i.e. ribose, of a first and a phosphate moiety of a second, adjacent monomer.
  • the specific succession of the monomers is called the RNA-sequence.
  • RNA may be obtainable by transcription of a DNA-sequence, e.g., inside a cell.
  • transcription is typically performed inside the nucleus or the mitochondria.
  • transcription of DNA usually results in the so-called premature RNA which has to be processed into so-called messenger-RNA, usually abbreviated as mRNA.
  • Processing of the premature RNA e.g. in eukaryotic organisms, comprises a variety of different posttranscriptional-modifications such as splicing, 5'- capping, polyadenylation, export from the nucleus or the mitochondria and the like. The sum of these processes is also called maturation of RNA.
  • the mature messenger RNA usually provides the nucleotide sequence that may be translated into an amino acid sequence of a particular peptide or protein.
  • a mature mRNA comprises a 5'-cap, a 5'UTR, an open reading frame, a 3'UTR and a poly(A) sequence.
  • sequence of a nucleic acid molecule The sequence of a nucleic acid molecule is typically understood to be the particular and individual order, i.e. the succession of its nucleotides.
  • the sequence of a protein or peptide is typically understood to be the order, i.e. the succession of its amino acids.
  • Sequence identity Two or more sequences are identical if they exhibit the same length and order of nucleotides or amino acids.
  • the percentage of identity typically describes the extent to which two sequences are identical, i.e. it typically describes the percentage of nucleotides that correspond in their sequence position with identical nucleotides of a reference-sequence.
  • the sequences to be compared are considered to exhibit the same length, i.e. the length of the longest sequence of the sequences to be compared. This means that a first sequence consisting of 8 nucleotides is 80% identical to a second sequence consisting of 10 nucleotides comprising the first sequence.
  • identity of sequences preferably relates to the percentage of nucleotides of a sequence which have the same position in two or more sequences having the same length. Gaps are usually regarded as non-identical positions, irrespective of their actual position in an alignment.
  • a stabilized nucleic acid molecule is a nucleic acid molecule, preferably a DNA or RNA molecule that is modified such, that it is more stable to disintegration or degradation, e.g., by environmental factors or enzymatic digest, such as by an exo- or endonuclease degradation, than the nucleic acid molecule without the modification.
  • a stabilized nucleic acid molecule in the context of the present invention is stabilized in a cell, such as a prokaryotic or eukaryotic cell, preferably in a mammalian cell, such as a human cell.
  • the stabilization effect may also be exerted outside of cells, e.g. in a buffer solution etc., for example, in a manufacturing process for a pharmaceutical composition comprising the stabilized nucleic acid molecule.
  • Transfection refers to the introduction of nucleic acid molecules, such as DNA or RNA (e.g. mRNA) molecules, into cells, preferably into eukaryotic cells.
  • nucleic acid molecules such as DNA or RNA (e.g. mRNA) molecules
  • the term 'transfection' encompasses any method known to the skilled person for introducing nucleic acid molecules into cells, preferably into eukaryotic cells, such as into mammalian cells. Such methods encompass, for example, electroporation, lipofection, e.g.
  • the introduction is non-viral.
  • a vaccine is typically understood to be a prophylactic or therapeutic material providing at least one antigen, preferably an immunogen.
  • the antigen or immunogen may be derived from any material that is suitable for vaccination.
  • the antigen or immunogen may be derived from a pathogen, such as from bacteria or virus particles etc., or from a tumor or cancerous tissue.
  • the antigen or immunogen stimulates the body's adaptive immune system to provide an adaptive immune response.
  • Vector The term 'vector' refers to a nucleic acid molecule, preferably to an artificial nucleic acid molecule.
  • a vector in the context of the present invention is suitable for incorporating or harboring a desired nucleic acid sequence, such as a nucleic acid sequence comprising an open reading frame.
  • Such vectors may be storage vectors, expression vectors, cloning vectors, transfer vectors etc.
  • a storage vector is a vector which allows the convenient storage of a nucleic acid molecule, for example, of an mRNA molecule.
  • the vector may comprise a sequence corresponding, e.g., to a desired mRNA sequence or a part thereof, such as a sequence corresponding to the open reading frame and the 3'UTR of an mRNA.
  • An expression vector may be used for production of expression products such as RNA, e.g. mRNA, or peptides, polypeptides or proteins.
  • an expression vector may comprise sequences needed for transcription of a sequence stretch of the vector, such as a promoter sequence, e.g.
  • a cloning vector is typically a vector that contains a cloning site, which may be used to incorporate nucleic acid sequences into the vector.
  • a cloning vector may be, e.g., a plasmid vector or a bacteriophage vector.
  • a transfer vector may be a vector which is suitable for transferring nucleic acid molecules into cells or organisms, for example, viral vectors.
  • a vector in the context of the present invention may be, e.g., an RNA vector or a DNA vector.
  • a vector is a DNA molecule.
  • a vector in the sense of the present application comprises a cloning site, a selection marker, such as an antibiotic resistance factor, and a sequence suitable for multiplication of the vector, such as an origin of replication.
  • a vector in the context of the present application is a plasmid vector.
  • Vehicle A vehicle is typically understood to be a material that is suitable for storing, transporting, and/or administering a compound, such as a pharmaceutically active compound.
  • it may be a physiologically acceptable liquid which is suitable for storing, transporting, and/or administering a pharmaceutically active compound.
  • 3'-untranslated region (3'UTR) A 3'UTR is typically the part of an mRNA which is located between the protein coding region (i.e.
  • a 3'UTR of the mRNA is not translated into an amino acid sequence.
  • the 3'UTR sequence is generally encoded by the gene which is transcribed into the respective mRNA during the gene expression process.
  • the genomic sequence is first transcribed into pre-mature mRNA, which comprises optional introns.
  • the pre-mature mRNA is then further processed into mature mRNA in a maturation process.
  • This maturation process comprises the steps of 5'capping, splicing the pre-mature mRNA to excise optional introns and modifications of the 3'-end, such as polyadenylation of the 3'-end of the premature mRNA and optional endo- or exonuclease cleavages etc.
  • a 3'UTR corresponds to the sequence of a mature mRNA which is located 3' to the stop codon of the protein coding region, preferably immediately 3' to the stop codon of the protein coding region, and which extends to the 5'-side of the poly(A) sequence, preferably to the nucleotide immediately 5' to the poly(A) sequence.
  • the 3'UTR sequence may be an RNA sequence, such as in the mRNA sequence used for defining the 3'UTR sequence, or a DNA sequence which corresponds to such RNA sequence.
  • a 3'UTR of a gene such as "a 3'UTR of an albumin gene” is the sequence which corresponds to the 3'UTR of the mature mRNA derived from this gene, i.e. the mRNA obtained by transcription of the gene and maturation of the pre-mature mRNA.
  • the term "3'UTR of a gene” encompasses the DNA sequence and the RNA sequence of the 3'UTR.
  • a 5'-untranslated region is typically understood to be a particular section of messenger RNA (mRNA). It is located 5' of the open reading frame of the mRNA. Typically, the 5'UTR starts with the transcriptional start site and ends one nucleotide before the start codon of the open reading frame.
  • the 5'UTR may comprise elements for controlling gene expression, also called regulatory elements. Such regulatory elements may be, for example, ribosomal binding sites or a 5'-Terminal Oligopyrimidine Tract.
  • the 5'UTR may be posttranscriptionally modified, for example by addition of a 5'-cap.
  • a 5'UTR corresponds to the sequence of a mature mRNA which is located between the 5'cap and the start codon.
  • the 5'UTR corresponds to the sequence which extends from a nucleotide located 3' to the 5'-cap, preferably from the nucleotide located immediately 3' to the 5'cap, to a nucleotide located 5' to the start codon of the protein coding region, preferably to the nucleotide located immediately 5' to the start codon of the protein coding region.
  • the nucleotide located immediately 3' to the 5'cap of a mature mRNA typically corresponds to the transcriptional start site.
  • the term “corresponds to” means that the 5'UTR sequence may be an RNA sequence, such as in the mRNA sequence used for defining the 5'UTR sequence, or a DNA sequence which corresponds to such RNA sequence.
  • a 5'UTR of a gene such as "a 5'UTR of a TOP gene” is the sequence which corresponds to the 5'UTR of the mature mRNA derived from this gene, i.e. the mRNA obtained by transcription of the gene and maturation of the pre-mature mRNA.
  • the term “5'UTR of a gene” encompasses the DNA sequence and the RNA sequence of the 5'UTR.
  • TOP 5'Terminal Oligopyrimidine Tract
  • the 5'terminal oligopyrimidine tract (TOP) is typically a stretch of pyrimidine nucleotides located at the 5' terminal region of a nucleic acid molecule, such as the 5' terminal region of certain mRNA molecules or the 5' terminal region of a functional entity, e.g. the transcribed region, of certain genes.
  • the sequence starts with a cytidine, which usually corresponds to the transcriptional start site, and is followed by a stretch of usually about 3 to 30 pyrimidine nucleotides, more often 3 to 1 5 pyrimidine nucleotides.
  • the TOP may comprise 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 1 6, 1 7, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30 or even more nucleotides.
  • Messenger RNA that contains a 5'-terminal oligopyrimidine tract is often referred to as TOP mRNA. Accordingly, genes that provide such messenger RNAs are referred to as TOP genes.
  • TOP sequences have, for example, been found in genes and mRNAs encoding peptide elongation factors and ribosomal proteins.
  • TOP motif In the context of the present invention, a TOP motif is a nucleic acid sequence which corresponds to a 5'TOP as defined above. Thus, a TOP motif in the context of the present invention is preferably a stretch of pyrimidine nucleotides having a length of 3-30 nucleotides.
  • the TOP-motif consists of at least 3 pyrimidine nucleotides, preferably at least 4 pyrimidine nucleotides, preferably at least 5 pyrimidine nucleotides, more preferably at least 6 nucleotides, more preferably at least 7 nucleotides, most preferably at least 8 pyrimidine nucleotides, wherein the stretch of pyrimidine nucleotides prefera- bly starts at its 5'end with a cytosine nucleotide.
  • the TOP- motif preferably starts at its 5'end with the transcriptional start site and ends one nucleotide 5' to the first purin residue in said gene or mRNA.
  • a TOP motif in the sense of the present invention is preferably located at the 5'end of a sequence which represents a 5'UTR or at the 5'end of a sequence which codes for a 5'UTR.
  • TOP motif a stretch of 3 or more pyrimidine nucleotides is called "TOP motif" in the sense of the present invention if this stretch is located at the 5'end of a respective sequence, such as the artificial nucleic acid molecule according to the present invention, the 5'UTR element of the artificial nucleic acid molecule according to the present invention, or the nucleic acid sequence which is derived from the 5'UTR of a TOP gene as described herein.
  • a stretch of 3 or more pyrimidine nucleotides which is not located at the 5'-end of a 5'UTR or a 5'UTR element but anywhere within a 5'UTR or a 5'UTR element is preferably not referred to as "TOP motif".
  • TOP genes are typically characterised by the presence of a 5' terminal oli- gopyrimidine tract. Furthermore, most TOP genes are characterized by a growth -associated translational regulation. However, also TOP genes with a tissue specific translational regulation are known.
  • the 5'UTR of a TOP gene corresponds to the sequence of a 5'UTR of a mature mRNA derived from a TOP gene, which preferably extends from the nucleotide located 3' to the 5'cap to the nucleotide located 5' to the start codon.
  • a 5'UTR of a TOP gene typically does not comprise any start codons, preferably no upstream AUGs (uAUGs) or upstream open reading frames (uORFs).
  • upstream AUGs and upstream open reading frames are typically understood to be AUGs and open reading frames that occur 5' of the start codon (AUG) of the open reading frame that should be translated.
  • the 5'UTRs of TOP genes are generally rather short.
  • the lengths of 5'UTRs of TOP genes may vary between 20 nucleotides up to 500 nucleotides, and are typically less than about 200 nucleotides, preferably less than about 150 nucleotides, more preferably less than about 100 nucleotides.
  • Exemplary 5'UTRs of TOP genes in the sense of the present invention are the nucleic acid sequences extending from the nucleotide at position 5 to the nucleotide located immediately 5' to the start codon (e.g. the ATG) in the sequences according to SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 and SEQ ID NO. 1422.
  • the present invention relates to an artificial nucleic acid molecule comprising a. at least one 5'-untranslated region element (5'UTR element) which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a TOP gene or which is derived from a variant of the 5'UTR of a TOP gene; and b. at least one open reading frame (ORF).
  • an artificial nucleic acid molecule may be DNA or RNA.
  • the artificial nucleic acid molecule is DNA it may be used for providing RNA, preferably an mRNA with a corresponding sequence as is described further below.
  • the inventive artificial nucleic acid molecule is particularly useful in gene therapy and genetic vaccination because it may provide increased and/or prolonged protein production of the protein encoded by the open reading frame. It is preferred, if the components (a) and (b) are heterologous, such that the inventive nucleic acid molecule does not occur naturally, but is an artificial chimeric recombinant nucleic acid molecule.
  • '5'UTR element' preferably refers to a nucleic acid sequence which represents a 5'UTR of an artificial nucleic acid sequence, such as an artificial mRNA, or which codes for a 5'UTR of an artificial nucleic acid molecule.
  • a 5'UTR element may be the 5'UTR of an mRNA, preferably of an artificial mRNA, or it may be the transcription template for a 5'UTR of an mRNA.
  • a 5'UTR element preferably is a nucleic acid sequence which corresponds to the 5'UTR of an mRNA, preferably to the 5'UTR of an artificial mRNA, such as an mRNA obtained by transcription of a genetically engineered vector construct.
  • a 5'UTR element in the sense of the present invention functions as a 5'UTR or codes for a nucleotide sequence that fulfils the function of a 5'UTR.
  • the term '5'UTR element' may also refer to a fragment or part of a 5'UTR of an artificial nucleic acid sequence, such as an artificial mRNA, or which codes for a part or fragment of a 5'UTR of an artificial nucleic acid molecule.
  • the 5'UTR element in the sense of the present invention may be comprised in the 5'UTR of an artificial nucleic acid sequence, such as an artificial mRNA, or which codes for a 5'UTR of an artificial nucleic acid molecule.
  • the 5'UTR element comprises or consists of a nucleic acid sequence that is derived from the 5'UTR of a TOP gene or from a variant of the 5'UTR of a TOP gene.
  • nucleic acid sequence which is derived from the 5'UTR of a TOP gene' preferably refers to a nucleic acid sequence which is based on the 5'UTR sequence of a TOP gene or on a fragment thereof. This term includes sequences corresponding to the entire 5'UTR sequence, i.e. the full length 5'UTR sequence of a TOP gene, and sequences corresponding to a fragment of the 5'UTR sequence of a TOP gene.
  • a fragment of a 5'UTR of a TOP gene consists of a continuous stretch of nucleotides corresponding to a continuous stretch of nucleotides in the full-length 5'UTR of a TOP gene, which represents at least 20%, preferably at least 30%, more preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, and most preferably at least 90% of the full-length 5'UTR of a TOP gene.
  • a fragment in the sense of the present invention, is preferably a functional fragment as described herein.
  • a particularly preferred fragment of a 5'UTR of a TOP gene is a 5'UTR of a TOP gene lacking the 5'TOP motif, which typically corresponds to a pyrimidine stretch of 3 to 30 pyrimidine nucleotides at the 5' terminus of the 5'UTR of a TOP gene.
  • the 5'UTR (comprised by the inventive nucleic acid molecule) starts with the first nucleotide following the most 3'-terminal nucleotide of the 5'TOP motif.
  • the 5' UTR (of the TOP gene) employed in the inventive nucleic acid may consist of the nucleotide sequence located upstream of the 5'terminus of the 5'TOP motif and/or of the nucleotide sequence located downstream of the 3'terminus of the 5'TOP motif.
  • the 5' motif of a 5'UTR of a TOP gene may be rendered dysfunctional by e.g.
  • Another way of rendering the 5' TOP motif dysfunctional is the deletion of one or more pyrimidine nucleotides of the 5'TOP motif sequence (either at the termini and/or within the 5'TOP motif).
  • the 5'UT of a TOP gene will not be derived from the 5'UTR of ribosomal proteins (rp) mRNA (in particular not from mammalian 5'UTR of rp mRNA, more specifically not from rpP2 (e.g. rat rpP2), rpL32, rpL30, rpL13a (e.g. mouse transplantation antigen P198), rpS20, rpS6, rpLI 2 or rpS1 6 mRNA or not from an rpS19 mRNA (e.g. from Xenopus).
  • rp ribosomal proteins
  • the 5'UTR of a TOP gene is not derived from the 5'UTR of a EF1 alpha or (hamster) EF2 mRNA.
  • the 5'UTRs of these afore-mentioned rp mRNAs are specifically not used, if they are linked to reporter genes in the ORF of the inventive nucleic acid. If e.g. the 5'UTR of rpS1 6 mRNA is used for the inventive nucleic acid, that 5'UTR will either not contain the 5'TOP motif sequence (composed ot the oligonucleotide (CCTTTTCC or CCUUUUCC) or will contain a dysfunctional variant therof by e.g.
  • the dysfunctional mutants may e.g. contain one or more purine nucleotides within the 5'TOP motif sequence thereby lacking the translational control function exerted by the 5'TOP motif, e.g. by abolishing its interaction with other regulatory compounds, e.g. miRNA or interaction with granule-associated proteins TIA-1 and TIAR.
  • '5'UTR of a TOP gene' preferably refers to the 5'UTR of a naturally occurring TOP gene.
  • the terms 'variant of the 5'UTR of a TOP gene' and 'variant thereof in the context of a 5'UTR of a TOP gene refers to a variant of the 5'UTR of a naturally occurring TOP gene, preferably to a variant of the 5'UTR of a vertebrate TOP gene, preferably to a variant of the 5'UTR of a mammalian TOP gene, more preferably to a variant of the 5'UTR of a human TOP gene.
  • Such variant may be a modified 5'UTR of a TOP gene.
  • a variant 5'UTR may exhibit one or more nucleotide deletions, insertions, additions and/or substitutions compared to the naturally occurring 5'UTR from which the variant is derived.
  • a variant of a 5'UTR of a TOP gene is at least 40%, preferably at least 50%, more preferably at least 60%, more preferably at least 70%, even more preferably at least 80%, even more preferably at least 90%, most preferably at least 95% identical to the naturally occurring 5'UTR the variant is derived from.
  • the variant is a functional variant as described herein.
  • a nucleic acid sequence that is derived from a variant of the 5'UTR of a TOP gene preferably refers to a nucleic acid sequence which is based on a variant of a 5'UTR sequence of a TOP gene or on a fragment thereof. This term includes sequences corresponding to the entire variant 5'UTR sequence, i.e. the full length variant 5'UTR sequence of a TOP gene, and sequences corresponding to a fragment of the variant 5'UTR sequence of a TOP gene.
  • a fragment of a variant of the 5'UTR of a TOP gene consists of a continuous stretch of nucleotides corresponding to a continuous stretch of nucleotides in the full-length variant 5'UTR of a TOP gene, which represents at least 20%, preferably at least 30%, more preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, and most preferably at least 90% of the full-length variant 5'UTR of a TOP gene.
  • a fragment of a variant in the sense of the present invention, is preferably a functional fragment as described herein.
  • the 5'UTR element of the artificial nucleic acid molecule may comprise or consist of a fragment of the 5'UTR of a TOP gene or of a fragment of a variant of the 5'UTR of a TOP gene or may comprise or consist of the entire 5'UTR of a TOP gene or may comprise or consist of a variant of the 5'UTR of a TOP gene.
  • the 5'UTR element is preferably suitable for increasing protein production from the artificial nucleic acid molecule.
  • the at least one 5'UTR element is functionally linked to the ORF.
  • the 5'UTR element is associated with the ORF such that it may exert a function, such as a protein production increasing function for the protein encoded by the ORF or a stabilizing function on the artificial nucleic acid molecule.
  • the 5'UTR element and the ORF are associated in 5'- 3' direction.
  • the artificial nucleic acid molecule comprises the structure 5'-5'UTR element-(optional)linker-ORF-3', wherein the linker may be present or absent.
  • the linker may be one or more nucleotides, such as a stretch of 1 -50 or 1 -20 nucleotides, e.g., comprising or consisting of one or more restriction enzyme recognition sites (restriction sites).
  • the 5'UTR element and the at least one open reading frame are heterologous.
  • the term 'heterologous' in this context means that the open reading frame and the 5'UTR element are not occurring naturally (in nature) in this combination.
  • the 5'UTR element is derived from a different gene than the open reading frame.
  • the ORF may be derived from a different gene than the 5'UTR element, e.g. encoding a different protein or the same protein but of a different species etc.
  • the ORF does not encode the protein which is encoded by the gene from which the 5'UTR element is derived.
  • the 5'UTR element preferably the artificial nucleic acid molecule, does not comprise a complete TOP-motif or 5'TOP sequence.
  • the 5'UTR element preferably the artificial nucleic acid molecule, does not comprise the complete TOP-motif of the TOP gene from which the nucleic acid sequence of the 5'UTR element is derived.
  • the 5'UTR element or the artificial nucleic acid molecule according to the present invention may comprise 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more pyrimidine residues of the TOP-motif or 5'TOP, preferably 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more pyrimidine residues of the TOP-motif located at the 3'side of the TOP-motif or 5'TOP.
  • the 5'UTR element may comprise or consist of a nucleic acid sequence which starts at its 5'end with a pyrimidine residue that corresponds to residue 2, 3, 4, 5, 6, 7, 8, 9, 10 etc. of the TOP-motif or 5'TOP of the TOP gene from which the nucleic acid sequence of the 5'UTR element is derived.
  • the 5'UTR element preferably the artificial nucleic acid molecule according to the present invention, does not comprise a TOP-motif or a 5'TOP.
  • the nucleic acid sequence of the 5'UTR element which is derived from a 5'UTR of a TOP gene starts at its 5'-end with a nucleotide located at position 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 downstream of the 5'terminal oligopyrimidine tract (TOP) of the 5'UTR of a TOP gene.
  • Position 1 downstream of the 5'terminal oligopyrimidine tract (TOP) is the first purine based nucleotide 3' of the TOP-motif or the 5'TOP.
  • position 1 downstream of the 5'terminal oligopyrimidine tract is the first nucleotide following the 3'- end of the 5'terminal oligopyrimidine tract in 5'-3'-direction.
  • position 2 downstream of the 5'TOP is the second nucleotide following the end of the 5'terminal oligopyrimidine tract, position 3 the third nucleotide and so on.
  • the 5'UTR element preferably starts 5, 10, 15, 20, 25, 30, 40 or 50 nucleotides downstream of the transcriptional start site of the 5'UTR of a TOP gene.
  • the nucleic acid sequence of the 5'UTR element which is derived from a 5'UTR of a TOP gene terminates at its 3'-end with a nucleotide located at position 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 upstream of the start codon (e.g. A(U/T)G) of the gene or mRNA it is derived from.
  • the 5'UTR element does not comprise any part of the protein coding region.
  • the only protein coding part of the inventive artificial nucleic acid molecule is provided by the open reading frame.
  • the open reading frame is preferably derived - as said above - from a gene that is different to the gene the 5'UTR element is derived from.
  • the 5'UTR element does not comprise a start codon, such as the nucleotide sequence A(U/T)G.
  • the artificial nucleic acid molecule will not comprise any upstream AUGs (or upstream ATGs in case it is a DNA molecule).
  • the AUG or ATG, respectively, of the open reading frame is the only start codon of the artificial nucleic acid molecule.
  • the 5'UTR element does not comprise an open reading frame.
  • the artificial nucleic acid molecule will not comprise any upstream open reading frames.
  • the nucleic acid sequence which is derived from the 5'UTR of a TOP gene is derived from a eukaryotic TOP gene, preferably a plant or animal TOP gene, more preferably a chordate TOP gene, even more preferably a vertebrate TOP gene, most preferably a mammalian TOP gene, such as a human or mouse TOP gene.
  • the artificial nucleic acid molecule according to the present invention comprises a 5'UTR element which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a TOP gene or which is derived from a variant of the 5'UTR of a TOP gene, wherein the TOP gene is a plant or animal TOP gene, more preferably a chordate TOP gene, even more preferably a vertebrate TOP gene, most preferably a mammalian TOP gene, such as a human or mouse TOP gene and which optionally does not comprise the nucleotide sequence A(U/T)C and optionally does not comprise an open reading frame; at least one open reading frame (ORF); wherein optionally the 5'UTR element does not comprise a TOP motif and wherein optionally the 5'UTR element starts at its 5'-end with a nucleotide located at position 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 downstream of the 5'terminal oligopyrimidine tract (TOP) of the 5'UT
  • the 5'UTR element comprises or consists of a nucleic acid sequence which is derived from a nucleic acid sequence selected from the group consisting of SEQ ID NOs. 1 - 1363, SEQ ID NO. 1395, SEQ ID NO. 1421 and SEQ ID NO. 1422, from the homologs of SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 and SEQ ID NO. 1422, from a variant thereof, or a corresponding RNA sequence.
  • the term "homologs of SEQ ID NOs. 1 - 1363, SEQ ID NO. 1395, SEQ ID NO. 1421 and SEQ ID NO. 1422" refers to sequences of other species, e.g.
  • SEQ ID NO. 1 relates to a sequence comprising the 5'UTR of Homo sapiens alpha 2 macroglobuiin (A2M). A homolog of SEQ ID NO.
  • A2M alpha 2 macroglobuiin
  • the 5'UTR element comprises or consists of a nucleic acid sequence which is derived from a nucleic acid sequence extending from nucleotide position 5 (i.e. the nucleotide that is located at position 5 in the sequence) to the nucleotide position immediately 5' to the start codon (located at the 3' end of the sequences), e.g. the nucleotide position immediately 5' to the ATG sequence, of a nucleic acid sequence selected from SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 or SEQ ID NO. 1422, from the homologs of SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO.
  • the 5' UTR element is derived from a nucleic acid sequence extending from the nucleotide position immediately 3' to the 5'TOP to the nucleotide position immediately 5' to the start codon (located at the 3' end of the sequences), e.g. the nucleotide position immediately 5' to the ATG sequence, of a nucleic acid sequence selected from SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 or SEQ ID NO. 1422, from the homologs of SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO.
  • the 5'UTR element comprises or consists of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to a nucleic acid sequence extending from nucleotide position 5 to the nucleotide position immediately 5' to the start codon (located at the 3' end of the sequences), e.g.
  • the at least one 5'UTR element comprises or consists of a fragment of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to a nucleic acid sequence extending from nucleotide position 5 to the nucleotide position immediately 5' to the start codon (located at the 3' end of the sequences), e.g.
  • nucleotide position immediately 5' to the ATG sequence of a nucleic acid sequence selected from SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 or SEQ ID NO. 1422, or a corresponding RNA sequence, wherein, preferably, the fragment is as described above, i.e. being a continuous stretch of nucleotides representing at least 20% etc. of the full-length 5'UTR the fragment is derived from.
  • the 5'UTR element comprises or consists of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to a nucleic acid sequence extending from the nucleotide position immediately 3' to the 5'TOP to the nucleotide position immediately 5' to the start codon (located at the 3' end of the sequences), e.g. the nucleotide position immediately 5' to the ATG sequence, of a nucleic acid sequence selected from SEQ ID NOs.
  • the at least one 5'UTR element comprises or consists of a fragment of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to a nucleic acid sequence extending from the nucleotide position immediately 3' to the 5'TOP to the nucleotide position immediately 5' to the start codon (located at the 3' end of the sequences), e.g.
  • nucleotide position immediately 5' to the ATG sequence of a nucleic acid sequence selected from SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 or SEQ ID NO. 1422, or a corresponding RNA sequence, wherein, preferably, the fragment is as described above, i.e. being a continuous stretch of nucleotides representing at least 20% etc. of the full-length 5'UTR the fragment is derived from.
  • the above defined fragments and variants are functional fragments and variants as described herein.
  • the artificial nucleic acid molecule according to the present invention may comprise more than one 5'UTR elements as described above.
  • the artificial nucleic acid molecule according to the present invention may comprise one, two, three, four or more 5'UTR elements, wherein the individual 5'UTR elements may be the same or they may be different.
  • the artificial nucleic acid molecule according to the present invention may comprise two essentially identical 5'UTR elements as described above, e.g. two 5'UTR elements comprising or consisting of a nucleic acid sequence which is derived from a nucleic acid sequence selected from the group consisting of SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 and SEQ ID NO. 1422, from the homologs of SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 and SEQ ID NO. 1422, from a variant thereof, or a corresponding RNA sequence or from functional variants thereof, functional fragments thereof, or functional variant fragments thereof as described above.
  • two 5'UTR elements comprising or consisting of a nucleic acid sequence which is derived from a nucleic acid sequence selected from the group consisting of SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 and SEQ ID NO
  • the 5'UTR element comprises or consists of a nucleic acid sequence which is derived from a 5'UTR of a TOP gene encoding a ribosomal protein or from a variant of a 5'UTR of a TOP gene encoding a ribosomal protein.
  • Particularly preferred 5'UTR elements comprise or consist of a nucleic acid sequence which are derived from a 5' UTR of a TOP gene coding for a ribosomal protein se- lected from RPSA, RPS2, RPS3, RPS3A, RPS4, RPS5, RPS6, RPS7, RPS8, RPS9, RPS10, RPS1 1 , RPS12, RPS13, RPS14, RPS1 5, RPS15A, RPS1 6, RPS1 7, RPS1 8, RPS19, RPS20, RPS21 , RPS23, RPS24, RPS25, RPS26, RPS27, RPS27A, RPS28, RPS29, RPS30, RPL3, RPL4, RPL5, RPL6, RPL7, RPL7A, RPL8, RPL9, RPL10, RPL10A, RPL1 1 , RPL12, RPL13, RPL13A, RPL14, RPL15, RPL1 7, RPL18, RPL
  • nucleic acid sequences which are derived from a 5' UTR of TOP genes vertebrate coding for ribosomal proteins, such as mammalian ribosomal proteins e.g. human or mouse ribosomal proteins.
  • the 5'UTR element comprises or consists of a nucleic acid sequence which is derived from a 5'UTR of a nucleic acid sequence according to any of SEQ ID NOs: 1 70, 232, 244, 259, 1284, 1285, 1286, 1287, 1288, 1289, 1290, 1291 , 1292, 1293, 1294, 1295, 1296, 1297, 1298, 1299, 1300, 1301 , 1302, 1303, 1304, 1305, 1306, 1307, 1308, 1309, 1310, 131 1 , 1312, 1313, 1314, 1315, 131 6, 131 7, 1318, 1319, 1320, 1 321 , 1322, 1323, 1324, 1325, 1326, 1327, 1328, 1329, 1330, 1331 , 1332, 1333, 1334, 1 335, 1336, 1337, 1338, 1339, 1340, 1341 , 1342, 1343, 1344, 1346, 1347, 1348
  • the sequence extending from position 5 to the nucleotide immediately 5' to the ATG corresponds to the 5'UTR of said sequences.
  • the 5'UTR element comprises or consists of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to the 5'UTR of a nucleic acid sequence according to any of SEQ ID NOs.: 1 70, 232, 244, 259, 1284, 1285, 1286, 1287, 1288, 1289, 1290, 1291 ,
  • the at least one 5'UTR element comprises or consists of a fragment of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to the 5'UTR of a nucleic acid sequence according to SEQ ID NOs: 1 70, 232, 244, 259, 1284, 1285, 1286, 1287, 1288, 1289, 1290, 1291 , 1292,
  • the fragment is as described above, i.e. being a continuous stretch of nucleotides representing at least 20% etc. of the full-length 5'UTR, preferably lacking the 5'TOP motif.
  • the fragment exhibits a length of at least about 20 nucleotides or more, preferably of at least about 30 nucleotides or more, more preferably of at least about 40 nucleotides or more.
  • the fragment is a functional fragment as described herein.
  • the 5'UTR element comprises or consists of a nucleic acid sequence which is derived from a 5'UTR of a TOP gene encoding a ribosomai Large protein (RPL) or from a variant of a 5'UTR of a TOP gene encoding a ribosomai Large protein (RPL).
  • RPL ribosomai Large protein
  • the 5'UTR element comprises or consists of a nucleic acid sequence which is derived from a 5'UTR of a nucleic acid sequence according to any of SEQ ID NOs: 67, 259, 1284-1318, 1344, 1346, 1348-1354, 1357, 1358, 1421 and 1422, a corresponding RNA sequence, a homolog thereof, or a variant thereof as described herein, preferably lacking the 5'TOP motif.
  • the 5'UTR element comprises or consists of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to the 5'UTR of a nucleic acid sequence according to any of SEQ ID NOs.
  • the at least one 5'UTR element comprises or consists of a fragment of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to the 5'UTR of a nucleic acid sequence according to SEQ ID NOs: 67, 259, 1284-1318, 1344, 1346, 1348-1354, 1357, 1358, 1421 and 1422 or a corresponding RNA sequence, wherein, preferably, the fragment is as described above, i.e.
  • the fragment exhibits a length of at least about 20 nucleotides or more, preferably of at least about 30 nucleotides or more, more preferably of at least about 40 nucleotides or more.
  • the fragment is a functional fragment as described herein.
  • the 5'UTR element comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a ribosomal protein Large 32 gene (RPL32), a ribosomal protein Large 35 gene (RPL35), a ribosomal protein Large 21 gene (RPL21 ), an ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 , cardiac muscle (ATP5A1 ) gene, an hydroxysteroid (1 7-beta) dehydrogenase 4 gene (HSD1 7B4), an androgen-induced 1 gene (Aid ), cytochrome c oxidase subunit Vic gene (COX6C), or a N-acylsphingosine amidohydrolase (acid ceramidase) 1 gene (ASAH1 ) or from a variant thereof, preferably from a vertebrate ribosomal protein Large 32 gene (RPL32), a vertebrate ribosomal protein Large 32
  • the 5'UTR element comprises or consists of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to the nucleic acid sequence according to SEQ ID No.
  • the at least one 5'UTR element comprises or consists of a fragment of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to the nucleic acid sequence according to SEQ ID No. 1368, or SEQ ID NOs 1412- 1420, wherein, preferably, the fragment is as described above, i.e. being a continuous stretch of nucleotides representing at least 20% etc.
  • the fragment exhibits a length of at least about 20 nucleotides or more, preferably of at least about 30 nucleotides or more, more preferably of at least about 40 nucleotides or more.
  • the fragment is a functional fragment as described herein.
  • the at least one 5'UTR element exhibits a length of at least about 20 nucleotides or more, preferably of at least about 30 nucleotides or more, more preferably of at least about 40 nucleotides or more.
  • the 5'UTR may have a length of less than about 200, preferably less than 150, more preferably less than 100 nucleotides.
  • the 5'UTR may have a length of less than about 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200 nucleotides
  • the 5'UTR element may have a length of about 20-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71- 80, 81-85, 86-90, 91-95, 96-100, 101-105, 106-110, 111-115, 116-120, 121-125, 126- 130, 131-135, 136-140, 141-145,
  • the 5'UTR element may have a length of about 20, 26, 31, 36, 41, 46, 51, 56, 61, 66, 71, 81, 86, 91, 96, 101, 106, 111, 116, 121, 126, 131, 136, 141, 146, 151, 156, 161, 166, 171,
  • the 5'UTR element may have a length from about 20, 30, 40 or more to less than about 200 nucleotides, more preferably from about 20, 30, 40 or more to less than about 150 nucleotides, most preferably from about 20, 30, 40 or more to less than about 100 nucleotides.
  • Preferred 5'UTR elements are derived from a 5' UTR of a TOP gene selected from RPSA, RPS2, RPS3, RPS3A, RPS4, RPS5, RPS6, RPS7, RPS8, RPS9, RPS10, RPS11, RPS12, RPS13, RPS14, RPS15, RPS15A, RPS16, RPS17, RPS18, RPS19, RPS20, RPS21, RPS23, RPS24, RPS25, RPS26, RPS27, RPS27A, RPS28, RPS29, RPS30, RPL3, RPL4, RPL5, RPL6, RPL7, RPL7A, RPL8, RPL9, RPL10, RPL10A, RPL11, RPL12, RPL13, RPL13A, RPL14, RPL15, RPL17, RPL18, RPL18A, RPL19, RPL21, RPL22, RPL23, RPL23A, RPL24, RPL26, R
  • the artificial nucleic acid molecule comprises a 5'UTR element which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a vertebrate TOP gene, such as a mammalian, e.g.
  • a human TOP gene selected from RPSA, RPS2, RPS3, RPS3A, RPS4, RPS5, RPS6, RPS7, RPS8, RPS9, RPS10, RPS1 1 , RPS12, RPS13, RPS14, RPS15, RPS15A, RPS16, RPS1 7, RPS18, RPS19, RPS20, RPS21 , RPS23, RPS24, RPS25, RPS26, RPS27, RPS27A, RPS28, RPS29, RPS30, RPL3, RPL4, RPL5, RPL6, RPL7, RPL7A, RPL8, RPL9, RPL10, RPL10A, RPL1 1 , RPL12, RPL13, RPL13A, RPL14, RPL15, RPL1 7, RPL18, RPL18A, RPL19, RPL21 , RPL22, RPL23, RPL23A, RPL24, RPL26, RPL27, RPL27A, RPL28
  • the artificial nucleic acid molecule according to the present invention further comprises c. at least one 3'UTR element which comprises or consists of a nucleic acid sequence derived from the 3'UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene, or from a variant of the 3'UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene.
  • '3'UTR element' refers to a nucleic acid sequence which comprises or consists of a nucleic acid sequence that is derived from a 3'UTR or from a variant of a 3'UTR.
  • a 3'UTR element in the sense of the present invention may represent the 3'UTR of an mRNA, e.g., in the event that the artificial nucleic acid molecule is an mRNA, or it may represent a sequence in a nucleic acid construct, such as a vector construct, that when transcribed represents the 3'UTR of the transcription product, such as the mRNA.
  • a 3'UTR element may be the 3'UTR of an mRNA, preferably of an artificial mRNA, or it may be the transcription template for a 3'UTR of an mRNA.
  • a 3'UTR element preferably is a nucleic acid sequence which corresponds to the 3'UTR of an mRNA, preferably to the 3'UTR of an artificial mRNA, such as an mRNA obtained by transcription of a genetically engineered vector construct.
  • the 3'UTR element fulfils the function of a 3'UTR or encodes a sequence which fulfils the function of a 3'UTR.
  • '3UTR element' furthermore refers to a fragment or part of a 3'UTR of an artificial nucleic acid sequence, such as an artificial mRNA, or which codes for a part or fragment of a 3'UTR of an artificial nucleic acid molecule.
  • the 3'UTR element in the sense of the present invention may be comprised in the 3'UTR of an artificial nucleic acid sequence, such as an artificial mRNA, or which codes for a 3'UTR of an artificial nucleic acid molecule.
  • the 3'UTR element and the at least one open reading frame are heterologous.
  • the artificial nucleic acid molecule may consist of at least two sequence parts that are derivable from two different genes, the 5'UTR element which is derivable from a TOP gene and the open reading frame and the 3'UTR which may be derivable from the gene encoding the desired protein product.
  • the artificial nucleic molecule consist of three sequence parts that are derivable from three different genes: the 5'UTR element which is derivable from a TOP gene, the open reading frame which is derivable from the gene encoding the desired gene product and the 3'UTR element which may be derivable from a gene that relates to an mRNA with an enhanced half-life, for example a 3'UTR element as defined and described below.
  • the at least one 3'UTR element is functionally linked to the ORF. This means preferably that the 3'UTR element is associated with the ORF such that it may exert a function, such as a stabilizing function on the expression of the ORF or a stabilizing function on the artificial nucleic acid molecule.
  • the ORF and the 3'UTR element are associated in 5'- 3' direction.
  • the artificial nucleic acid molecule comprises the structure 5'-ORF-(optional)linker-3'UTR element-3', wherein the linker may be present or absent.
  • the linker may be one or more nucleotides, such as a stretch of 1 -50 or 1 -20 nucleotides, e.g., comprising or consisting of one or more restriction enzyme recognition sites (restriction sites).
  • the at least one 5'UTR element and the at least one 3'UTR element are functionally linked to the ORF.
  • the 5'UTR element and the 3'UTR element are associated with the ORF such that they may exert a function, preferably in an additive, more preferably in a synergistic manner, such as a stabilizing function on the expression of the ORF, a protein production increasing function for the protein encoded by the ORF, or a stabilizing function on the artificial nucleic acid molecule.
  • the 5'UTR element, the ORF, and the 3'UTR element are associated in 5'->3' direction.
  • the artificial nucleic acid molecule comprises the structure 5'-5'UTR element- (optional)linker-ORF-(optional)linker-3'UTR element-3', wherein the linker may be present or absent.
  • the linker may be one or more nucleotides, such as a stretch of 1 -50 or 1 -20 nucleotides, e.g., comprising or consisting of one or more restriction enzyme recognition sites (restriction sites).
  • the 5'UTR element and the 3'UTR element are heterologous, e.g. preferably the 5'UTR and the 3'UTR are derived from different genes of the same or of different species.
  • the 3'UTR is not derived from the TOP gene the 5'UTR is derived from.
  • the 3'UTR element is chosen such that it exerts at least an additive, preferably a synergistic function with the 5'UTR element on the protein production from the ORF of the artificial nucleic acid molecule.
  • the protein production is increased in at least an additive, preferably a synergistic way by the 3'UTR element and the 5'UTR element.
  • the protein amount of the protein encoded by the ORF such as a reporter protein, e.g. luciferase, at a certain time point after initiation of expression of the ORF, e.g.
  • the additive preferably the synergistic effect may, for example, be determined by the following assay.
  • Samples are taken at specific time points after initiation of expression, for example, after 6 hours, 24 hours, 48 hours, and 72 hours and the amount of protein produced by expression of the ORF contained in the artificial nucleic acid molecules is measured, for example, by an ELISA assay or a luciferase test, depending on the type of protein encoded by the ORF.
  • the predicted amount of protein at a certain time point after initiation of expression obtained by construct E1 E2 if the effects of the 3'UTR element and the 5'UTR element were purely additive (PPA) may be calculated as follows:
  • E0 is the amount of protein obtained for the construct E0 (lacking UTRs)
  • E1 is the amount of protein obtained for the construct E1
  • E2 is the protein amount obtained for the construct E2
  • x is the time point after initiation of expression.
  • E1 E2 X PPA X and synergistic in the sense of the present invention if E1 E2 X > PPA X , wherein E1 E2 X is the amount of protein obtained from construct E1 E2 at time point x.
  • E1 E2 is at least 1 .0, preferably at least 1 .1 , more preferably at least 1 .3, more preferably at least 1 .5, even more preferably at least 1.75 times PPA at a given time point post initiation of expression, such as 24 hours, 48 hours or 72 hours post initiation of expression.
  • the present invention provides an artificial nucleic acid molecule comprising (a.) at least one 5'UTR element which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a TOP gene or which is derived from a variant of the 5'UTR of a TOP gene; (b.) at least one open reading frame (ORF); and (c.) at least one 3'UTR element, wherein the 3'UTR element and the 5'UTR element act at least additively, preferably synergistically to increase protein production from the ORF, preferably wherein El E2 > PPA, preferably E1 E2 is at least 1 .0 times PPA, preferably El E2 is at least 1 .1 times PPA, more preferably E1 E2 is at least 1.3 times PPA, even more preferably El E2 is at least 1 .5 times PPA at a given time point post initiation of expression of the ORF, for example 24 hours, preferably 48 hours post initiation of expression
  • the 3'UTR element and the 5'UTR element have at least an additive, preferably a synergistic effect on the total protein production from the artificial nucleic acid molecule in a certain time span, such as within 24 hours, 48 hours, or 72 hours post initiation of expression.
  • the additive or the synergistic effect may be determined as described above, with the difference that the area under the curve (AUC) for the amount of protein over time predicted for E1 E2 if the effects were purely additive is compared to the actual AUC measured for E1 E2.
  • the 3'UTR element comprises or consists of a nucleic acid sequence which is derived from the 3'UTR of a stable mRNA or from a variant of the 3'UTR of a stable mRNA.
  • the 3'UTR element comprises or consists of a sequence which is derived from a gene providing a stable mRNA or from a variant of a 3'UTR of a gene providing a stable mRNA.
  • stable mRNA preferably refers to mRNAs which exhibit a longer half-life in mammalian cells than the average half- life of mRNA molecules in mammalian cells.
  • a stable mRNA in the sense of the present application refers to an mRNA which exhibits a half-life of more than 5 hours, preferably more than 8 hours, in a mammalian cell, such as in a mammalian cell line, e.g. in HELA cells, or in primary cells, e.g. in HDF cells, preferably determined by using a transcription inhibitor such as actinomycin D.
  • a mammalian cell such as in a mammalian cell line, e.g. in HELA cells, or in primary cells, e.g. in HDF cells, preferably determined by using a transcription inhibitor such as actinomycin D.
  • the half-life of an mRNA in mammalian cells, such as HELA or HDF cells may be determined by culturing the cells in presence of a transcription inhibitor, e.g.
  • actinomycin D 5,6-dichloro-1-P-D-ribofuranosylbenzimidazole (DRB), or oc-amanitin
  • DRB 5,6-dichloro-1-P-D-ribofuranosylbenzimidazole
  • oc-amanitin harvesting the cells at different time points after inhibition of transcription, and determining the amount of the mRNA present in the cell samples by methods well known to the person skilled in the art, e.g. by quantitative RT-PCR.
  • the half-life of a particular mRNA may be calculated based on the amounts of the particular mRNA measured at the different time points post inhibition of transcription.
  • pulse-chase methods e.g. using radioactively labelled nucleotides, or constructs comprising inducible promoters may be used for determining the half-life of an mRNA in mammalian cells.
  • the enhanced stability of a stable mRNA in the sense of the present invention is affected by its 3'UTR.
  • the 3'UTR element comprises or consists of a nucleic acid sequence which is derived from the 3'UTR of a stable mRNA which exhibits a half-life of more than 5 hours, preferably more than 8 hours, in a mammalian cell, such as in a mammalian cell line, e.g. in HeLa cells, or in mammalian primary cells, e.g. in HDF cells, preferably determined by using a transcription inhibitor such as actinomycin D, wherein the enhanced stability of said stable mRNA is effected by its 3'UTR.
  • a 3'UTR for enhancing stability may be tested as described herein, e.g. by using a reporter open reading frame such as a luciferase encoding open reading frame.
  • an artificial construct encoding the test stable mRNA may be generated, wherein the 3'UTR of the stable mRNA is replaced with a reference 3'UTR, such as a 3'UTR of a short lived mRNA, e.g. a Myc 3'UTR.
  • the stability of the wild type stable mRNA and the 3'UTR modified mRNA may be determined as described above. In the event the 3'UTR modified mRNA exhibits a shorter half-life than the wild type stable mRNA, it may be concluded that a stability enhancing effect is exerted by the 3'UTR of the stable mRNA.
  • the 3'UTR element comprises or consists of a nucleic acid sequence which is derived from a 3'UTR of a gene selected from the group consisting of an albumin gene, an a-globin gene, a ⁇ -globin gene, a tyrosine hydroxylase gene, a lipoxygenase gene, and a collagen alpha gene, such as a collagen alpha 1 (1) gene, or from a variant of a 3'UTR of a gene selected from the group consisting of an albumin gene, an a-globin gene, a ⁇ -globin gene, a tyrosine hydroxylase gene, a lipoxygenase gene, and a collagen alpha gene, such as a collagen alpha 1 (1) gene.
  • the 3'UTR element comprises or consists of a nucleic acid sequence which is derived from a 3'UTR of an albumin gene, preferably a vertebrate albumin gene, more preferably a mammalian albumin gene, most preferably a human albumin gene.
  • the 3'UTR element comprises or consists of a nucleic acid sequence which is derived from a 3'UTR of an ⁇ -globin gene, preferably a vertebrate ⁇ -globin gene, more preferably a mammalian ⁇ -globin gene, most preferably a human a- globin gene.
  • the 3'UTR element may comprise or consist of the center, a- complex-binding portion of the 3'UTR of an ⁇ -globin gene, such as of a human a-globin gene.
  • the at least one 3'UTR element comprises or consists of a nucleic acid sequence which is derived from the 3'UTR of a vertebrate albumin gene, a vertebrate ⁇ -globin gene, a vertebrate ⁇ -globin gene, a vertebrate tyrosine hydroxylase gene, a vertebrate lipoxygenase gene, and a vertebrate collagen alpha gene, such as a vertebrate collagen alpha 1 (1) gene, or from a variant thereof, preferably from the 3'UTR of a mammalian albumin gene, a mammalian ⁇ -globin gene, a mammalian ⁇ -globin gene, a mammalian tyrosine hydroxylase gene, a mammalian lipoxygenase gene, and a mammalian collagen alpha gene, such as a mammalian collagen alpha 1 (I) gene, or from a variant thereof, more preferably from the 3'UTR of a human albumin
  • the 3'UTR element is not derived from the 3'UTR of a Xenopus albumin gene.
  • the 3'UTR element does not comprise a poly(A) limiting element B (PLEB) of a 3'UTR from a Xenopus albumin gene.
  • the 3'UTR element does not consist of a PLEB of a 3'UTR from a Xenopus albumin gene.
  • the 3'UTR element and the at least one open reading frame are heterologous, e.g. preferably the 3'UTR element and the ORF are derived from different genes of the same or of different species.
  • the ORF does not encode an ⁇ -globin protein if the 3'UTR element is derived from an cc-globin gene.
  • the ORF does not encode a ⁇ - globin protein if the 3'UTR element is derived from a ⁇ -globin gene.
  • the ORF does not encode an albumin protein if the 3'UTR element is derived from an albumin gene.
  • the ORF does not encode a tyrosine hydroxylase protein if the 3'UTR element is derived from a tyrosine hydroxylase gene.
  • the ORF does not encode a lipoxygenase protein if the 3'UTR element is derived from a lipoxygenase gene.
  • the ORF does not encode a collagen alpha protein if the 3'UTR element is derived from a collagene alpha gene.
  • the ORF does not code for a protein selected from the group consisting of albumin proteins, growth hormones, e.g.
  • the open reading frame does not code for a reporter protein, e.g., selected from the group consisting of globin proteins, in particular beta-globin,, luciferase protein, GFP proteins, e.g. EGFP, or variants thereof, for example, variants exhibiting at least 70% sequence identity to a globin protein, a luciferase protein, or a GFP protein.
  • a reporter protein e.g., selected from the group consisting of globin proteins, in particular beta-globin,, luciferase protein, GFP proteins, e.g. EGFP, or variants thereof, for example, variants exhibiting at least 70% sequence identity to a globin protein, a luciferase protein, or a GFP protein.
  • nucleic acid sequence which is derived from the 3'UTR of a noted gene' preferably refers to a nucleic acid sequence which is based on the 3'UTR sequence of a noted gene or on a part thereof, such as on the 3'UTR of an albumin gene, an a-globin gene, a ⁇ - globin gene, a tyrosine hydroxylase gene, a lipoxygenase gene, or a collagen alpha gene, such as a collagen alpha 1 (1) gene, preferably of an albumin gene or on a part thereof.
  • This term includes sequences corresponding to the entire 3'UTR sequence, i.e.
  • the full length 3'UTR sequence of a gene and sequences corresponding to a fragment of the 3'UTR sequence of a gene, such as an albumin gene, ⁇ -globin gene, ⁇ -globin gene, tyrosine hydroxylase gene, lipoxygenase gene, or collagen alpha gene, such as a collagen alpha 1 (1) gene, preferably of an albumin gene.
  • a gene such as an albumin gene, ⁇ -globin gene, ⁇ -globin gene, tyrosine hydroxylase gene, lipoxygenase gene, or collagen alpha gene, such as a collagen alpha 1 (1) gene, preferably of an albumin gene.
  • a fragment in this context preferably consists of a continuous stretch of nucleotides corresponding to a continuous stretch of nucleotides in the full-length 3'UTR, which represents at least 20%, preferably at least 30%, more preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, and most preferably at least 90% of the full-length 3'UTR.
  • Such a fragment in the sense of the present invention, is preferably a functional fragment as described herein.
  • '3'UTR of a section gene' preferably refers to the 3'UTR of a naturally occurring gene, such as of a naturally occurring albumin gene, oc-globin gene, ⁇ -globin gene, tyrosine hydroxylase gene, lipoxygenase gene, or collagen alpha gene, such as a collagen alpha 1 (1) gene, preferably of a naturally occurring albumin gene.
  • a naturally occurring gene such as of a naturally occurring albumin gene, oc-globin gene, ⁇ -globin gene, tyrosine hydroxylase gene, lipoxygenase gene, or collagen alpha gene, such as a collagen alpha 1 (1) gene, preferably of a naturally occurring albumin gene.
  • the terms 'variant of the 3'UTR of a section gene' and 'variant thereof in the context of a 3'UTR refers to a variant of the 3'UTR of a naturally occurring gene, such as a naturally occurring albumin gene, a naturally occurring a-globin gene, a naturally occurring ⁇ -globin gene, a naturally occurring tyrosine hydroxylase gene, a naturally occurring lipoxygenase gene, or a naturally occurring collagen alpha gene, such as a naturally occurring collagen alpha 1 (1) gene, preferably to a variant of the 3'UTR of a vertebrate albumin gene, a vertebrate a-globin gene, a vertebrate ⁇ -globin gene, a vertebrate tyrosine hydroxylase gene, a vertebrate lipoxygenase gene, and a vertebrate collagen alpha gene, such as a vertebrate collagen alpha 1 (1) gene, preferably to a variant of the 3'UTR of a mammalian albumin
  • Such variant may be a modified 3'UTR of a gene.
  • a variant 3'UTR may exhibit one or more nucleotide deletions, insertions, additions and/or substitutions compared to the naturally occurring 3'UTR from which the variant is derived.
  • a variant of a 3'UTR is at least 40%, preferably at least 50%, more preferably at least 60%, more preferably at least 70%, even more preferably at least 80%, even more preferably at least 90%, most preferably at least 95% identical to the naturally occurring 3'UTR the variant is derived from.
  • the variant is a functional variant as described herein.
  • nucleic acid sequence which is derived from a variant of the 3'UTR of a noted gene' preferably refers to a nucleic acid sequence which is based on a variant of the 3'UTR sequence of a gene, such as on a variant of the 3'UTR of an albumin gene, an a-globin gene, a ⁇ -globin gene, a tyrosine hydroxylase gene, a lipoxygenase gene, or a collagen alpha gene, such as a collagen alpha 1 (I) gene, or on a part thereof as described above.
  • This term includes sequences corresponding to the entire sequence of the variant of the 3'UTR of a gene, i.e.
  • a fragment in this context preferably consists of a continuous stretch of nucleotides corresponding to a continuous stretch of nucleotides in the full-length variant 3'UTR, which represents at least 20%, preferably at least 30%, more preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, and most preferably at least 90% of the full-length variant 3'UTR.
  • Such a fragment of a variant in the sense of the present invention, is preferably a functional fragment of a variant as described herein.
  • 'functional variant', 'functional fragment', and 'functional fragment of a variant' mean that the fragment of the 5'UTR or the 3'UTR, the variant of the 5'UTR or the 3'UTR, or the fragment of a variant of the 5'UTR or the 3'UTR of a gene fulfils at least one, preferably more than one, function of the naturally occurring 5'UTR or 3'UTR of the gene of which the variant, the fragment, or the fragment of a variant is derived.
  • Such function may be, for example, stabilizing mRNA and/or stabilizing and/or prolonging protein production from an mRNA and/or increasing protein production from an mRNA, preferably in a mammalian cell, such as in a human cell. It is particularly preferred that the variant, the fragment, and the variant fragment in the context of the present invention fulfil the function of stabilizing an mRNA, preferably in a mammalian cell, such as a human cell, compared to an mRNA comprising a reference 5'UTR and/or a reference 3'UTR or lacking a 5'UTR and/or a 3'UTR, and/or the function of stabilizing and/or prolonging protein production from an mRNA, preferably in a mammalian cell, such as in a human cell, compared to an mRNA comprising a reference 5'UTR and/or a reference 3'UTR or lacking a 5'UTR and/or a 3'UTR, and/or the function of increasing protein production from an mRNA
  • a reference 3'UTR may be, for example, a 3'UTR naturally occurring in combination with the ORF.
  • a functional variant, a functional fragment, or a functional variant fragment of a 5'UTR or of a 3'UTR of a gene preferably does not have a substantially diminishing effect on the efficiency of translation of the mRNA which comprises such variant of a 5'UTR and/or such variant of a 3'UTR compared to the wild type 5'UTR and/or 3'UTR from which the variant is derived.
  • a particularly preferred function of a "functional fragment", a “functional variant” or a “functional fragment of a variant” of the 3'UTR of a gene such as an albumin gene, a-globin gene, ⁇ -globin gene, tyrosine hydroxylase gene, lipoxygenase gene, or collagen alpha gene, such as a collagen alpha 1 (1) gene, in the context of the present invention is the stabilization and/or prolongation of protein production by expression of an mRNA carrying the functional fragment, functional variant or functional fragment of a variant as described above.
  • a particularly preferred function of a "functional fragment", a “functional variant” or a “functional fragment of a variant” of the 5'UTR in the context of the present invention is the protein production increasing function.
  • the efficiency of the one or more functions exerted by the functional variant, the functional fragment, or the functional variant fragment is at least 40%, more preferably at least 50%, more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, most preferably at least 90% of the mRNA and/or protein production stabilizing efficiency and/or the protein production increasing efficiency exhibited by the naturally occurring 5'UTR and/or 3'UTR of which the variant, the fragment or the variant fragment is derived.
  • a fragment or part of the 3'UTR of a gene such as an albumin gene, a-globin gene, ⁇ -globin gene, tyrosine hydroxylase gene, lipoxygenase gene, or collagen alpha gene, such as a collagen alpha 1 (I) gene, or of a variant thereof preferably exhibits a length of at least about 40 nucleotides, preferably of at least about 50 nucleotides, preferably of at least about 75 nucleotides, more preferably of at least about 100 nucleotides, even more preferably of at least about 125 nucleotides, most preferably of at least about 150 nucleotides.
  • such fragment of the 3'UTR of a gene or of a variant of the 3'UTR of a gene is a functional fragment as described above.
  • a fragment or part of the 5'UTR of a TOP gene or of a variant thereof preferably exhibits a length of at least about 20 nucleotides, preferably of at least about 30 nucleotides, more preferably of at least about 50 nucleotides.
  • such fragment of the 5'UTR of a TOP gene or of a variant of the 5'UTR of a TOP gene is a functional fragment as described above.
  • the at least one 3'UTR element of the artificial nucleic acid molecule according to the present invention comprises or consists of a "functional fragment", a "functional variant” or a "functional fragment of a variant” of the 3'UTR of a gene, such as of an albumin gene, cc-globin gene, ⁇ -globin gene, tyrosine hydroxylase gene, lipoxygenase gene, or collagen alpha gene, such as a collagen alpha 1 (I) gene, or of a variant thereof.
  • a gene such as of an albumin gene, cc-globin gene, ⁇ -globin gene, tyrosine hydroxylase gene, lipoxygenase gene, or collagen alpha gene, such as a collagen alpha 1 (I) gene, or of a variant thereof.
  • the at least one 5'UTR element of the artificial nucleic acid molecule according to the present invention comprises or consists of a "functional fragment", a “functional variant” or a “functional fragment of a variant” of the 5'UTR of a TOP gene.
  • the at least one 3'UTR element of the artificial nucleic acid molecule according to the present invention increases the stability of the artificial nucleic acid molecule, e.g. increases the stability of an mRNA according to the present invention, compared to a respective mRNA (reference mRNA) lacking a 3'UTR element or comprising a reference 3'UTR element, such as a 3'UTR naturally occurring in combination with the ORF.
  • the at least one 3'UTR element of the artificial nucleic acid molecule according to the present invention increases the stability of protein production from the artificial nucleic acid molecule according to the present invention, e.g.
  • the at least one 3'UTR element of the artificial nucleic acid molecule according to the present invention prolongs protein production from the artificial nucleic acid molecule according to the present invention, e.g. from an mRNA according to the present invention, compared to a respective mRNA lacking a 3'UTR element or comprising a reference 3'UTR element, such as a 3'UTR naturally occurring in combination with the ORF.
  • the at least one 3'UTR element of the artificial nucleic acid molecule according to the present invention increases the protein production from the artificial nucleic acid molecule according to the present invention, e.g. from an mRNA according to the present invention, compared to a respective mRNA lacking a 3'UTR element or comprising a reference 3'UTR element, such as a 3'UTR naturally occurring in combination with the ORF.
  • the at least one 3'UTR element of the artificial nucleic acid molecule according to the present invention does not negatively influence translational efficiency of an mRNA compared to the translational efficiency of a respective mRNA lacking a 3'UTR element or comprising a reference 3'UTR element, such as a 3'UTR naturally occurring in combination with the ORF.
  • the term 'respective mRNA' in this context means that - apart from the different 3'UTR - the reference mRNA is comparable, preferably identical, to the mRNA comprising the 3'UTR element.
  • the at least one 5'UTR element of the artificial nucleic acid molecule according to the present invention increases the stability of the artificial nucleic acid molecule, e.g. increases the stability of an mRNA according to the present invention, compared to a respective mRNA (reference mRNA) lacking a 5'UTR element or comprising a reference 5'UTR element, such as a 5'UTR naturally occurring in combination with the ORF.
  • the at least one 5'UTR element of the artificial nucleic acid molecule according to the present invention increases protein production from the artificial nucleic acid molecule according to the present invention, e.g.
  • mRNA from an mRNA according to the present invention, compared to a respective mRNA lacking a 5'UTR element or comprising a reference 5'UTR element, such as a 5'UTR naturally occurring in combination with the ORF.
  • the term 'respective mRNA' in this context means that - apart from the different 5'UTR - the reference mRNA is comparable, preferably identical, to the mRNA comprising the inventive 5'UTR element.
  • the at least one 5'UTR element and the at least one 3'UTR element act synergistically to increase protein production from the artificial nucleic acid molecule according to the present invention, e.g. from an mRNA according to the present invention, as described above.
  • 'stabilizing and/or prolonging protein production from an mRNA' preferably means that the protein production from the mRNA is stabilized and/or prolonged compared to the protein production from a reference mRNA, e.g. comprising a reference 3'UTR element or lacking a 3'UTR element.
  • 'Stabilized protein expression' in this context preferably means that there is more uniform protein production from the artificial nucleic acid molecule according to the present invention over a predetermined period of time, such as over 24 hours, more preferably over 48 hours, even more preferably over 72 hours, when compared to a reference nucleic acid molecule, for example, an mRNA comprising a reference 3'UTR element or lacking a 3'UTR element.
  • a reference nucleic acid molecule for example, an mRNA comprising a reference 3'UTR element or lacking a 3'UTR element.
  • the level of protein production e.g. in a mammalian system, from the artificial nucleic acid molecule comprising a 3'UTR element according to the present invention, e.g.
  • the amount of a protein (encoded by the ORF) observed 6 hours after initiation of expression, e.g. 6 hours post transfection of the artificial nucleic acid molecule according to the present invention into a cell, such as a mammalian cell may be comparable to the amount of protein observed 48 hours after initiation of expression, e.g. 48 hours post transfection.
  • the ratio of the amount of protein encoded by the ORF, such as of a reporter protein, e.g., luciferase, observed at 48 hours post initiation of expression e.g.
  • 48 hours post transfection to the amount of protein observed 6 hours after initiation of expression, e.g. 6 hours post transfection, is preferably above 0.4, preferably above 0.5, more preferably above 0.6, even more preferably above 0.7, e.g. between about 0.4 and about 4, preferably between about 0.65 and about 3, more preferably between about 0.7 and about 2 for a nucleic acid molecule according to the present invention.
  • a nucleic acid molecule e.g. an mRNA comprising a reference 3'UTR element or lacking a 3'UTR element
  • said ratio may be, e.g. between about 0.05 and about 0.3.
  • the present invention provides an artificial nucleic acid molecule comprising an ORF and a 3'UTR element as described above, wherein the ratio of the (reporter) protein amount observed 48 hours after initiation of expression to the (reporter) protein amount observed 6 hours after initiation of expression, preferably in a mammalian expression system, such as in mammalian cells, is preferably above 0.4, preferably above 0.5, more preferably above 0.6, even more preferably above 0.7, e.g. between about 0.4 and about 4, preferably between about 0.65 and about 3, more preferably between about 0.7 and about 2.
  • the protein level observed at a certain time point after initiation of expression, e.g. after transfection, of the artificial nucleic acid molecule according to the present invention, e.g. after transfection of an mRNA according to the present invention, for example, 24, 48, or 72 hours post transfection, or the total protein produced in a time span of, e.g. 24, 48 or 72 hours, is preferably higher than the protein level observed at the same time point after initiation of expression, e.g.
  • a reference nucleic acid molecule such as a reference mRNA comprising a reference 5' and/or a reference 3'UTR or lacking a 5'UTR element and/or 3'UTR element.
  • a reference nucleic acid molecule such as a reference mRNA comprising a reference 5' and/or a reference 3'UTR or lacking a 5'UTR element and/or 3'UTR element.
  • the increase in protein production effected by the 5'UTR element compared to a reference nucleic acid molecule lacking such 5'UTR element at a given time point post initiation of expression is at least 1 .5-fold, more preferably at least 2- fold, more preferably at least 3-fold, even more preferably at least 4-fold, most preferably at least 5-fold of the protein production observed for a reference nucleic acid molecule lacking the 5'UTR element.
  • Said increase in stability of the artificial nucleic acid molecule, said increase in stability of protein production, said prolongation of protein production and/or said increase in protein production is preferably determined by comparison with a respective reference nucleic acid molecule lacking a 5'UTR element and/or a 3'UTR element, e.g. an mRNA lacking a 5'UTR element and/or a 3'UTR element, or a reference nucleic acid molecule comprising a reference 5'UTR element and/or a reference 3'UTR element, such as a 3'UTR and/or a 5'UTR naturally occurring with the ORF or a 5'UTR and/or a 3'UTR of a reference gene.
  • a respective reference nucleic acid molecule lacking a 5'UTR element and/or a 3'UTR element
  • a reference nucleic acid molecule comprising a reference 5'UTR element and/or a reference 3'UTR element, such as a 3'UTR and/or a
  • the mRNA and/or protein production stabilizing effect and efficiency and/or the protein production increasing effect and efficiency of the variants, fragments and/or variant fragments of the 3'UTR of an albumin gene as well as the mRNA and/or protein production stabilizing effect and efficiency and/or the protein production increasing effect and efficiency of the at least one 3'UTR element, the at least one 5'UTR element, or the at least one 3'UTR element and the at least one 5'UTR element of the artificial nucleic acid molecule according to the present invention may be determined by any method suitable for this purpose known to the skilled person.
  • artificial mRNA molecules may be generated comprising a coding sequence for a reporter protein, such as luciferase, and no 3'UTR and/or no 5'UTR, a 5'UTR element derived from a TOP gene and/or a 3'UTR elem,ent derived from a gene as described above, a 5'UTR element derived from a reference gene and/or a 3'UTR derived from a reference gene (i.e., a reference 3'UTR element or a reference 5'UTR element, such as a 5'UTR or a 3'UTR naturally occurring with the ORF), as 3'UTR a variant of a 3'UTR of a gene as described above, as 3'UTR a fragment of a 3'UTR of a gene as described above, or as 3'UTR a fragment of a variant of a 3'UTR of a gene as described above, as 5'UTR a variant of a 5'UTR of a gene as described
  • Such mRNAs may be generated, for example, by in vitro transcription of respective vectors such as plasmid vectors, e.g. comprising a T7 promoter and a sequence encoding the respective mRNA sequences.
  • the generated mRNA molecules may be transfected into cells by any transfection method suitable for transfecting mRNA, for example they may be electroporated into mammalian cells, such as HELA or HDF cells, and samples may be analyzed certain time points after transfection, for example, 6 hours, 24 hours, 48 hours, and 72 hours post transfection. Said samples may be analyzed for mRNA quantities and/or protein quantities by methods well known to the skilled person.
  • the quantities of reporter mRNA present in the cells at the sample time points may be determined by quantitative PCR methods.
  • the quantities of reporter protein encoded by the respective mRNAs may be determined, e.g., by ELISA assays or reporter assays such as luciferase assays depending on the reporter protein used.
  • the effect of stabilizing protein expression and/or prolonging protein expression may be, for example, analyzed by determining the ratio of the protein level observed 48 hours post transfection and the protein level observed 6 hours post transfection. The closer said value is to 1 , the more stable the protein expression is within this time period. Said value may also be above 1 if the protein level is higher at the later time point.
  • Such measurements may of course also be performed at 72 or more hours and the ratio of the protein level observed 72 hours post transfection and the protein level observed 6 hours post transfection may be determined to determine stability of protein expression.
  • the at least one 3'UTR element of the artificial nucleic acid molecule according to the present invention comprises or consists of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99%, most preferably of 100% to a nucleic acid sequence selected from SEQ ID No. 1369-1377, 1391 , 1392, and 1393 and wherein the variants of the sequences according to SEQ ID No. 1369-1377, 1391 , 1 392 and 1393 are preferably functional variants as described above.
  • the at least one 3'UTR element of the artificial nucleic acid molecule according to the present invention may also comprise or consist of a fragment of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99%, most preferably of 100% to the nucleic acid sequence according to SEQ ID No. 1369-1377, 1391 , 1392, or 1393 wherein the fragment is preferably a functional fragment or a functional variant fragment as described above.
  • the fragment is as described above, i.e.
  • Such fragment preferably exhibits a length of at least about 40 nucleotides, preferably of at least about 50 nucleotides, preferably of at least about 75 nucleotides, more preferably of at least about 100 nucleotides, even more preferably of at least about 125 nucleotides, most preferably of at least about 150 nucleotides.
  • such fragment may exhibit a nucleic acid sequence according to SEQ ID Nos. 1378-1390, such as
  • CAGCCTACCA TGAGAATAAG AGAAAGAAAA TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT (SEQ ID No. 1381 )
  • ATAAATTTCT TTAATCATTT TGCCTCTTTT CTCTGTGCTT CAATTAATAA (SEQ ID No. 1385) ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT
  • CAGCCTACCA TGAGAATAAG AGAAAGAAAA TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT
  • TGCCTCTTTT CTCTGTGCTT CAATTAATAA A (SEQ ID No . 1387) TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT TGCCTCTTTT CTCTGTGCTT CAATTAATAA
  • the at least one 3'UTR element of the artificial nucleic acid molecule according to the present invention may comprise or consist of a nucleic acid fragment as described above.
  • the thymidine nucleotides comprised in the fragments according to SEQ ID Nos. 1378-1390 may be replaced by uridine nucleotides.
  • said variants, fragments or variant fragments are functional variants, functional fragments, or functional variant fragments as described above, exhibiting at least one function of the nucleic acid sequence according to SEQ ID Nos. 1369-1377, 1391 , 1392, or 1393 such as stabilization of the artificial nucleic acid molecule according to the invention, stabilizing and/or prolonging protein expression from the artificial nucleic acid molecule according to the invention, and/or increasing protein production, preferably with an efficiency of at least 40%, more preferably of at least 50%, more preferably of at least 60%, even more preferably of at least 70%, even more preferably of at least 80%, most preferably of at least 90% of the stabilizing efficiency and/or protein production increasing efficiency exhibited by the nucleic acid sequence according to SEQ ID Nos.
  • variants, fragments or variant fragments are functional variants, functional fragments, or functional variant fragments exhibit the function of acting synergistically with the 5'UTR element to increase protein production from the artificial nucleic acid molecule.
  • the at least one 3'UTR element of the artificial nucleic acid molecule according to the present invention exhibits a length of at least about 40 nucleotides, preferably of at least about 50 nucleotides, preferably of at least about 75 nucleotides, more preferably of at least about 100 nucleotides, even more preferably of at least about 125 nucleotides, most preferably of at least about 150 nucleotides.
  • the 3'UTR may exhibit a length of about 50 to about 300 nucleotides, preferably of about 100 to about 250 nucleotides, more preferably of about 150 to about 200 nucleotides.
  • the artificial nucleic acid molecule according to the present invention may comprise more than one 3'UTR elements as described above.
  • the artificial nucleic acid molecule according to the present invention may comprise one, two, three, four or more 3'UTR elements, wherein the individual 3'UTR elements may be the same or they may be different.
  • the artificial nucleic acid molecule according to the present invention may comprise two essentially identical 3'UTR elements as described above, e.g.
  • two 3'UTR elements comprising or consisting of a nucleic acid sequence which is derived from the 3'UTR of an albumin gene or from a variant of the 3'UTR of an albumin gene, such as a nucleic acid sequence according to SEQ ID No. 1369 or 1 376, functional variants thereof, functional fragments thereof, or functional variant fragments thereof as described above.
  • an artificial nucleic acid molecule comprising a 5'UTR element comprising or consisting of a nucleic acid sequence derived from a TOP gene as described above may represent or may provide an mRNA molecule exhibiting strongly enhanced protein production from said artificial nucleic acid molecule.
  • the artificial nucleic acid molecule according to the present invention may be RNA, such as mRNA, DNA, such as a DNA vector, or may be a modified RNA or DNA molecule. It may be provided as a double-stranded molecule having a sense strand and an anti-sense strand, for example, as a DNA molecule having a sense strand and an anti-sense strand.
  • the artificial nucleic acid molecule according to the present invention may further comprise a 5'-cap.
  • the optional 5'-cap is preferably attached to the 5'-side of the 5'UTR element.
  • the artificial nucleic acid sequence comprises a 5'UTR element which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a TOP gene encoding a ribosomal protein as described above, for example, encoding a ribosomal Large protein, or from a variant thereof, and a 3'UTR element which comprises or consists of a nucleic acid sequence which is derived from the 3'UTR of an albumin gene or a variant thereof as described above.
  • the artificial nucleic acid sequence comprises a 5'UTR element which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a ribosomal protein Large 32 gene (RPL32), a ribosomal protein Large 35 gene (RPL35), a ribosomal protein Large 21 gene (RPL21 ), an ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 , cardiac muscle (ATP5A1 ) gene, an hydroxysteroid (1 7-beta) dehydrogenase 4 gene (HSD1 7B4), an androgen-induced 1 gene (AIG1 ), cytochrome c oxidase subunit Vic gene (COX6C), or a N-acylsphingosine amidohydrolase (acid ceramidase) 1 gene (ASAH1 ) or from a variant thereof, preferably from a vertebrate ribosomal protein Large 32 gene (RPL32), a
  • the artificial nucleic acid molecule according to the present invention comprises a 5'UTR element which comprises or consists of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to the nucleic acid sequence according to SEQ ID No.
  • a 5'UTR element which comprises or consists of a nucleic acid sequence which has an identity of at least about 90% to the nucleic acid sequence according to SEQ ID No. 1368 or a corresponding RNA sequence and a 3'UTR element which comprises or consist of a nucleic acid sequence which has an identity of at least about 90% to the nucleic acid sequence according to SEQ ID No. 1369, 1376, 1377, 1391 , or 1392.
  • the artificial nucleic acid molecule according to the present invention further comprises a poly(A) sequence and/or a polyadenylation signal.
  • the optional poly(A) sequence is located 3' to the ORF or the at least one 3'UTR element, preferably is connected to the 3'-end of the ORF or the 3'UTR element.
  • the connection may be direct or indirect, for example, via a stretch of 2, 4, 6, 8, 10, 20 etc. nucleotides, such as via a linker of 1 -50, preferably of 1 -20 nucleotides, e.g. comprising or consisting of one or more restriction sites.
  • the optional polyadenylation signal is located within the 3'UTR element.
  • consensus sequence may be recognised by most animal and bacterial cell-systems, for example by the polyadenylation-factors, such as cleavage/polyadenylation specificity factor (CPSF) cooperating with CstF, PAP, PAB2, CFI and/or CFII.
  • CPSF cleavage/polyadenylation specificity factor
  • the polyadenylation signal preferably the consensus sequence NNUANA
  • the polyadenylation signal is located less than about 50 nucleotides, more preferably less than about 30 nucleotides, most preferably less than about 25 nucleotides, for example 21 nucleotides, upstream of the 3'-end of the 3'UTR element.
  • the inventive artificial nucleic acid molecule may be a DNA molecule comprising a 3'UTR element as described above and a polyadenylation signal, which may result in polyadenylation of an RNA upon transcription of this DNA molecule. Accordingly, a resulting RNA may comprise a combination of the 3'UTR element followed by a poly(A) sequence.
  • transcription of an artificial nucleic acid molecule according to the invention e.g. transcription of an artificial nucleic acid molecule comprising a 5'UTR element, an open reading frame, a 3'UTR element and a polyadenylation-signal, may result in an mRNA molecule comprising a 5'UTR element, an open reading frame, a 3'UTR element and a poly(A) sequence.
  • the invention also provides an artificial nucleic acid molecule which is an mRNA molecule comprising a, 5'UTR element, an open reading frame, an optional 3'UTR element as described above and a poly(A) sequence.
  • the invention provides an artificial nucleic acid molecule which is an artificial DNA molecule comprising a 5'UTR element as described above, an open reading frame and optionally a nucleic acid sequence according to any one of SEQ ID Nos. 1369- 1377, 1391 , and 1392 or a sequence having an identity of at least about 40% or more to a nucleic acid sequence according to any one of SEQ ID Nos. 1369-1377, 1391 , and 1392 or a fragment thereof.
  • the invention provides an artificial nucleic acid molecule which is an artificial RNA molecule comprising a 5'UTR element as described above, an open reading frame and optionally an RNA sequence corresponding to a sequence according to any one of SEQ ID Nos. 1369-1377, 1391 , and 1392 or a sequence having an identity of at least about 40 % or more to any one of SEQ ID Nos. 1369-1377, 1391 , and 1392, or a fragment thereof.
  • the invention provides an artificial nucleic acid molecule which may be a template for an RNA molecule, preferably for an mRNA molecule, which is stabilised and optimized with respect to translation efficiency.
  • the artificial nucleic acid molecule may be a DNA or RNA which may be used for production of an mRNA.
  • the obtainable mRNA may, in turn, be translated for production of a desired peptide or protein encoded by the open reading frame.
  • the artificial nucleic acid molecule is a DNA, it may, for example, be used as a double-stranded storage form for continued and repetitive in vitro or in vivo production of mRNA.
  • the artificial nucleic acid molecule according to the present invention further comprises a poly(A) sequence.
  • the length of the poly(A) sequence may vary.
  • the poly(A) sequence may have a length of about 20 adenine nucleotides up to about 300 adenine nucleotides, preferably of about 40 to about 200 adenine nucleotides, more preferably from about 50 to about 100 adenine nucleotides, such as about 60, 70, 80, 90 or 100 adenine nucleotides.
  • the artificial nucleic acid molecule according to the present invention may comprise a nucleic acid sequence corresponding to the DNA sequence
  • Such artificial RNA molecule may also be obtainable in vitro by common methods of chemical synthesis without being necessarily transcribed from a DNA progenitor.
  • the artificial nucleic acid molecule according to the present invention is an RNA molecule, preferably an mRNA molecule comprising in 5'-to- 3'-direction a 5'UTR element as described above, an open reading frame, a 3'UTR element as described above and a poly(A) sequence.
  • the open reading frame does not code for human albumin, provided that the 3'UTR element is identical to the 3'UTR of human albumin. In some further embodiments, it is preferred that the open reading frame does not code for human albumin according to GenBank Accession number NM_000477.5 provided that the 3'UTR element is identical to the 3'UTR of human albumin. In some further embodiments, it is preferred that the open reading frame does not code for human albumin or variants thereof provided that the 3'UTR element is a sequence which is identical to SEQ ID No. 1369.
  • the open reading frame does not code for a reporter protein, e.g., selected from the group consisting of globin proteins, luciferase proteins, GFP proteins or variants thereof, for example, variants exhibiting at least 70% sequence identity to a globin protein, a luciferase protein, or a GFP protein.
  • a reporter protein e.g., selected from the group consisting of globin proteins, luciferase proteins, GFP proteins or variants thereof, for example, variants exhibiting at least 70% sequence identity to a globin protein, a luciferase protein, or a GFP protein.
  • the 3'UTR element does not consist of a histone stem-loop, preferably does not comprise a histone stem-loop.
  • the artificial nucleic acid molecule according to the present invention does not comprise a histone stem-loop.
  • the 3'UTR element of the artificial nucleic acid molecule or the artificial nucleic acid molecule according to the present invention may comprise a histone stem-loop in addition to the nucleic acid sequence derived form the 3'UTR of an albumin gene.
  • Such artificial nucleic acid molecule may comprise in 5'-to-3'-direction a 5'UTR element, an ORF, a 3'UTR element, preferably comprising a polyadenylation signal, an optional histone stem-loop and an optional poly(A) sequence. It may also comprise in 5'-to-3'- direction a 5'UTR element as described above, an ORF, a 3'UTR element, e.g. comprising a polyadenylation signal, a poly(A) sequence and an optional histone stem-loop.
  • such a histone stem-loop is typically derived from a histone gene and comprises an intramolecular base pairing of two neighbored entirely or partially reverse complementary sequences, thereby forming a stem-loop.
  • a stem-loop can occur in single-stranded DNA or, more commonly, in RNA.
  • the structure is also known as a hairpin or hairpin loop and usually consists of a stem and a (terminal) loop within a consecutive sequence, wherein the stem is formed by two neighbored entirely or partially reverse complementary sequences separated by a short sequence as sort of spacer, which builds the loop of the stem-loop structure.
  • the two neighbored entirely or partially reverse complementary sequences may be defined as e.g. stem-loop elements steml and stem2.
  • the stem loop is formed when these two neighbored entirely or partially reverse complementary sequences, e.g. stem-loop elements steml and stem2, form base-pairs with each other, leading to a double stranded nucleic acid sequence comprising an unpaired loop at its terminal ending formed by the short sequence located between stem-loop elements steml and stem2 on the consecutive sequence.
  • the unpaired loop thereby typically represents a region of the nucleic acid which is not capable of base pairing with either of these stem-loop elements.
  • the resulting lollipop-shaped structure is a key building block of many RNA secondary structures.
  • a stem-loop structure is thus dependent on the stability of the resulting stem and loop regions, wherein the first prerequisite is typically the presence of a sequence that can fold back on itself to form a paired double strand.
  • the stability of paired stem-loop elements is determined by the length, the number of mismatches or bulges it contains (a small number of mismatches is typically tolerable, especially in a long double strand), and the base composition of the paired region.
  • optimal loop length is 3-10 bases, more preferably 3 to 8, 3 to 7, 3 to 6 or even more preferably 4 to 5 bases, and most preferably 4 bases.
  • the artificial nucleic acid molecule according to the present invention comprises (a.) at least one 5'UTR element as described herein, (b.) at least one open reading frame, and at least one histone-stem loop which may, for example, comprise or consist of a sequence having a sequence identity of at least about 75%, preferably of at least about 80%, preferably at least about 85%, more preferably at least about 90%, even more preferably at least about 95% to the sequence according to SEQ ID NO.
  • the artificial nucleic acid molecule comprises further elements such as a 5'-cap, a poly(C) sequence and/or an IRES-motif.
  • a 5'-cap may be added post- transcriptionally to the 5'end of an RNA.
  • the inventive artificial nucleic acid molecule particularly if the nucleic acid is in the form of an mRNA or codes for an mRNA, may be modified by a sequence of at least 10 cytidines, preferably at least 20 cytidines, more preferably at least 30 cytidines (so-called "poly(C) sequence").
  • the inventive nucleic acid molecule may contain, especially if the nucleic acid is in the form of an (m)RNA or codes for an mRNA, a poly(C) sequence of typically about 10 to 200 cytidine nucleotides, preferably about 10 to 100 cytidine nucleotides, more preferably about 10 to 70 cytidine nucleotides or even more preferably about 20 to 50 or even 20 to 30 cytidine nucleotides.
  • IRES internal ribosome entry side
  • IRES-motif may separate several open reading frames, for example if the artificial nucleic acid molecule encodes for two or more peptides or proteins.
  • An IRES-sequence may be particularly helpful if the mRNA is a bi- or multicistronic RNA.
  • the artificial nucleic acid molecule may comprise additional 5'-elements such as a promoter containing-sequence.
  • the promoter may drive and or regulate transcription of the artificial nucleic acid molecule according to the present invention, for example of an artificial DNA-molecule according to the present invention.
  • the invention provides artificial nucleic acid molecules, prefer- ably m NA molecules, comprising in 5'-to-3'-direction at least one of the following structures
  • the artificial nucleic acid molecule preferably the open reading frame
  • the inventive artificial nucleic acid molecule may be thermodynamically stabilized by modifying the G (guanosine)/C (cytidine) content of the molecule.
  • the G/C content of the open reading frame of an artificial nucleic acid molecule according to the present invention may be increased compared to the G/C content of the open reading frame of a corresponding wild type sequence, preferably by using the degeneration of the genetic code.
  • the encoded amino acid sequence of the nucleic acid molecule is preferably not modified by the G/C modification compared to the coded amino acid sequence of the particular wild type sequence.
  • the codons of a coding sequence or a whole nucleic acid molecule, e.g. an mRNA, may therefore be varied compared to the wild type coding sequence, such that they include an increased amount of G/C nucleotides while the translated amino acid sequence is maintained.
  • the most favourable codons for the stability can be determined (so-called alternative codon usage).
  • nucleic acid sequence e.g. the open reading frame
  • codons which contain exclusively G or C nucleotides
  • no modification of the codon is necessary.
  • the codons for Pro (CCC or CCG), Arg (CGC or CGG), Ala (GCC or GCG) and Gly (GGC or GGG) require no modifica- tion, since no A or U/T is present.
  • codons which contain A and/or U T nucleotides may be modified by substitution of other codons which code for the same amino acids but contain no A and/or U/T.
  • codons for Pro can be modified from CC(U/T) or CCA to CCC or CCG;
  • the codons for Arg can be modified from CG(U/T) or CGA or AGA or AGG to CGC or CGG; the codons for Ala can be modified from GC(U/T) or GCA to GCC or GCG;
  • the codons for Gly can be modified from GG(U/T) or GGA to GGC or GGG.
  • a or (U/T) nucleotides cannot be eliminated from the codons, it is however possible to decrease the A and (U/T) content by using codons which contain a lower content of A and/or (U/T) nucleotides. Examples of these are:
  • the codons for Phe can be modified from (U T)(U T)(U/T) to (U T) (UAT)C;
  • the codons for Leu can be modified from (U/T) (U/T) A, (U/T) (U T)G, C(U T) (U/T) or C(U T)A to C(UJT)C or C(UJT)G;
  • the codons for Ser can be modified from (U/T)C(U/T) or (U T)CA or AG(U/T) to (UAT)CC, (U DCG or AGC;
  • the codon for Tyr can be modified from (U T)A(U T) to (UAT)AC;
  • the codon for Cys can be modified from (U/T)G(U/T) to (U/T)GC;
  • the codon for His can be modified from CA(U/T) to CAC;
  • the codon for Gin can be modified from CAA to CAG;
  • the codons for lie can be modified from A(UAT)(U T) or A(U T)A to A(U T)C;
  • the codons for Thr can be modified from AC(U/T) or ACA to ACC or ACG;
  • the codon for Asn can be modified from AA(U/T) to AAC;
  • the codon for Lys can be modified from AAA to AAG;
  • the codons for Val can be modified from G(U/T)(U/T) or G(U/T)A to G(U T)C or G(U/T)G; the codon for Asp can be modified from GA(U/T) to GAC;
  • the codon for Glu can be modified from GAA to GAG;
  • the stop codon (U T)AA can be modified to (U T)AG or (U T)GA.
  • the codons for Met (A(U/T)G) and Trp ((U/T)GG) on the other hand, there is no possibility of sequence modification without altering the encoded amino acid sequence.
  • substitutions listed above can be used either individually or in all possible combinations to increase the G/C content of the open reading frame of the inventive nucleic acid sequence as defined herein, compared to its particular wild type open reading frame (i.e. the original sequence).
  • all codons for Thr occurring in the wild type sequence can be modified to ACC (or ACG).
  • the G/C content of the open reading frame of the inventive artificial nucleic acid molecule as defined herein is increased by at least 7%, more preferably by at least 1 5%, particularly preferably by at least 20%, compared to the G/C content of the wild type coding region.
  • at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, more preferably at least 70 %, even more preferably at least 80% and most preferably at least 90%, 95% or even 100% of the substitutable codons in the open reading frame of the inventive artificial nucleic acid molecule or a fragment, variant or derivative thereof are substituted, thereby increasing the G/C content of said open reading frame.
  • the open reading frame is preferably at least partially codon-optimized. Codon-optimization is based on the finding that the translation efficiency may be determined by a different frequency in the occurrence of transfer RNAs (tRNAs) in cells. Thus, if so-called "rare codons" are present in the coding region of the inventive artificial nucleic acid molecule as defined herein, to an increased extent, the translation of the corresponding modified nucleic acid sequence is less efficient than in the case where codons coding for relatively "frequent" tRNAs are present.
  • tRNAs transfer RNAs
  • the open reading frame of the inventive nucleic acid sequence is preferably modified compared to the corresponding wild type coding region such that at least one codon of the wild type sequence which codes for a tRNA which is relatively rare in the cell is exchanged for a codon which codes for a tRNA which is comparably frequent in the cell and carries the same amino acid as the relatively rare tRNA.
  • the open reading frame of the inventive artificial nucleic acid molecule as defined herein is modified such that codons for which frequently occurring tRNAs are available may replace codons which correspond to rare tRNAs.
  • all codons of the wild type open reading frame which code for a rare tRNA may be exchanged for a codon which codes for a tRNA which is more frequent in the cell and which carries the same amino acid as the rare tRNA.
  • Which tRNAs occur relatively frequently in the cell and which, in contrast, occur relatively rarely is known to a person skilled in the art; cf. e.g. Akashi, Curr. Opin. Genet. Dev. 2001 , 1 1 (6): 660-666.
  • the open reading frame is codon-optimized, preferably with respect to the system in which the nucleic acid molecule according to the present invention is to be ex- pressed, preferably with respect to the system in which the nucleic acid molecule according to the present invention is to be translated.
  • the codon usage of the open reading frame is codon-optimized according to mammalian codon usage, more preferably according to human codon usage.
  • the open reading frame is codon-optimized and G/C-content modified. For further improving degradation resistance, e.g.
  • the artificial nucleic acid molecule may further comprise modifications, such as backbone modifications, sugar modifications and/or base modifications, e.g., lipid-modifications or the like.
  • modifications such as backbone modifications, sugar modifications and/or base modifications, e.g., lipid-modifications or the like.
  • the tran- scription and/or the translation of the artificial nucleic acid molecule according to the present invention is not significantly impaired by said modifications.
  • Nucleotide analogues/modifications that may be used in the context of the present invention may be selected, for example, from 2-amino-6-chloropurineriboside-5'-triphosphate, 2- aminoadenosine-5'-triphosphate, 2-thiocytidine-5'-triphosphate, 2-thiouridine-5'- triphosphate, 4-thiouridine-5'-triphosphate, 5-aminoallylcytidine-5'-triphosphate, 5- aminoallyluridine-5'-triphosphate, 5-bromocytidine-5'-triphosphate, 5-bromouridine-5'- triphosphate, 5-iodocytidine-5'-triphosphate, 5-iodouridine-5'-triphosphate, 5- methylcytidine-5 '-triphosphate, 5-methyluridine-5 '-triphosphate, 6-azacytidine-5'- triphosphate, 6-azauridine-5'-triphosphate, 6-chloropurineriboside-5'-triphosphate,
  • nucleotides for base modifications selected from the group of base-modified nucleotides consisting of 5-methylcytidine-5'-triphosphate, 7-deazaguanosine-5'- triphosphate, 5 -bromocytidine-5' -triphosphate, and pseudouridine-5'-triphosphate.
  • lipid-modified artificial nucleic acid molecules may typically comprise at least one linker which is covalently linked with the artificial nucleic acid molecule, and at least one lipid which is covalently linked with this linker.
  • a lipid-modified artificial nu- cleic acid molecule may comprise at least one artificial nucleic acid molecule as defined herein and at least one, preferably bifunctional lipid which is covalently linked, preferably without a linker, with that artificial nucleic acid molecule.
  • a lipid-modified artificial nucleic acid molecule may comprise an artificial nucleic acid molecule as defined herein, at least one linker which is covalently linked with that artificial nucleic acid molecule, at least one lipid which is covalently linked with this linker, and additionally at least one, preferably bifunctional lipid which is covalently linked, preferably without a linker, with the artificial nucleic acid molecule.
  • the present invention provides a vector comprising
  • 5'-untranslated region element which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a TOP gene or which is derived from a variant of the 5'UTR of a TOP gene;
  • ORF open reading frame
  • At least one 3'UTR element which comprises or consists of a nucleic acid sequence derived from the 3'UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene, or from a variant of the 3'UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene.
  • the at least one 5'UTR element, the optional at least one 3'UTR element and the at least one ORF are as described herein for the artificial nucleic acid molecule according to the present invention.
  • the cloning site may be any sequence that is suitable for introducing an open reading frame or a sequence comprising an open reading frame, such as one or more restriction sites.
  • the vector comprising a cloning site is preferably suitable for inserting an open reading frame into the vector 3' to the 5'UTR element, preferably directly 3' to the 5'UTR element.
  • the vector comprising a cloning site is preferably suitable for inserting an open reading frame into the vector, preferably for inserting an open reading frame between the 5'UTR element and the optional 3'UTR element, preferably 5' to the optional 3'UTR element and 3' to the 5'UTR element.
  • the cloning site or the ORF is located 5' to the 3'UTR element, preferably in close proximity to the 5'-end of the 3'UTR element.
  • the cloning site or the ORF may be directly connected to the 5'-end of the 3'UTR element or they may be connected via a stretch of nucleotides, such as by a stretch of 2, 4, 6, 8, 10, 20 etc.
  • the cloning site or the ORF is located 3' to the 5'UTR element, preferably in close proximity to the 3'-end of the 5'UTR element.
  • the cloning site or the ORF may be directly connected to the 3'-end of the 5'UTR element or they may be connected via a stretch of nucleotides, such as by a stretch of 2, 4, 6, 8, 10, 20 etc. nucleotides as described above for the artificial nucleic acid molecule according to the present invention.
  • the vector according to the present invention is suitable for producing the artificial nucleic acid molecule according to the present invention, preferably for producing an artificial mRNA according to the present invention, for example, by optionally inserting an open reading frame or a sequence comprising an open reading frame into the vector and transcribing the vector.
  • the vector comprises elements needed for transcription, such as a promoter, e.g. an RNA polymerase promoter.
  • the vector is suitable for transcription using eukaryotic, prokaryotic, viral or phage transcription systems, such as eukaryotic cells, prokaryotic cells, or eukaryotic, prokaryotic, viral or phage in vitro transcription systems.
  • the vector may comprise a promoter sequence, which is recognized by a polymerase, such as by an RNA polymerase, e.g. by a eukaryotic, prokaryotic, viral, or phage RNA polymerase.
  • a polymerase such as by an RNA polymerase, e.g. by a eukaryotic, prokaryotic, viral, or phage RNA polymerase.
  • the vector comprises a phage RNA polymerase promoter such as an SP6 or T7, preferably a T7 promoter.
  • the vector is suitable for in vitro transcription using a phage based in vitro transcription system, such as a T7 RNA polymerase based in vitro transcription system.
  • the vector may further comprise a poly(A) sequence and/or a polyadenylation signal as described above for the artificial nucleic acid molecule according to the present invention.
  • the vector may be an RNA vector or a DNA vector.
  • the vector is a DNA vector.
  • the vector may be any vector known to the skilled person, such as a viral vector or a plasmid vector.
  • the vector is a plasmid vector, preferably a DNA plasmid vector.
  • the vector according to the present invention comprises the artificial nucleic acid molecule according to the present invention.
  • a vector according to the present invention comprises a sequence according to SEQ ID NOs. 1 -1363, 1395, 1421 , 1422, 1368, or 1412-1420, or a sequence having an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%; even more preferably of at least about 99%; even more preferably of 100% sequence identity to a sequence according to any one of SEQ ID NOs. 1 -1363, 1395, 1421 , 1422, 1368, or 1412- 1420, or a fragment thereof, preferably a functional fragment thereof, or a corresponding RNA sequence.
  • the vector is a circular molecule.
  • the vector is a double-stranded molecule, such as a double stranded DNA molecule.
  • Such circular, preferably double stranded DNA molecule may be used conveniently as a storage form for the inventive artificial nucleic acid molecule.
  • it may be used for transfection of cells, for example, cultured cells.
  • it may be used for in vitro transcription for obtaining an artificial RNA molecule according to the invention.
  • the vector, preferably the circular vector is linearizable, for example, by restriction enzyme digestion.
  • the vector comprises a cleavage site, such as a restriction site, preferably a unique cleavage site, located immediately 3' to the ORF, or - if present - immediately 3' to the 3'UTR element, or - if present - immediately 3' to the poly(A) sequence or polyadenylation signal, or - if present - located 3' to the poly(C) sequence, or - if present - located 3' to the histone stem-loop".
  • a cleavage site such as a restriction site, preferably a unique cleavage site, located immediately 3' to the ORF, or - if present - immediately 3' to the 3'UTR element, or - if present - immediately 3' to the poly(A) sequence or polyadenylation signal, or - if present - located 3' to the poly(C) sequence, or - if present - located 3' to the histone stem-loop.
  • the product obtained by linearizing the vector terminates at the 3'end with the stop codon, or - if present - the 3'-end of the 3'UTR element, or - if present - with the 3'-end of the poly(A) sequence or with the 3'-end of the polyadenylation signal, or - if present - with the 3'-end of the poly(C) sequence, or - if present - with the 3'-end of the histone stem-loop, plus optionally some nucleotides remaining from the restriction site after cleavage.
  • the present invention relates to a cell comprising the artificial nucleic acid molecule according to the present invention or the vector according to present invention.
  • the cell may be any cell, such as a bacterial cell, insect cell, plant cell, vertebrate cell, e.g. a mammalian cell. Such cell may be, e.g., used for replication of the vector of the present invention, for example, in a bacterial cell.
  • the cell may be used for transcribing the artificial nucleic acid molecule or the vector according to the present invention and/or translating the open reading frame of the artificial nucleic acid molecule or the vector according to the present invention.
  • the cell may be used for recombinant protein production.
  • the cells according to the present invention are, for example, obtainable by standard nucleic acid transfer methods, such as standard transfection methods.
  • the artificial nucleic acid molecule or the vector according to the present invention may be transferred into the cell by electroporation, lipofection, e.g. based on cationic lipids and/or liposomes, calcium phosphate precipitation, nanoparticle based transfection, virus based transfection, or based on cationic polymers, such as DEAE-dextran or polyethylenimine etc.
  • the cell is a mammalian cell, such as a cell of human subject, a domestic animal, a laboratory animal, such as a mouse or rat cell.
  • the cell is a human cell.
  • the cell may be a cell of an established cell line, such as a CHO, BHK, 293T, COS-7, HELA, HEK etc. cell, or the cell may be a primary cell, e.g. a HDF cell, preferably a cell isolated from an organism.
  • the cell is an isolated cell of a mammalian subject, preferably of a human subject.
  • the cell may be an immune cell, such as a dendritic cell, a cancer or tumor cell, or any somatic cell etc., preferably of a mammalian subject, preferably of a human subject.
  • the present invention provides a pharmaceutical composition comprising the artificial nucleic acid molecule according to the present invention, the vector according the present invention, or the cell according to the present invention.
  • the pharmaceutical composition according to the invention may be used, e.g., as a vaccine, for example, for genetic vaccination.
  • the O F may, e.g., encode an antigen to be administered to a patient for vaccination.
  • the pharmaceutical composition according to the present invention is a vaccine.
  • the pharmaceutical composition according to the present invention may be used, e.g., for gene therapy.
  • the pharmaceutical composition further comprises one or more pharmaceuti- cally acceptable excipients, vehicles, fillers and/or diluents.
  • a pharmaceutically acceptable vehicle typically includes a liquid or non-liquid basis for the inventive pharmaceutical composition.
  • the pharmaceutical composition is provided in liquid form.
  • the vehicle is based on water, such as pyrogen-free water, isotonic saline or buffered (aqueous) solutions, e.g. phosphate, citrate etc. buffered solutions.
  • the buffer may be hypertonic, isotonic or hypotonic with reference to the specific reference medium, i.e.
  • the buffer may have a higher, identical or lower salt content with reference to the specific reference medium, wherein preferably such concentrations of the afore mentioned salts may be used, which do not lead to damage of mammalian cells due to osmosis or other concentration effects.
  • Reference media are e.g. liquids occurring in "in vivd' methods, such as blood, lymph, cytosolic liquids, or other body liquids, or e.g. liquids, which may be used as reference media in "in vitrd' methods, such as common buffers or liquids. Such common buffers or liquids are known to a skilled person. Ringer-Lactate solution is particularly preferred as a liquid basis.
  • compatible solid or liquid fillers or diluents or encapsulating compounds suitable for administration to a patient may be used as well for the inventive pharmaceutical composition.
  • the term "compatible” as used herein preferably means that these components of the inventive pharmaceutical composition are capable of being mixed with the inventive nucleic acid, vector or cells as defined herein in such a manner that no interaction occurs which would substantially reduce the pharmaceutical effectiveness of the inventive pharmaceutical composition under typical use conditions.
  • the pharmaceutical composition according to the present invention may optionally further comprise one or more additional pharmaceutically active components.
  • a pharmaceutically active component in this context is a compound that exhibits a therapeutic effect to heal, ameliorate or prevent a particular indication or disease.
  • Such compounds include, without implying any limitation, peptides or proteins, nucleic acids, (therapeutically active) low molecular weight organic or inorganic compounds (molecular weight less than 5000, preferably less than 1000), sugars, antigens or antibodies, therapeutic agents already known in the prior art, antigenic cells, antigenic cellular fragments, cellular fractions, cell wall components (e.g. polysaccharides), modified, attenuated or de-activated (e.g. chemically or by irradiation) pathogens (virus, bacteria etc.).
  • the inventive pharmaceutical composition may comprise a carrier for the artificial nucleic acid molecule or the vector.
  • Such a carrier may be suitable for mediating dissolution in physiological acceptable liquids, transport and cellular uptake of the pharmaceutical active artificial nucleic acid molecule or the vector.
  • a carrier may be a component which may be suitable for depot and delivery of an artificial nucleic acid molecule or vector according to the invention.
  • Such components may be, for example, cationic or polycationic carriers or compounds which may serve as transfection or com- plexation agent.
  • transfection or complexation agents are cationic or polycationic compounds, including protamine, nucleoline, spermine or spermidine, or other cationic peptides or proteins, such as poly-L-lysine (PLL), poly-arginine, basic polypeptides, cell penetrating peptides (CPPs), including HIV-binding peptides, HIV-1 Tat (HIV), Tat-derived peptides, Penetratin, VP22 derived or analog peptides, HSV VP22 (Herpes sim- plex), MAP, KALA or protein transduction domains (PTDs), PpT620, prolin-rich peptides, arginine-rich peptides, lysine-rich peptides, MPG-peptide(s), Pep-1 , L-oligomers, Calcitonin peptide(s), Antennapedia-derived peptides (particularly from Drosophila antennapedia), p
  • cationic or polycationic compounds or carriers may be cationic or polycationic peptides or proteins, which preferably comprise or are additionally modified to comprise at least one -SH moiety.
  • a cationic or polycationic carrier is selected from cationic peptides having the following sum formula (I):
  • the cationic or polycationic peptide or protein when defined according to formula ⁇ (Arg)i;(Lys) m ;(His) n ;(Orn) 0 ;(Xaa) x ⁇ (formula (I)) as shown above and which comprise or are additionally modified to comprise at least one -SH moeity, may be, without being restricted thereto, selected from subformula (la):
  • cationic or polycationic compounds which can be used as transfection or complexation agent may include cationic polysaccharides, for example chitosan, poly- brene, cationic polymers, e.g. polyethyleneimine (PEI), cationic lipids, e.g.
  • cationic polysaccharides for example chitosan, poly- brene
  • cationic polymers e.g. polyethyleneimine (PEI)
  • PEI polyethyleneimine
  • cationic lipids e.g.
  • DOTMA [1 - (2,3-sioleyloxy)propyl)]-N,N,N-trimethylammonium chloride, DMRIE, di-C14-amidine, DOTIM, SAINT, DC-Choi, BGTC, CTAP, DOPC, DODAP, DOPE: Dioleyl phosphati- dylethanol-amine, DOSPA, DODAB, DOIC, DMEPC, DOGS: Dioctadecylamidoglicylspermin, DIMRI: Dimyristo-oxypropyl dimethyl hydroxyethyl ammonium bromide, DOTAP: dioleoyloxy-3-(trimethylammonio)propane, DC-6-14: O,O- ditetradecanoyl-N ⁇ a rimethylammonioacetyl)diethanolamine chloride, CLIP1 : rac-[(2,3- dioctadecyloxypropyl)(2-hydroxyethyl)]-
  • modified polyaminoacids such as ⁇ -aminoacid- polymers or reversed polyamides, etc.
  • modified polyethylenes such as PVP (poly(N-ethyl- 4-vinylpyridinium bromide)), etc.
  • modified acrylates such as pDMAEMA (poly(dimethylaminoethyl methylacrylate)), etc.
  • modified Amidoamines such as pAMAM (poly(amidoamine)), etc.
  • modified polybetaaminoester (PBAE) such as diamine end modi- fied 1 ,4 butanediol diacrylate-co-5-amino-l -pentanol polymers, etc.
  • dendrimers such as polypropylamine dendrimers or pAMAM based dendrimers, etc.
  • polyimine(s) such as PEI: poly(ethyleneimine), poly(propyleneimine), etc., polyallylamine,
  • inventive artificial nucleic acid molecule or the inventive vector is complexed at least partially with a cationic or polycationic compound, preferably cationic proteins or peptides.
  • a cationic or polycationic compound preferably cationic proteins or peptides.
  • the ratio of complexed nucleic acid to: free nucleic acid is selected from a range, of about 5:1 (w/w) to about 1 :10 (w/w), more preferably from a range of about 4:1 (w/w) to about 1 :8 (w/w), even more preferably from a range of about 3:1 (w/w) to about 1 :5 (w/w) or 1 :3 (w/w), and most preferably the ratio of complexed nucleic acid to free nucleic acid is selected from a ratio of about 1 :1 (w/w).
  • the pharmaceutical composition according to the present invention may optionally further comprise one or more adjuvants, for example, adjuvants for stimulating the innate immune system or for enhancing cellular uptake of the artificial nucleic acid molecule or vector.
  • an adjuvant may be understood as any compound, which is suitable to initiate or increase an immune response of the innate immune system, i.e. a non-specific immune response.
  • the inventive pharmaceutical composition when administered, preferably elicits an innate immune response due to the adjuvant, optionally contained therein.
  • such an adjuvant may be an adjuvant supporting the induction of an innate immune response in a mammal.
  • Such an adjuvant may be, for example, an immunostimulatory nucleic acid, i.e. a nucleic acid that may bind to a Toll-like-receptor or the like, preferably an immunostimulatory RNA.
  • Such adjuvants preferably such immunostimulatory nucleic acids, may induce an innate, i.e. unspecific, immune response which may support a specific, i.e. adaptive, immune response to the peptide or protein, i.e. the antigen, encoded by the artificial nucleic acid molecule of the pharmaceutical composition, preferably the vaccine.
  • the inventive pharmaceutical composition may also additionally comprise any further compound, which is known to be immunostimulating due to its binding affinity (as ligands) to human Toll-like receptors TLR1 , TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, or due to its binding affinity (as ligands) to murine Toll-like receptors TLR1 , TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR1 1 , TLR12 or TLR13.
  • any further compound which is known to be immunostimulating due to its binding affinity (as ligands) to human Toll-like receptors TLR1 , TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR1 1 , TLR12 or TLR13.
  • emulsifiers such as, for example, Tween ®
  • wetting agents such as, for example, sodium lauryl sulfate
  • colouring agents such as, for example, sodium lauryl sulfate
  • taste-imparting agents pharmaceutical carriers
  • tablet- forming agents such as, for example, stabilizers; antioxidants; preservatives etc.
  • the pharmaceutical composition according to the present invention preferably comprises a "safe and effective amount" of the components of the pharmaceutical composition, particularly of the inventive nucleic acid sequence, the vector and/or the cells as defined herein.
  • a "safe and effective amount” means an amount sufficient to significantly induce a positive modification of a disease or disorder as defined herein.
  • a "safe and effective amount” preferably avoids serious side-effects and permits a sensible relationship between advantage and risk. The determination of these limits typically lies within the scope of sensible medical judgment.
  • the present invention provides the artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention for use as a medicament, for example, as vaccine (in genetic vaccination) or in gene therapy.
  • the artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention are particularly suitable for any medical application which makes use of the therapeutic action or effect of peptides, polypeptides or proteins, or where supplementation of a particular peptide or protein is needed.
  • the present invention provides the artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention for use in the treatment or prevention of diseases or disorders amenable to treatment by the therapeutic action or effect of peptides, polypeptides or proteins or amenable to treatment by supplementation of a particular peptide, polypeptide or protein.
  • the artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention may be used for the treatment or prevention of genetic diseases, autoimmune diseases, cancerous or tumour-related diseases, infectious diseases, chronic diseases or the like, e.g., by genetic vaccination or gene therapy.
  • such therapeutic treatments which benefit from a stable, prolonged and/or increased presence of therapeutic peptides, polypeptides or proteins in a subject to be treated are especially suitable as medical application in the context of the present invention, since the 5'UTR element optionally in combination with the 3'UTR element provides for increased protein expression from the ORF and the 3'UTR element provides for a stable and prolonged expression of the ORF of the inventive nucleic acid molecule.
  • a particularly suitable medical application for the artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention is vaccination, for example against infections or tumours.
  • the present invention provides the artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention for vaccination of a subject, preferably a mammalian subject, more preferably a human subject.
  • Preferred vaccination treatments are vaccination against infectious diseases, such as bacterial, protozoal or viral infections, and anti-tumour-vaccination. Such vaccination treatments may be prophylactic or therapeutic.
  • the ORF may be selected.
  • the open reading frame may code for a protein that has to be supplied to a patient suffering from total lack or at least partial loss of function of a protein, such as a patient suffering from a genetic disease.
  • the open reading frame may be chosen from an ORF coding for a peptide or protein which beneficially influences a disease or the condition of a subject.
  • the open reading frame may code for a peptide or protein which effects down-regulation of a pathological overproduction of a natural peptide or protein or elimination of cells expressing pathologically a protein or peptide. Such lack, loss of function or overproduction may, e.g., occur in the context of tumour and neoplasia, autoimmune diseases, allergies, infections, chronic diseases or the like.
  • the open reading frame may code for an antigen or immunogen, e.g. for an epitope of a pathogen or for a tumour antigen.
  • the artificial nucleic acid molecule or the vector according to the present invention comprises an ORF encoding an amino acid sequence comprising or consisting of an antigen or immunogen, e.g. an epitope of a pathogen or a tumour-associated antigen, a 5'UTR element as described above, and optional further components, such as a 3'UTR element and/or a poly(A) sequence etc. as described above.
  • an antigen or immunogen e.g. an epitope of a pathogen or a tumour-associated antigen, a 5'UTR element as described above, and optional further components, such as a 3'UTR element and/or a poly(A) sequence etc. as described above.
  • the artificial nucleic acid molecule according to the present invention is RNA, preferably mRNA, since DNA harbours the risk of eliciting an anti-DNA immune response and tends to insert into genomic DNA.
  • a viral delivery vehicle such as an adenoviral delivery vehicle
  • the artificial nucleic acid molecule or the vector is a DNA molecule.
  • the artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, intracra- nial, transdermal, intradermal, intrapulmonal, intraperitoneal, intracardial, intraarterial, and sublingual injection or infusion techniques.
  • the artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the phar- maceutical composition according to the present invention is administered parenterally, e.g. by parenteral injection, more preferably by subcutaneous, intravenous, intramuscular, intraarticular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, intracranial, transdermal, intradermal, intrapulmonal, intraperitoneal, intracardial, intraarterial, sublingual injection or via infusion techniques. Particularly preferred is intradermal and intramus- cular injection.
  • Sterile injectable forms of the inventive pharmaceutical composition may be aqueous or oleaginous suspension.
  • suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention may also be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • the artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention may also be administered topically, espe- dally when the target of treatment includes areas or organs readily accessible by topical application, e.g. including diseases of the skin or of any other accessible epithelial tissue. Suitable topical formulations are readily prepared for each of these areas or organs.
  • the artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention may be formulated in a suitable ointment suspended or dissolved in one or more carriers.
  • the use as a medicament comprises the step of transfection of mammalian cells, preferably in vitro transfection of mammalian cells, more preferably in vitro transfection of isolated cells of a subject to be treated by the medicament. If the use comprises the in vitro transfection of isolated cells, the use as a medicament may further comprise the (re)administration of the transfected cells to the patient.
  • the use of the inventive artificial nucleic acid molecules or the vector as a medicament may further comprise the step of selection of successfully transfected isolated cells. Thus, it may be beneficial if the vector further comprises a selection marker.
  • the use as a medicament may comprise in vitro transfection of isolated cells and purification of an expression- product, i.e. the encoded peptide or protein from these cells. This purified peptide or protein may subsequently be administered to a subject in need thereof.
  • the present invention also provides a method for treating or preventing a disease or disorder as described above comprising administering the artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention to a subject in need thereof.
  • the present invention provides a method for treating or preventing a disease or disorder comprising transfection of a cell with an artificial nucleic acid molecule according to the present invention or with the vector according to the present invention.
  • Said transfection may be performed in vitro or in vivo.
  • transfection of a cell is performed in vitro and the transfected cell is administered to a subject in need thereof, preferably to a human patient.
  • the cell which is to be transfected in vitro is an isolated cell of the subject, preferably of the human patient.
  • the present invention provides a method of treatment comprising the steps of isolating a cell from a subject, preferably from a human patient, transfecting the isolated cell with the artificial nucleic acid molecule according to the present invention or the vector according to the present invention, and administering the transfected cell to the subject, preferably the human patient.
  • the method of treating or preventing a disorder according to the present invention is preferably a vaccination method and/or a gene therapy method as described above.
  • the 5'UTR element and the optional 3'UTR element are capable of increasing protein production from an artificial nucleic acid molecule, such as an mRNA or vector, comprising the 5'UTR element and an ORF.
  • the present invention relates to a method for increasing protein production from an artificial nucleic acid molecule
  • a method for increasing protein production from an artificial nucleic acid molecule comprising the step of associating the artificial nucleic acid molecule, preferably the ORF contained within the artificial nucleic acid molecule, with (i) at least one 5'-untranslated region element (5'UTR element) which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a TOP gene or which is derived from a variant of the 5'UTR of a TOP gene as described above and (ii) optionally at least one 3'UTR element which comprises or consists of a nucleic acid sequence derived from the 3'UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene, or from a variant of the 3'UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene,
  • the term "associating the artificial nucleic acid molecule or the vector with a 5 'UTR element and an optional 3'UTR element" in the context of the present invention preferably means functionally associating or functionally combining the artificial nucleic acid molecule, such as the mRNA or the vector, with the 5'UTR element and the optional 3'UTR element.
  • the artificial nucleic acid molecule preferably the ORF contained within the artificial nucleic acid molecule, the 5'UTR element and the optional 3'UTR element as described above are associated or coupled such that the function of the 5'UTR element and the optional 3'UTR element, e.g., protein production increasing function, is exerted.
  • the 5'UTR element and the optional 3'UTR element are integrated into the artificial nucleic acid molecule, preferably into the m NA molecule or the vector, such that the open reading frame is positioned 3' to the 5'UTR element, preferably between the 5'UTR element and the optional 3'UTR element.
  • the present invention provides the use of at least one 5 '-untranslated region element (5'UTR element) which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a TOP gene or which is derived from a variant of the 5'UTR of a TOP gene as described above and optionally at least one 3'UTR element which comprises or consists of a nucleic acid sequence derived from the 3'UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene, or from a variant of the 3'UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene as described above for increasing protein production from an artificial nucleic acid molecule, such as an mRNA or a vector.
  • 5'UTR element which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a TOP gene or which is
  • the use according to the present invention preferably comprises associating the artificial nucleic acid molecule with the 5'UTR element and the optional 3'UTR element as described above.
  • the method for increasing protein production from an artificial nucleic acid molecule and the above use may also comprise associating the artificial nucleic acid molecules with one or more further elements, such as a polyadenylation signal, a poly(A) sequence, a poly(C) sequence and/or a histone stem loop as described above.
  • the compounds and ingredients of the inventive pharmaceutical composition may also be manufactured and traded separately of each other.
  • kit or kit of parts comprising an artificial nucleic acid molecule according to the invention, a vector according the invention, a cell according to the invention, and/or a pharmaceutical composition according to the invention.
  • kit or kit of parts may, additionally, comprise instructions for use, cells for transfection, an adjuvant, a means for administration of the pharmaceutical composition, a pharmaceutically acceptable carrier and/or an pharmaceutically acceptable solution for dissolution or dilution of the artificial nucleic acid molecule, the vector, the cells or the pharmaceutical composition.
  • Figures, Sequences and Examples are intended to illustrate the invention further. They are not intended to limit the subject-matter of the invention thereto.
  • Fig. 1 shows the nucleotide sequence of a Photinus pyralis luciferase encoding nucleic acid molecule PpLuc(GC) - A64N64. This artificial construct does not comprise a 5'UTR element or a 3'UTR element in the sense of the present invention. The coding region for PpLuc(GC) is depicted in italics.
  • Fig. 2 shows the nucleotide sequence of PpLuc(GC) - albumin7 - A64N64.
  • the coding region for PpLuc(GC) is depicted in italics.
  • the albumin 3'UTR is underlined.
  • Fig. 3 shows the nucleotide sequence of RPL32 - PpLuc(GC) - A64N64.
  • the coding region for PpLuc(GC) is depicted in italics.
  • the RPL32 5'UTR is underlined.
  • Fig. 4 shows the nucleotide sequence of RPL32 - PpLuc(GC) - albumin7 - A64N64.
  • the 5'UTR of human ribosomal protein Large 32 gene lacking the 5' terminal oligopyrimidine tract (RPL32) according to SEQ ID NO. 1368 and the albumin7 3'UTR element according to SEQ ID NO. 1376 were inserted 5' and 3' of the ORF in the construct shown in Figure 1 , respectively.
  • Fig. 5 is a graphical representation of the effect of the TOP 5'UTR element which is derived from the 5'UTR of the TOP gene RPL23 according to SEQ ID NO. 1368, the albumin 3' UTR element according to SEQ ID NO. 1376 and the combination of the TOP 5'UTR element and the albumin 3'UTR element on luciferase expression from mRNA.
  • a variety of mRNAs were transfected into human dermal fibroblasts (HDF) by lipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection.
  • the albumin 3'UTR element extends luciferase expression, while the TOP 5'UTR element increases luciferase levels compared to mRNA lacking 5'- and 3'UTR elements. Strikingly, the combination of TOP 5'UTR element and albumin 3'UTR element further strongly increases the luciferase level, much above the level observed with either of the individual elements, thus acting synergistically. Data are graphed as mean RLU ⁇ SD (relative light units ⁇ standard deviation) for triplicate transfections. RLU are summarized in Example 5.1 . shows the nucleotide sequence of RPL35 - PpLuc(GC) - albumin7 - A64N64.
  • the 5'UTR of human ribosomal protein Large 35 gene lacking the 5' terminal oligopyrimidine tract (RPL35) according to SEQ ID NO. 1412 and the albumin7 3'UTR element according to SEQ ID NO. 1376 were inserted 5' and 3' of the ORF in the construct shown in Figure 1 , respectively. shows the nucleotide sequence of RPL21 - PpLuc(GC) - albumin7 - A64N64.
  • HSD1 7B4 shows the nucleotide sequence of HSD1 7B4 - PpLuc(GC) - albumin7 - A64N64.
  • the 5'UTR of human hydroxysteroid (17-beta) dehydrogenase 4 gene lacking the 5' terminal oligopyrimidine tract (HSD1 7B4) according to SEQ ID NO. 1415 and the albumin7 3'UTR element according to SEQ ID NO. 1376 were inserted 5' and 3' of the ORF in the construct shown in Figure 1 , respectively. shows the nucleotide sequence of A1G1 - PpLuc(GC) - albumin7 - A64N64.
  • the 5'UTR of human androgen-induced 1 gene lacking the 5' terminal oligopyrimidine tract (AIG1 ) according to SEQ ID NO. 141 6 and the albumin7 3'UTR element according to SEQ ID NO. 1376 were inserted 5' and 3' of the ORF in the construct shown in Figure 1 , respectively.
  • Fig. 1 1 shows the nucleotide sequence of COX6C - PpLuc(GC) - albumin7 - A64N64.
  • the 5'UTR of human cytochrome c oxidase subunit Vic gene lacking the 5' terminal oligopyrimidine tract (COX6C) according to SEQ ID NO. 141 7 and the albumin7 3'UTR element according to SEQ ID NO. 1376 were inserted 5' and 3' of the ORF in the construct shown in Figure 1 , respectively.
  • Fig. 12 shows the nucleotide sequence of ASAH1 - PpLuc(GC) - albumin7 - A64N64.
  • the 5'UTR of human N-acylsphingosine amidohydrolase (acid cera- midase) 1 lacking the 5' terminal oligopyrimidine tract (ASAH1 ) according to SEQ ID NO. 1418 and the albumin7 3'UTR according to SEQ ID NO. 1376 were inserted 5' and 3' of the ORF in the construct shown in Figure 1 , respectively.
  • Fig. 13 shows the nucleotide sequence of mRPL21 - PpLuc(GC) - albumin7 - A64N64.
  • Fig. 14 shows the nucleotide sequence of mRPL35A - PpLuc(GC) - albumin7 - A64N64.
  • the 5'UTR of murine ribosomal protein Large 35a gene lacking the 5' terminal oligopyrimidine tract (mRPL35A) according to SEQ ID NO. 1420 and the albumin7 3'UTR element according to SEQ ID NO. 1376 were inserted 5' and 3' of the ORF in the construct shown in Figure 1 , respectively.
  • Fig. 15 shows the nucleotide sequence of RPL35 - PpLuc(GC) - A64N64.
  • Fig. 16 shows the nucleotide sequence of RPL21 - PpLuc(GC) - A64N64.
  • 5'UTR of human ribosomal protein Large 21 gene lacking the 5' terminal oli- gopyrimidine tract (RPL21 ) according to SEQ ID NO. 1413 was inserted 5' of the ORF in the construct shown in Figure 1 . shows the nucleotide sequence of atp5a1 - PpLuc(GC) - A64N64.
  • the 5'UTR of human ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 gene lacking the 5' terminal oligopyrimidine tract (atp5a1 ) according to SEQ ID NO. 1414 was inserted 5' of the ORF in the construct shown in Figure 1 .
  • FIG. 14 shows the nucleotide sequence of HSD1 7B4 - PpLuc(GC) - A64N64.
  • the 5'UTR of human hydroxysteroid (1 7-beta) dehydrogenase 4 gene lacking the 5' terminal oligopyrimidine tract (HSD1 7B4) according to SEQ ID NO. 1415 was inserted 5' of the ORF in the construct shown in Figure 1 .
  • the 5'UTR of human androgen-induced 1 gene lacking the 5' terminal oligopyrimidine tract (AIG1 ) according to SEQ ID NO. 1416 was inserted 5' of the ORF in the construct shown in Figure 1 .
  • FIG. 1 shows the nucleotide sequence of COX6C - PpLuc(GC) - A64N64.
  • the 5'UTR of human cytochrome c oxidase subunit Vic gene lacking the 5' terminal oligopyrimidine tract (COX6C) according to SEQ ID NO. 141 7 was inserted 5' of the ORF in the construct shown in Figure 1 .
  • FIG. 1418 was inserted 5' of the ORF in the construct shown in Figure 1 .
  • Figure 1 is a graphical representation of the effect of different TOP 5'UTR elements on luciferase expression from mRNA.
  • a variety of mRNAs were transfected into human dermal fibroblasts (HDF) by lipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection.
  • TOP 5'UTR elements strongly increase luciferase levels compared to mRNA lacking a 5'UTR element.
  • mRNAs comprising 5'UTR elements derived from the 5'UTRs of the TOP genes ASAH1 , COX6C, AIG1 , HSD17B4, atp5a1 , RPL21 , RPL35 and RPL32 were transfected into human dermal fibroblasts (HDF) by Iipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection. The TOP 5'UTR elements increases luciferase levels compared to mRNA lacki ng a 5'UTR element. Data are graphed as mean RLU + SEM (relative light units + standard error) for triplicate transfections. RLU are summarized in Example 5.2.
  • Fig. 23 is a graphical representation of the effect of the RPL35 TOP 5'UTR element, the albumin 3'UTR element and the combi nation of RPL35 TOP 5' UTR element and al bum i n 3 'UTR element on luciferase expression from mRNA.
  • a variety of mRNAs were transfected into human dermal fibroblasts (HDF) by Iipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection.
  • the albumin 3'UTR element extends luciferase expression, while the RPL35 TOP 5'UTR element increases luciferase levels compared to mRNA lacking 5'- and 3 'UTR elements.
  • Fig. 24 is a graphical representation of the effect of the RPL21 TOP 5'UTR element, the albumin 3'UTR element and the combination of RPL21 TOP 5'UTR element and albumin 3'UTR element on luciferase expression from mRNA.
  • a variety of mRNAs were transfected into human dermal fibroblasts (HDF) by Iipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection.
  • the albumin 3'UTR element extends luciferase expression, while the RPL21 TOP 5'UTR element increases luciferase levels compared to mRNA lacking 5'- and 3'UTR elements.
  • Example Fig. 25 is a graphical representation of the effect of the atp5a1 TOP 5'UTR element, the albumin 3'UTR element and the combi nation of atp5a1 TOP 5 ' UTR element and album i n 3 ' UTR element on luciferase expression from mRNA.
  • mRNAs were transfected into human dermal fibroblasts (HDF) by lipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection.
  • the albumin 3'UTR element extends luciferase expression, while the atp5a1 TOP 5'UTR element increases luciferase levels compared to mRNA lacking 5'- and 3'UTR elements. Stri kingly, the combination of atp5a1 TOP 5'UTR element and albumin 3'UTR element further strongly increases the luciferase level, much above the level observed with either of the individual elements, thus acting synergistically. Data are graphed as mean RLU ⁇ SEM (relative light units ⁇ standard error) for triplicate transfections. Synergy is summarized in Example 5.3.
  • Fig. 26 is a graphical representation of the effect of the HSD17B4 TOP 5'UTR element, the albumin 3'UTR element and the combi nation of HSD 1 7B4 TOP 5' UTR element and a lbu m i n 3 'UTR element on luciferase expression from mRNA.
  • a variety of mRNAs were transfected into human dermal fibroblasts (HDF) by lipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection.
  • the albumin 3'UTR element extends luciferase expression, while the HSD1 7B4 TOP 5'UTR element increases luciferase levels compared to mRNA lacking 5'- and 3'UTR elements.
  • Fig. 27 is a graphical representation of the effect of the AIG1 TOP 5'UTR element, the albumin 3'UTR element and the combi nation of AIG 1 TOP 5 'UTR element and albumi n 3 ' UTR element on luciferase expression from mRNA.
  • a variety of mRNAs were transfected into human dermal fibroblasts (HDF) by lipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection.
  • the albumin 3'UTR element extends luciferase expression, while the AIG1 TOP 5'UTR element increases luciferase levels compared to mRNA lacki ng 5'- and 3'UTR elements.
  • Fig. 28 is a graphical representation of the effect of the COX6C TOP 5'UTR element, the albumin 3'UTR element and the combi nation of COX6C TOP 5 ' UTR element and album i n 3 ' UTR element on luciferase expression from mRNA.
  • a variety of mRNAs were transfected into human dermal fibroblasts (HDF) by lipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection.
  • the albumin 3'UTR element extends luciferase expression, while the COX6C TOP 5'UTR element increases luciferase levels compared to mRNA lacking 5'- and 3'UTR elements.
  • Fig. 29 is a graphical representation of the effect of the ASAH1 TOP 5'UTR element, the albumin 3'UTR element and the combi nation of ASAH 1 TOP 5 ' UTR element and album i n 3 ' UTR element on luciferase expression from mRNA.
  • a variety of mRNAs were transfected into human dermal fibroblasts (HDF) by lipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection.
  • the albumin 3'UTR element extends luciferase expression, while the ASAH1 TOP 5'UTR element increases luciferase levels compared to mRNA lacking 5'- and 3'UTR elements.
  • Fig. 30 is a graphical representation of the effect of the TOP 5'UTR element from mouse genes on luciferase expression from mRNA.
  • mRNAs containing either a mouse or a human TOP 5'UTR element were transfected into human dermal fibroblasts (HDF) by lipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection.
  • Mouse TOP 5'UTR elements strongly increase luciferase levels compared to mRNA lacking a 5'-element, similarly as the human TOP 5'UTR element.
  • Data are graphed as mean RLU + SEM (relative light units ⁇ standard error) for triplicate transfections. RLU are summarized in
  • SEQ ID NO. 1416 5'UTR of human androgen-induced 1 (AIG1 ) lacking the 5' terminal oligopyrimidine tract
  • a vector for in vitro transcription was constructed containing a T7 promoter followed by a GC-enriched sequence coding for Photinus pyralis luciferase (PpLuc(GQ) and an A64 poly(A) sequence.
  • the poly(A) sequence was followed by a restriction site used for linearization of the vector before in vitro transcription.
  • mRNA obtained from this vector accordingly by in vitro transcription is designated as skillPpLuc(GC) - A64N64".
  • This vector was modified to include untranslated sequences 5' or 3' of the open reading frame (5'UTR or 3'UTR, respectively).
  • vectors comprising the following mRNA encoding sequences have been generated (the mRNA coding sequences are depicted in Figures 1 to 4 and 6 to 21 ):
  • the DNA-tempIate according to Example 1 was linearized and transcribed in vitro using T7- Polymerase.
  • the DNA-template was then digested by DNase-treatment.
  • mRNA transcripts contained a 5'-CAP structure obtained by adding an excess of N7-Methyl-Guanosine-5'- Triphosphate-5'-Guanosine to the transcription reaction. mRNA thus obtained was purified and resuspended in water.
  • HDF Human dermal fibroblasts
  • lysis buffer 25 mM Tris, pH 7.5 (HCI), 2 mM EDTA, 10% glycerol, 1 % Triton X-100, 2 mM DTT, 1 mM PMSF. Lysates were stored at -20°C until luciferase activity was measured.
  • HDF were seeded in 96 well plates three days before transfection at a density of 10 4 cells per well.
  • cells were washed in opti-MEM.
  • Cells were lipofected with 25 ng of PpLuc-encoding mRNA per well com- plexed with Lipofectamine2000.
  • mRNA coding for Renilla reniformis luciferase (RrLuc) was transfected together with PpLuc mRNA to control for transfection efficiency (2.5 ng of RrLuc mRNA per well).
  • opti- MEM was exchanged for medium. 24, 48, 72 hours after transfection, medium was aspirated and cells were lysed in 100 ⁇ of lysis buffer (Passive Lysis Buffer, Promega). Lysates were stored at -80°C until luciferase activity was measured.
  • Luciferase activity was measured as relative light units (RLU) in a BioTek SynergyHT plate reader.
  • PpLuc activity was measured at 15 seconds measuring time using 50 ⁇ of lysate and 200 ⁇ of luciferin buffer (75 ⁇ luciferin, 25 mM Glycylglycin, pH 7.8 (NaOH), 15 mM MgS04, 2 mM ATP).
  • RrLuc activity was measured at 15 seconds measuring time using 50 ⁇ of lysate and 200 ⁇ of coelenterazin buffer (40 ⁇ coelenterazin in phosphate buffered saline adjusted to 500 mM NaCl).
  • luciferase activity was measured as relative light units (RLU) in a Hidex Cha- meleon plate reader.
  • PpLuc activity was measured at 2 seconds measuring time using 20 ⁇ of lysate and 50 ⁇ of luciferin buffer (Beetle-Juice, PJK GmbH).
  • RrLuc activity was measured at 2 seconds measuring time using 20 ⁇ of lysate and 50 ⁇ of coelenterazin buffer (Renilla-Juice, PJK GmbH).
  • mRNAs with different UTRs were synthesized: mRNAs either lacked both TOP 5'UTR element and albumin 3'UTR element, or contained either a TOP 5'UTR element (RPL32) or an albumin 3'UTR element (albumin7), or both TOP 5'UTR element and albumin 3'UTR element.
  • Luciferase encoding mRNAs or control mRNA were transfected into human dermal fibroblasts (HDF). Luciferase levels were measured at 24, 48, and 72 hours after transfection. The PpLuc signal was corrected for transfection efficiency by the signal of cotransfected RrLuc (see following Table 1 and Figure 5).
  • Luciferase was clearly expressed from mRNA having neither TOP 5'UTR nor albumin 3'UTR (PpLuc(GC)-A64N64).
  • the albumin 3'UTR element extended luciferase expression, while the TOP 5'UTR element increased luciferase levels compared to mRNA lacking 5'- and 3'UTR elements. Strikingly however, the combination of TOP 5'UTR element and albumin 3'UTR element further strongly increased the luciferase level, much above the level observed with either of the individual elements.
  • the magnitude of the rise in luciferase level due to combining TOP 5'UTR element and albumin 3'UTR element in the same mRNA demonstrates that they are acting synergistically.
  • the synergy between TOP 5'UTR element and albumin 3'UTR element was quantified by dividing the signal from mRNA combining both elements by the sum of the signal from mRNA lacking both elements plus the rise in signal effected by the TOP 5'UTR element plus the rise in signal effected by the albumin 3'UTR element. This calculation was performed for the three time points individually and for total protein expressed from 0 to 72 hours calculated from the area under the curve (AUC) (see following Table 2).
  • the synergy thus calculated specifies how much higher the luciferase level from mRNA combining TOP 5'UTR element and albumin 3'UTR element is than would be expected if the effects of TOP 5'UTR element and albumin 3'UTR element were purely additive.
  • the luciferase level from mRNA combining TOP 5'UTR element and albumin 3'UTR element was up to two times higher than if their effects were purely additive. This result confirms that the combination of TOP 5'UTR element and albumin 3'UTR element effects a markedly synergistic increase in protein expression.
  • TOP 5'UTR elements increase protein expression from mRNA.
  • mRNAs comprising different TOP 5'UTR elements were synthesized.
  • mRNAs contained the albumin7 3'UTR element.
  • Luciferase encoding mRNAs were transfected into human dermal fibroblasts (HDF). Luciferase levels were measured at 24, 48, and 72 hours after transfection (see following Table 3 and Figure 22).
  • mRNAs comprising different UTR elements were synthesized: mRNAs either lacked both TOP 5'UTR element and albumin 3'UTR element, or contained an albumin 3'UTR element, or contained one of different TOP 5'UTR elements, or contained both one of different TOP 5'UTR elements and an albumin 3'UTR element.
  • Luciferase encoding mRNAs were transfected into human dermal fibroblasts (HDF). Luciferase levels were measured at 24, 48, and 72 hours after transfection (see Figures 23 to 30).
  • Luciferase was clearly expressed from mRNA having neither a TOP 5'UTR element nor an albumin 3'UTR element.
  • the albumin 3'UTR element extended luciferase expression, while TOP 5'UTR elements increased luciferase levels compared to mRNA lacking 5' and 3'UTRs. Strikingly however, the combinations of TOP 5'UTR elements and albumin 3'UTR element further strongly increased the luciferase level, much above the level observed with either of the individual elements.
  • the magnitude of the rise in luciferase level due to combining TOP 5'UTR element and albumin 3'UTR element in the same mRNA demonstrates that they are acting synergisti- cally.
  • the synergy between TOP 5'UTR element and albumin 3'UTR element was quantified by dividing the signal from mRNA combining both elements by the sum of the signal from mRNA lacking both elements plus the rise in signal effected by the TOP 5'UTR element plus the rise in signal effected by the albumin 3'UTR element. This calculation was performed for total protein expressed from 0 to 72 hours calculated from the area under the curve (AUC) (see following Table 4). Table 4:
  • the synergy thus calculated specifies how much higher the luciferase level from mRNA combining TOP 5'UTR elements and albumin 3'UTR element is than would be expected if the effects of TOP 5'UTR element and albumin 3'UTR element were purely additive.
  • the luciferase level from mRNA combining TOP 5'UTR element and albumin 3'UTR element was up to three times higher than if their effects were purely additive. This result confirms that the combination of TOP 5'UTR element and albumin 3'UTR element effects a markedly synergistic increase in protein expression.
  • TOP 5'UTR elements from mouse genes increase protein expression from mRNA.
  • mRNAs with two different mouse TOP 5'UTR elements were synthesized.
  • Luciferase encoding mRNAs were transfected into human dermal fibroblasts (HDF).
  • HDF human dermal fibroblasts
  • Luciferase levels were measured at 24, 48, and 72 hours after transfection (see following Table 5 and Figure 30). Table 5:
  • A2M alpha-2-macroglobulin
  • gctccttctttctgcaacatg (Seq ID No: 1)
  • ACADM acyl-CoA dehydrogenase
  • arylsulfatase E Chondrodysplasia punctata 1
  • ARSE arylsulfatase E : cttcctcttcttgatcggggattcaggaaggagcccaggagcagaggaagtagagagagagacaac atg (Seq ID No: 3 )
  • BTK Bruton agammaglobulinemia tyrosine kinase
  • CDK4 Homo sapiens cyclin-dependent kinase 4
  • cytochrome P450 family 17, subfamily A, polypeptide 1 (CYP17A1) : agctcttctactccactgctgtctatcttgcctgccggcacccagccaccatg (Seq ID No: 7)
  • GLC galactosylceramidase
  • GJB1 Homo sapiens gap junction protein, beta 1, 32kDa (GJB1) :
  • GPI glucose-6-phosphate isomerase
  • HSDHA HFDHA : ctgtcctcttcagctcaagatg (Seq ID No: 16)
  • SGCG 35kDa dystrophin-associated glycoprotein
  • LPL lipoprotein lipase
  • NPC1 Homo sapiens Niemann-Pick disease, type CI
  • PEX12 Homo sapiens peroxisomal biogenesis factor 12
  • PEX6 Homo sapiens peroxisomal biogenesis factor 6
  • PFKM phosphofructokinase, muscle
  • aldehyde dehydrogenase 3 family member A2 (ALDH3A2) : ccgcctcccactccccagcgcccccggaccgtgcagttctctgcaggaccaggccatg
  • BLMH Homo sapiens bleomycin hydrolase
  • CSK Homo sapiens cathepsin K
  • GM2A Homo sapiens GM2 ganglioside activator
  • HSD17B4 Homo sapiens hydroxysteroid (17-beta) dehydrogenase 4 (HSD17B4) : ccgcctcctcctgtcccgcagtcggcgtccagcggctctgcttgttcgtgtgtgtcgttgcagg ccttattcatg (Seq ID No: 34)
  • NCF2 neutrophil cytosolic factor 2
  • arylsulfatase A :
  • EPN Homo sapiens elastin
  • HBA2 Homo sapiens hemoglobin, alpha 2
  • HBA2 cactcttctggtccccaca- gactcagagagaacccaccatg
  • HEXB Homo sapiens hexosaminidase B (beta polypeptide)
  • MAN2B1 Homo sapiens mannosidase, alpha, class 2B, member 1 (MAN2B1) :
  • RAG2 Homo sapiens recombination activating gene 2
  • CD53 Homo sapiens CD53 molecule
  • Fc fragment of IgG, low affinity Ilia, receptor (CD16a) (FCGR3A) : tggtccctttagggctccggatatctttggtgacttgtccactccag- tgtggcatcatg (Seq ID No: 46)
  • IL1B Homo sapiens interleukin 1, beta
  • CD4 molecule CD4 :
  • serpin peptidase inhibitor clade A (al- pha-1 antiproteinase, antitrypsin) , member 5 (SERPINA5) :
  • VTN vitronectin
  • aldehyde dehydrogenase 9 family member Al (ALDH9A1) : ccgcccctcccgcggcccccgcccctcccgcggcccgtcagcctctgccgcggagctgcgtccgcca ctcatg (Seq ID No: 51)
  • ANXAl Homo sapiens annexin Al
  • ATP1A1 alpha 1 polypeptide
  • ATP1A2 alpha 2 polypeptide
  • CACNB3 Homo sapiens calcium channel, voltage-dependent, beta 3 subunit
  • cytochrome P450 family 51, subfamily A, polypeptide 1 (CYP51A1) :
  • HMGCR 3-hydroxy-3-methylglutaryl-CoA reductase
  • LTA4H Homo sapiens leukotriene A4 hydrolase
  • NPY1R neuropeptide Y receptor Yl
  • PDHB Homo sapiens pyruvate dehydrogenase (lipoamide) beta (PDHB) :
  • UDP-glucose pyrophosphorylase 2 (UGP2)
  • ATP1B1 beta 1 polypeptide
  • Homo sapiens wntless homolog (Drosophila) (WLS) :
  • MCTP1 transmembrane 1
  • cagcctcttttgccggtattcagtgaagaaagcaagtctaaatatgcagttctctcactggagtga aagatgttttgttcatttctaatcaactatg (Seq ID No: 74)
  • SMC4 Homo sapiens structural maintenance of chromosomes 4 :
  • GLE1 Homo sapiens GLEl RNA export mediator homolog (yeast) (GLE1) :
  • TAM6 Homo sapiens tripartite motif containing 6
  • gagtctttcggcctgggtggaggacgcggctgcttcaagtccttggctctgatccaggccacagat tccaggattctacaggcaggaaacatcttagaaatcagggttgggcaggcaggagccaggagagta gctacaatg (Seq ID No: 77)
  • EMI2A Homo sapiens ecotropic viral integration site 2A
  • HNRNPL Hemo sapiens heterogeneous nuclear ribonucleoprotein L
  • HNRNPL heterogeneous nuclear ribonucleoprotein L
  • MTIF2 mitochondrial translational initiation factor 2
  • NFKBIZ nuclear factor of kappa light polypeptide gene enhanc er in B-cells inhibitor
  • ERBB3 Homo sapiens v-erb-b2 erythroblastic leukemia viral oncogene homol og 3 (avian) (ERBB3) :
  • PDPN podoplanin
  • RRMl Homo sapiens ribonucleotide reductase Ml
  • Homo sapiens solute carrier family 2 (facilitated glucose transporter) , member 4 (SLC2A4) :
  • TBXAS1 Homo sapiens thromboxane A synthase 1 (platelet) (TBXAS1) :
  • TKT Homo sapiens transketolase
  • TNFRSF1A tumor necrosis factor receptor superfamily, member 1A
  • TUBB2A Homo sapiens tubulin, beta 2A class Ila
  • ADSS adenylosuccinate synthase
  • ANPEP Homo sapiens alanyl (membrane) aminopeptidase
  • BTF3 Homo sapiens basic transcription factor 3
  • Homo sapiens complement component 1, q subcomponent binding protei n (C1QBP) : ttgtcctttgcatctgcacgtgttcgcagtcgtttccgcgatg
  • CAV3 Homo sapiens caveolin 3
  • CD68 Homo sapiens CD68 molecule
  • gagcctctcctcaaagcctggctcccacggaaaatatgctcagtgcagccgcgtgcatgaatgaaaacgccgccgggcgcttctagtcggacaaaatg (Seq ID No: 102)
  • LIM domain binding 2 LIM domain binding 2
  • Homo sapiens chloride channel, nucleotide-sensitive, 1A (CLNS1A) : ctgcctcttccagggcgggcggtgtggtgcacgcattgctgtgctccaactccctcagggcctgtg ttgccgcactctgctgctatg (Seq ID No: 106)
  • CRMP1 collapsin response mediator protein 1
  • DGKA diacylglycerol kinase, alpha 80kDa
  • DARS Homo sapiens aspartyl-tRNA synthetase
  • DHYSL2 dihydropyrimidinase-like 2
  • DRG2 developmentally regulated GTP binding protein 2
  • EEF1A1 Homo sapiens eukaryotic translation elongation factor 1 alpha 1 (EEF1A1) :
  • EEF1G Homo sapiens eukaryotic translation elongation factor 1 gamma
  • EIF4B eukaryotic translation initiation factor 4B
  • Homo sapiens eukaryotic translation initiation factor 4 gamma, 2 (EIF4G2) : tattcttttgaagattcttcgttgtcaagccgccaaagtg
  • EMP1 epithelial membrane protein 1
  • FBL Homo sapiens fibrillarin
  • EXTL2 Homo sapiens exostoses (multiple) -like 2
  • Homo sapiens solute carrier family 37 (glucoses-phosphate transporter) , member 4 (SLC37A4) : ccgcctctgttcaggacactgggtccccttggagcctcccaggcttaatgattgtccagaaggcg gctataaagggagcctgggaggctgggtggaggagggagcagaaaaacccaactcagcagatctg ggaactgtgtgagagcggcaagcaggaactgtggtcagaggctgtgcgtcttggctggtagggcctgc tcttaccatg (Seq ID No: 123)
  • GDI2 Homo sapiens GDP dissociation inhibitor 2
  • GMDS GDP-mannose 4, 6-dehydratase
  • HDAC2 histone deacetylase 2
  • CD79A binding protein 1 IGBP1
  • IGBP1 gttcctctctccccaagatg
  • EIF3E Homo sapiens eukaryotic translation initiation factor 3, subunit E (EIF3E) : actcccttttctttggcaagatg (Seq ID No: 130)
  • ACAM activated leukocyte cell adhesion molecule
  • AOAH Homo sapiens acyloxyacyl hydrolase
  • ADP-ribosylation factor 1 ADP-ribosylation factor 1
  • ADP-ribosylation factor 6 ADP-ribosylation factor 6
  • RHOA Homo sapiens ras homolog family member A
  • Homo sapiens ras homolog family member G (RHOG) :
  • ATP synthase H+ transporting, mitochondrial Fl compl ex, 0 subunit (ATP50) : ctctcttcccactcgggtttgacctacagccgcccgggagaa- gatg (Seq ID No: 137)
  • B lymphoid tyrosine kinase BLK
  • BCG1 Homo sapiens B-cell translocation gene 1, anti-proliferative
  • CAMLG Homo sapiens calcium modulating ligand
  • CAV1 Homo sapiens caveolin 1, caveolae protein, 22kDa
  • CD1D Homo sapiens CDld molecule
  • CD22 Homo sapiens CD22 molecule
  • CD37 Homo sapiens CD37 molecule
  • CD38 Homo sapiens CD38 molecule
  • CD48 Homo sapiens CD48 molecule
  • chromogranin B secretogranin 1 (CHGB) :
  • cytochrome c oxidase subunit IV isoform 1 (COX4I1) : ctacccttttccgctccacggtgacctccgtgcggccgggtgcgggcggagtcttcctcgatcccg tggtgctccgcggcgcggccttgctcttccggtcgcgggacaccgggtgtagagggcggtcgcg gcgggcagtggcggcagaatg (Seq ID No: 152)
  • ATF2 Homo sapiens activating transcription factor 2
  • CSNK1A1 Homo sapiens casein kinase 1, alpha 1
  • DCTD Homo sapiens dCMP deaminase
  • DDB1 Homo sapiens damage-specific DNA binding protein 1, 127kDa (DDB1) : ctgtcttttcgcttgtgtccctctttctagtgtcgcgctcgagtcccgacgggccgctccaagcct cgacatg (Seq ID No: 158)
  • DES Homo sapiens desmin
  • DHPS deoxyhypusine synthase
  • ENRA Homo sapiens endothelin receptor type A
  • EEF1A2 Homo sapiens eukaryotic translation elongation factor 1 alpha 2
  • EEF2 Homo sapiens eukaryotic translation elongation factor 2 (EEF2) : cgttctcttccgccgtcgtcgccgccatcctcggcgcgactcgcttctttcggttctacctgggag aatccaccgccatccgccaccatg (Seq ID No: 165)
  • Homo sapiens eukaryotic translation initiation factor 4A2 Homo sapiens eukaryotic translation initiation factor 4A2
  • Homo sapiens enolase 2 (gamma, neuronal) (EN02) :
  • FMOD Homo sapiens fibromodulin
  • FTH1 Homo sapiens ferritin, heavy polypeptide 1 (FTH1) :
  • GPDH Homo sapiens glyceraldehyde-3-phosphate dehydrogenase (GAPDH) : cgctctctgctcctcctgttcgacagtcagccgcatcttcttttgcgtcgccagccgagccacatc gctcagacaccatg (Seq ID No: 174)
  • GAS glycyl-tRNA synthetase
  • GAT2 glutamic-oxaloacetic transaminase 2
  • GAT2 mitochondrial (aspartate aminotransferase 2)
  • GTF2F1 Homo sapiens general transcription factor IIF, polypeptide 1, 74kD a (GTF2F1) :
  • GYS1 Homo sapiens glycogen synthase 1 (muscle) (GYS1) :
  • Homo sapiens major histocompatibility complex class I, C (HLA-C) : cattctccccagaggccgagatg (Seq ID No: 179)
  • Homo sapiens major histocompatibility complex class II, DP beta 1 (HLA-DPB1) :
  • H GCS1 3-hydroxy-3-methylglutaryl-CoA synthase 1 (soluble)
  • HPCA Homo sapiens hippocalcin
  • Homo sapiens hydroxysteroid (17-beta) dehydrogenase 2 (HSD17B2) : ctcccttcttgactctctgttcacagaactcaggctgcctccagccagcctttgcccgctagactc actggccctgagcacttgaaggtgcagcaagtcactgagaatg (Seq ID No: 183)
  • Homo sapiens heat shock 60kDa protein 1 (chaperonin) (HSPD1) :
  • ICM3 intercellular adhesion molecule 3
  • IRF2 interferon regulatory factor 2
  • ITIH2 inter-alpha-trypsin inhibitor heavy chain 2
  • KPNBl Homo sapiens karyopherin (importin) beta 1 (KPNBl) :
  • KPNA3 Homo sapiens karyopherin alpha 3 (importin alpha 4) (KPNA3) :
  • LAMB1 Homo sapiens laminin, beta 1 (LAMB1) :
  • RPSA ribosomal protein SA
  • L-plastin lymphocyte cytosolic protein 1
  • LCP1 lymphocyte cytosolic protein 1
  • LGALS1 Homo sapiens lectin, galactoside-binding, soluble, 1
  • LGALS1 Homo sapiens lectin, galactoside-binding, soluble, 1
  • MAN2A1 Homo sapiens mannosidase, alpha, class 2A, member 1 (MAN2A1) :
  • MBP myelin basic protein
  • M1R melanocortin 1 receptor
  • MEF2C myocyte enhancer factor 2C
  • GAT1 Homo sapiens mannosyl (al- pha-1, 3-) -glycoprotein beta-1, 2-N-acetylglucosaminyltransferase ( GAT1) :
  • mitogen-activated protein kinase kinase kinase 11 (MAP3K11) :
  • NCBPl nuclear cap binding protein subunit 1, 80kDa
  • tggcctctcggttccgcggcgcaccggagggcagcatg (Seq ID No: 206)
  • NNN Homo sapiens necdin homolog
  • NADH dehydrogenase ubiquinone
  • Fe-S protein 4 18kDa (NADH-coenzyme Q reductase) (NDUFS4) :
  • NFKB2 Homo sapiens nuclear factor of kappa light polypeptide gene enhanc er in B-cells 2 (p49/pl00) (NFKB2) :
  • NME2 Homo sapiens non-metastatic cells 2, protein (NM23B) expressed in (NME2) :
  • nucleophosmin nucleolar phosphoprotein B23, numatrin
  • N5E Homo sapiens 5 ' -nucleotidase, ecto (CD73) (NT5E) :
  • PEBP1 Homo sapiens phosphatidylethanolamine binding protein 1 (PEBP1) : gcgtcttcccgagccagtgtgctgagctctccgcgtcgcctctgtcgcgcctggcctaccgc ggcactcccggctgcacgctctgcttggcctcgccatg (Seq ID No: 214)
  • PTD phosphogluconate dehydrogenase
  • PGM1 Homo sapiens phosphoglucomutase 1
  • Homo sapiens solute carrier family 25 (mitochon- drial carrier; phosphate carrier) , member 3 (SLC25A3) :
  • PIMl pim-1 oncogene
  • PLM2 Homo sapiens pyruvate kinase, muscle
  • PLD2 Homo sapiens phospholipase D2
  • PGP2 colonic epithelium-enriched
  • PPAT phosphoribosyl pyrophosphate amidotransferase
  • Homo sapiens protein phosphatase 1, catalytic subunit, gamma isozy me PPP1CC:
  • Homo sapiens protein phosphatase 1, regulatory subunit 8 PPP1R8
  • PPP1R8 protein phosphatase 1, regulatory subunit 8
  • Homo sapiens protein phosphatase 6, catalytic subunit PPP6C: cggcctccgccgctgccgccgctgctacagccgccgccgctgttgccgcggcttgttatt cttaaatg (Seq ID No: 229)
  • mitogen-activated protein kinase 6 MAPK6
  • PRPSAP1 Homo sapiens phosphoribosyl pyrophosphate synthetase-associated pr otein 1 (PRPSAP1) :

Abstract

The invention relates to an artificial nucleic acid molecule comprising at least one 5'UTR element which is derived from a TOP gene, at least one open reading frame and optionally at least one 3'UTR element comprising a nucleic acid sequence which is preferably derived from the 3'UTR of a gene providing a stable mRNA, such as an albumin gene, or from a variant of the 3'UTR of a gene providing a stable mRNA. The invention further relates to the use of such an artificial nucleic acid molecule in gene therapy and/or genetic vaccination.

Description

Artificial nucleic acid molecules comprising a 5'TOP UTR
The invention relates to artificial nucleic acid molecules comprising a 5'UTR element derived from the 5'UTR of a TOP gene, an open reading frame, and optionally a 3'UTR element, a poly(A) sequence and/or a polyadenylation signal. The invention relates further to a vector comprising a 5'UTR element derived from the 5'UTR of a TOP gene, to a pharmaceutical composition comprising the artificial nucleic acid molecule or the vector, and to a kit comprising the artificial nucleic acid molecule, the vector and/or the pharmaceutical composition, preferably for use in the field of gene therapy and/or genetic vaccination. Gene therapy and genetic vaccination belong to the most promising and quickly developing methods of modern medicine. They may provide highly specific and individual options for therapy of a large variety of diseases. Particularly, inherited genetic diseases but also autoimmune diseases, cancerous or tumour-related diseases as well as inflammatory diseases may be the subject of such treatment approaches. Also, it is envisaged to prevent (early) onset of such diseases by these approaches.
The main conceptual rational behind gene therapy is appropriate modulation of impaired gene expression associated with pathological conditions of specific diseases. Pathologically altered gene expression may result in lack or overproduction of essential gene products, for example, signalling factors such as hormones, housekeeping factors, metabolic enzymes, structural proteins or the like. Altered gene expression may not only be due to mis- regulation of transcription and/or translation, but also due to mutations within the ORF coding for a particular protein. Pathological mutations may be caused by e.g. chromosomal aberration, or by more specific mutations, such as point or frame-shift-mutations, all of them resulting in limited functionality and, potentially, total loss of function of the gene product. However, misregulation of transcription or translation may also occur, if mutations affect genes encoding proteins which are involved in the transcriptional or translational machinery of the cell. Such mutations may lead to pathological up- or down-regulation of genes which are - as such - functional. Genes encoding gene products which exert such regulating functions, may be, e.g., transcription factors, signal receptors, messenger proteins or the like. However, loss of function of such genes encoding regulatory proteins may, under certain circumstances, be reversed by artificial introduction of other factors acting further downstream of the impaired gene product. Such gene defects may also be compensated by gene therapy via substitution of the affected gene itself.
Genetic vaccination allows evoking a desired immune response to selected antigens, such as characteristic components of bacterial surfaces, viral particles, tumour antigens or the like. Generally, vaccination is one of the pivotal achievements of modern medicine. However, effective vaccines are currently available only for a smaller number of diseases. Accordingly, infections that are not preventable by vaccination still affect millions of people every year.
Commonly, vaccines may be subdivided into "first", "second" and "third" generation vaccines. "First generation" vaccines are, typically, whole-organism vaccines. They are based on either live and attenuated or killed pathogens, e.g. viruses, bacteria or the like. The major drawback of live and attenuated vaccines is the risk for a reversion to life- threatening variants. Thus, although attenuated, such pathogens may still intrinsically bear unpredictable risks. Killed pathogens may not be as effective as desired for generating a specific immune response. In order to minimize these risks, "second generation" vaccines were developed. These are, typically, subunit vaccines, consisting of defined antigens or recombinant protein components which are derived from pathogens.
Genetic vaccines, i.e. vaccines for genetic vaccination, are usually understood as "third generation" vaccines. They are typically composed of genetically engineered nucleic acid molecules which allow expression of peptide or protein (antigen) fragments characteristic for a pathogen or a tumor antigen in vivo. Genetic vaccines are expressed upon administration to a patient and uptake by competent cells. Expression of the administered nucleic acids results in production of the encoded proteins. In the event these proteins are recognized as foreign by the patient's immune system, an immune response is triggered.
As can be seen from the above, both methods, gene therapy and genetic vaccination, are essentially based on the administration of nucleic acid molecules to a patient and subsequent transcription and/or translation of the encoded genetic information. Alternatively, genetic vaccination or gene therapy may also comprise methods which include isolation of specific body cells from a patient to be treated, subsequent in vitro transfection of such cells, and re-administration of the treated cells to the patient.
DNA as well as RNA may be used as nucleic acid molecules for administration in the context of gene therapy or genetic vaccination. DNA is known to be relatively stable and easy to handle. However, the use of DNA bears the risk of undesired insertion of the administered DNA-fragments into the patient's genome potentially resulting in loss of function of the impaired genes. As a further risk, the undesired generation of anti-DNA antibodies has emerged. Another drawback is the limited expression level of the encoded peptide or protein that is achievable upon DNA administration and its transcription/translation. Among other reasons, the expression level of the administered DNA will be dependent on the presence of specific transcription factors which regulate DNA transcription. In the absence of such factors, DNA transcription will not yield satisfying amounts of RNA. As a result, the level of translated peptide or protein obtained is limited.
By using RNA instead of DNA for gene therapy or genetic vaccination, the risk of undesired genomic integration and generation of anti-DNA antibodies is minimized or avoided. However, RNA is considered to be a rather unstable molecular species which may readily be degraded by ubiquitous RNAses.
In vivo, RNA-degradation contributes to the regulation of the RNA half-life time. That effect was considered and proven to fine tune the regulation of eukaryotic gene expression (Friedel et a/., Conserved principles of mammalian transcriptional regulation revealed by RNA half-life, Nucleic Acid Research, 2009, 1 -12). Accordingly, each naturally occurring mRNA has its individual half-life depending on the gene from which the mRNA is derived. It contributes to the regulation of the expression level of this gene. Unstable RNAs are important to realize transient gene expression at distinct points in time. However, long-lived RNAs may be associated with accumulation of distinct proteins or continuous expression of genes. In vivo, the half life of mRNAs may also be dependent on environmental factors, such as hormonal treatment, as has been shown, e.g., for insulin-like growth factor I, actin, and albumin mRNA Gohnson et a/., Newly synthesized RNA: Simultaneous measurement in intact cells of transcription rates and RNA stability of insulin-like growth factor I, actin, and albumin in growth hormone-stimulated hepatocytes, Proc. Natl. Acad. Sci., Vol. 88, pp. 5287-5291 , 1991 ).
For gene therapy and genetic vaccination, usually stable RNA is desired. This is, on the one hand, due to the fact that the product encoded by the RNA-sequence shall accumulate in vivo. On the other hand, the RNA has to maintain its structural and functional integrity when prepared for a suitable dosage form, in the course of its storage, and when administered. Thus, considerable attention was dedicated to provide stable RNA molecules for gene therapy or genetic vaccination in order to prevent them from being subject to early degradation or decay. It has been reported that the G/C-content of nucleic acid molecules may influence their stability. Thus, nucleic acids comprising an increased amount of guanine (G) and/or cytosine (C) residues may be functionally more stable than nucleic acids containing a large amount of adenine (A) and thymine (T) or uracil (U) nucleotides. In this context, WO02/098443 provides a pharmaceutical composition containing an mRNA that is stabilised by sequence modifications in the translated region. Such a sequence modification takes advantage of the degeneracy of the genetic code. Accordingly, codons which contain a less favourable combination of nucleotides (less favourable in terms of RNA stability) may be substituted by alternative codons without altering the encoded amino acid sequence. This method of RNA stabilization is limited by the provisions of the specific nucleotide sequence of each single RNA molecule which is not allowed to leave the space of the desired amino acid sequence. Also, that approach is restricted to coding regions of the RNA.
As an alternative option for mRNA stabilisation, it has been found that naturally occurring eukaryotic mRNA molecules contain characteristic stabilising elements. For example, they may comprise so-called untranslated regions (UTR) at their 5'-end (5'UTR) and/or at their 3'- end (3'UTR) as well as other structural features, such as a 5'-cap structure or a 3'- poly(A) tail. Both, 5'UTR and 3'UTR are typically transcribed from the genomic DNA and are, thus, an element of the premature mRNA. Characteristic structural features of mature mRNA, such as the 5'-cap and the 3'-poly(A) tail (also called poly(A) tail or poly(A) sequence) are usually added to the transcribed (premature) mRNA during mRNA processing.
A 3'-poly(A) tail is typically a monotonous sequence stretch of adenine nucleotides added to the 3 '-end of the transcribed mRNA. It may comprise up to about 400 adenine nucleotides. It was found that the length of such a 3'-poly(A) tail is a potentially critical element for the stability of the individual mRNA. Also, it was shown that the 3'UTR of a-globin mRNA may be an important factor for the well-known stability of α-globin mRNA (Rodgers et a/., Regulated α-globin mRNA decay is a cytoplasmic event proceeding through 3'-to-5' exosome-dependent decapping, RNA, 8, pp. 1526-1537, 2002). The 3'UTR of α-globin mRNA is obviously involved in the formation of a specific ribonucleoprotein-complex, the a-complex, whose presence correlates with mRNA stability in vitro (Wang et a/., An mRNA stability complex functions with poly(A)-binding protein to stabilize mRNA in vitro, Molecular and Cellular biology, Vol 19, No. 7, July 1999, p. 4552-4560).
Irrespective of factors influencing mRNA stability, effective translation of the administered nucleic acid molecules by the target cells or tissue is crucial for any approach using nucleic acid molecules for gene therapy or genetic vaccination. Along with the regulation of stability, also translation of the majority of mRNAs is regulated by structural features like UTRs, 5'-cap and 3'-poly(A) tail. In this context, it has been reported that the length of the poly(A) tail may play an important role for translational efficiency as well. Stabilizing 3'- elements, however, may also have an attenuating effect on translation. Further regulative elements, which may have an influence on expression levels, may be found in the 5'UTR. For example, it has been reported that synthesis of particular proteins, e.g. proteins belonging to the translational apparatus, may be regulated not only at the transcriptional but also at the translational level. For example, translation of proteins encoded by so called 'TOP-genes' may be down-regulated by translational repression. Therein, the term 'TOP-gene' relates to a gene corresponding to an mRNA that is characterized by the presence of a TOP sequence at the 5'end and in most cases by a growth-associated translation regulation (ladevaia et a/., All translation elongation factors and the e, f, and h subunits of translation initiation factor 3 are encoded by 5'-terminal oligopyrimidine (TOP) mRNAs; RNA, 2008, 14:1 730-1 736). In this context, a TOP sequence - also called the '5'-terminal oligopyrimidine tract' - typically consists of a C residue at the cap site, followed by an uninterrupted sequence of up to 13 or even more pyrimidines (Avni et a/., Vertebrate mRNAs with a 5'-terminal pyrimidine tract are Candidates for translational repression in quiescent cells: characterization of the translational cis-regulatory element, Molecular and Cellular Biology, 1994, p. 3822-3833). These TOP sequences are reported to be present in many mRNAs encoding components of the translational machinery and to be responsible for selective repression of the translation of these TOP containing mRNAs due to growth arrest (Meyuhas, eta/., Translational Control of Ribosomal Protein mRNAs in Eukaryotes, Translational Control. Cold Spring Harbor Monograph Archive. Cold Spring Harbor Laboratory Press, 1996, p. 363-388). These TOP sequences are thought to serve as a cis-regulatory element which inhibits the binding of translational regulatory proteins or the translational machinery itself. As a result, the translation of these genes is inhibited at the growth arrest of cells. More specifically, when a cell is faced with starvation or treated by some chemicals such as 12-Otetradecanoyl-1 - phorbol-13-acetate (TPA), mRNAs of TOP genes, which are normally associated with polysomes, change their status into the translational ly inactive 'sub-polysome' while most non-TOP mRNAs stay in the'polysome' state (Yamashita et a/., Comprehensive detection of human terminal oligo-pyrimidine (TOP) genes and analysis of their characteristics. Nucleic Acids Res. 2008 Jun;36(1 1 ):3707-15. doi: 10.1093/nar/gkn248. Epub 2008 May 14). In this context, it was shown that the oligopyrimidine tract at the 5'end of the 5'UTR (TOP motif) was required for translational repression of TOP genes. The oligopyrimidine tract at the 5' end of mammalian ribosomal protein mRNAs is required for their translational control (Levy et a/., Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):331 9-23). Furthermore, it was shown that miRNA miR-10a positively controls the translation of ribosomal proteins by binding downstream of the TOP motif present in the 5'UTRs of TOP genes. Such an enhancement of translation was dependent on the presence of the TOP motif in the 5'UTR. Furthermore this translational regulation of ribosomal TOP genes was dependent on the presence of miR-10a or its human homolog miR-10b which is highly overexpressed in several tumor types and is reportedly involved in the progression of cancer (0rom et a/., MicroRNA-10a binds the 5'UTR of ribosomal protein mRNAs and enhances their translation. Mol Cell. 2008 May 23;30(4):460-71 ).
It is the object of the invention to provide nucleic acid molecules which may be suitable for application in gene therapy and/or genetic vaccination. Particularly, it is the object of the invention to provide artificial nucleic acid molecules, such as an mRNA species, which provide for increased protein production from said artificial nucleic acid molecules, preferably which exhibit increased translational efficiency. Another object of the present invention is to provide nucleic acid molecules coding for such a superior mRNA species which may be amenable for use in gene therapy and/or genetic vaccination. It is a further object of the present invention to provide a pharmaceutical composition for use in gene therapy and/or genetic vaccination. In summary, it is the object of the present invention to provide improved nucleic acid species which overcome the above discussed disadvantages of the prior art by a cost-effective and straight-forward approach. The object underlying the present invention is solved by the claimed subject-matter.
For the sake of clarity and readability the following definitions are provided. Any technical feature mentioned for these definitions may be read on each and every embodiment of the invention. Additional definitions and explanations may be specifically provided in the context of these embodiments. Adaptive immune response: The adaptive immune response is typically understood to be an antigen-specific response of the immune system. Antigen specificity allows for the generation of responses that are tailored to specific pathogens or pathogen-infected cells. The ability to mount these tailored responses is usually maintained in the body by "memory cells". Should a pathogen infect the body more than once, these specific memory cells are used to quickly eliminate it. In this context, the first step of an adaptive immune response is the activation of naive antigen-specific T cells or different immune cells able to induce an antigen-specific immune response by antigen-presenting cells. This occurs in the lymphoid tissues and organs through which naive T cells are constantly passing. The three cell types that may serve as antigen-presenting cells are dendritic cells, macrophages, and B cells. Each of these cells has a distinct function in eliciting immune responses. Dendritic cells may take up antigens by phagocytosis and macropinocytosis and may become stimulated by contact with e.g. a foreign antigen to migrate to the local lymphoid tissue, where they differentiate into mature dendritic cells. Macrophages ingest particulate antigens such as bacteria and are induced by infectious agents or other appropriate stimuli to express MHC molecules. The unique ability of B cells to bind and internalize soluble protein antigens via their receptors may also be important to induce T cells. MHC-molecules are, typically, responsible for presentation of an antigen to T-cells. Therein, presenting the antigen on MHC molecules leads to activation of T cells which induces their proliferation and differentiation into armed effector T cells. The most important function of effector T cells is the killing of infected cells by CD8+ cytotoxic T cells and the activation of macrophages by Th1 cells which together make up cell-mediated immunity, and the activation of B cells by both Th2 and Th1 cells to produce different classes of antibody, thus driving the humoral immune response. T cells recognize an antigen by their T cell receptors which do not recognize and bind the antigen directly, but instead recognize short peptide fragments e.g. of pathogen-derived protein antigens, e.g. so-called epitopes, which are bound to MHC molecules on the surfaces of other cells.
Adaptive immune system: The adaptive immune system is essentially dedicated to eliminate or prevent pathogenic growth. It typically regulates the adaptive immune response by providing the vertebrate immune system with the ability to recognize and remember specific pathogens (to generate immunity), and to mount stronger attacks each time the pathogen is encountered. The system is highly adaptable because of somatic hypermutation (a process of accelerated somatic mutations), and V(D)J recombination (an irreversible genetic recombination of antigen receptor gene segments). This mechanism allows a small number of genes to generate a vast number of different antigen receptors, which are then uniquely expressed on each individual lymphocyte. Because the gene rearrangement leads to an irreversible change in the DNA of each cell, all of the progeny (offspring) of such a cell will then inherit genes encoding the same receptor specificity, including the Memory B cells and Memory T cells that are the keys to long-lived specific immunity.
Adjuvant/adjuvant component: An adjuvant or an adjuvant component in the broadest sense is typically a pharmacological and/or immunological agent that may modify, e.g. enhance, the effect of other agents, such as a drug or vaccine. It is to be interpreted in a broad sense and refers to a broad spectrum of substances. Typically, these substances are able to increase the immunogenicity of antigens. For example, adjuvants may be recognized by the innate immune systems and, e.g., may elicit an innate immune response. "Adjuvants" typically do not elicit an adaptive immune response. Insofar, "adjuvants" do not qualify as antigens. Their mode of action is distinct from the effects triggered by antigens resulting in an adaptive immune response.
Antigen: In the context of the present invention "antigen" refers typically to a substance which may be recognized by the immune system, preferably by the adaptive immune system, and is capable of triggering an antigen-specific immune response, e.g. by formation of antibodies and/or antigen-specific T cells as part of an adaptive immune response. Typically, an antigen may be or may comprise a peptide or protein which may be presented by the MHC to T-cells.
Artificial nucleic acid molecule: An artificial nucleic acid molecule may typically be understood to be a nucleic acid molecule, e.g. a DNA or an RNA, that does not occur naturally. In other words, an artificial nucleic acid molecule may be understood as a non- natural nucleic acid molecule. Such nucleic acid molecule may be non-natural due to its individual sequence (which does not occur naturally) and/or due to other modifications, e.g. structural modifications of nucleotides which do not occur naturally. An artificial nucleic acid molecule may be a DNA molecule, an RNA molecule or a hybrid-molecule comprising DNA and RNA portions. Typically, artificial nucleic acid molecules may be designed and/or generated by genetic engineering methods to correspond to a desired artificial sequence of nucleotides (heterologous sequence). In this context an artificial sequence is usually a sequence that may not occur naturally, i.e. it differs from the wild type sequence by at least one nucleotide. The term 'wild type' may be understood as a sequence occurring in nature. Further, the term 'artificial nucleic acid molecule' is not restricted to mean 'one single molecule' but is, typically, understood to comprise an ensemble of identical molecules. Accordingly, it may relate to a plurality of identical molecules contained in an aliquot.
Bicistronic RNA, multicistronic RNA: A bicistronic or multicistronic RNA is typically an RNA, preferably an mRNA, that typically may have two (bicistronic) or more (multicistronic) open reading frames (ORF). An open reading frame in this context is a sequence of codons that is translatable into a peptide or protein. Carrier / polymeric carrier: A carrier in the context of the invention may typically be a compound that facilitates transport and/or complexation of another compound (cargo). A polymeric carrier is typically a carrier that is formed of a polymer. A carrier may be associated to its cargo by covalent or non-covalent interaction. A carrier may transport nucleic acids, e.g. RNA or DNA, to the target cells. The carrier may - for some embodiments - be a cationic component.
Cationic component: The term "cationic component" typically refers to a charged molecule, which is positively charged (cation) at a pH value typically from 1 to 9, preferably at a pH value of or below 9 (e.g. from 5 to 9), of or below 8 (e.g. from 5 to 8), of or below 7 (e.g. from 5 to 7), most preferably at a physiological pH, e.g. from 7.3 to 7.4. Accordingly, a cationic component may be any positively charged compound or polymer, preferably a cationic peptide or protein which is positively charged under physiological conditions, particularly under physiological conditions in vivo. A 'cationic peptide or protein' may contain at least one positively charged amino acid, or more than one positively charged amino acid, e.g. selected from Arg, His, Lys or Orn. Accordingly, 'polycationic' components are also within the scope exhibiting more than one positive charge under the conditions given.
5'-cap: A 5'-cap is an entity, typically a modified nucleotide entity, which generally
'caps' the 5'-end of a mature mRNA. A 5 '-cap may typically be formed by a modified nucleotide, particularly by a derivative of a guanine nucleotide. Preferably, the 5'-cap is linked to the 5'-terminus via a 5'-5'-triphosphate linkage. A 5'-cap may be methylated, e.g. m7GpppN, wherein N is the terminal 5' nucleotide of the nucleic acid carrying the 5'-cap, typically the 5'-end of an RNA. Further examples of 5'cap structures include glyceryl, inverted deoxy abasic residue (moiety), 4', 5' methylene nucleotide, 1 -(beta-D- erythrofuranosyl) nucleotide, 4'-thio nucleotide, carbocyclic nucleotide, 1 ,5-anhydrohexitol nucleotide, L-nucleotides, alpha-nucleotide, modified base nucleotide, threo-pentofuranosyl nucleotide, acyclic 3',4'-seco nucleotide, acyclic 3,4-dihydroxybutyl nucleotide, acyclic 3,5 dihydroxypentyl nucleotide, 3 '-3 '-inverted nucleotide moiety, 3 '-3 '-inverted abasic moiety, 3'-2'-inverted nucleotide moiety, 3'-2'-inverted abasic moiety, 1 ,4-butanediol phosphate, 3'-phosphoramidate, hexylphosphate, aminohexyl phosphate, 3'-phosphate, 3'phosphorothioate, phosphorodithioate, or bridging or non-bridging methylphosphonate moiety. Cellular immunity/cellular immune response: Cellular immunity relates typically to the activation of macrophages, natural killer cells (NK), antigen-specific cytotoxic T- lymphocytes, and the release of various cytokines in response to an antigen. In more general terms, cellular immunity is not based on antibodies, but on the activation of cells of the immune system. Typically, a cellular immune response may be characterized e.g. by activating antigen-specific cytotoxic T-lymphocytes that are able to induce apoptosis in cells, e.g. specific immune cells like dendritic cells or other cells, displaying epitopes of foreign antigens on their surface. Such cells may be virus-infected or infected with intracellular bacteria, or cancer cells displaying tumor antigens. Further characteristics may be activation of macrophages and natural killer cells, enabling them to destroy pathogens and stimulation of cells to secrete a variety of cytokines that influence the function of other cells involved in adaptive immune responses and innate immune responses.
DNA: DNA is the usual abbreviation for deoxy-ribonucleic-acid. It is a nucleic acid molecule, i.e. a polymer consisting of nucleotides. These nucleotides are usually deoxy- adenosine-monophosphate, deoxy-thymidine-monophosphate, deoxy-guanosine- monophosphate and deoxy-cytidine-monophosphate monomers which are - by themselves - composed of a sugar moiety (deoxyribose), a base moiety and a phosphate moiety, and polymerize by a characteristic backbone structure. The backbone structure is, typically, formed by phosphodiester bonds between the sugar moiety of the nucleotide, i.e. deoxyribose, of a first and a phosphate moiety of a second, adjacent monomer. The specific order of the monomers, i.e. the order of the bases linked to the sugar/phosphate-backbone, is called the DNA-sequence. DNA may be single stranded or double stranded. In the double stranded form, the nucleotides of the first strand typically hybridize with the nucleotides of the second strand, e.g. by A/T-base-pairing and G/C-base-pairing. Epitope: Epitopes (also called 'antigen determinant') can be distinguished in T cell epitopes and B cell epitopes. T cell epitopes or parts of the proteins in the context of the present invention may comprise fragments preferably having a length of about 6 to about 20 or even more amino acids, e.g. fragments as processed and presented by MHC class I molecules, preferably having a length of about 8 to about 10 amino acids, e.g. 8, 9, or 10, (or even 1 1 , or 12 amino acids), or fragments as processed and presented by MHC class II molecules, preferably having a length of about 13 or more amino acids, e.g. 13, 14, 15, 1 6, 1 7, 18, 19, 20 or even more amino acids, wherein these fragments may be selected from any part of the amino acid sequence. These fragments are typically recognized by T cells in form of a complex consisting of the peptide fragment and an MHC molecule, i.e. the fragments are typically not recognized in their native form. B cell epitopes are typically fragments located on the outer surface of (native) protein or peptide antigens as defined herein, preferably having 5 to 15 amino acids, more preferably having 5 to 12 amino acids, even more preferably having 6 to 9 amino acids, which may be recognized by antibodies, i.e. in their native form.
Such epitopes of proteins or peptides may furthermore be selected from any of the herein mentioned variants of such proteins or peptides. In this context antigenic determinants can be conformational or discontinuous epitopes which are composed of segments of the proteins or peptides as defined herein that are discontinuous in the amino acid sequence of the proteins or peptides as defined herein but are brought together in the three-dimensional structure or continuous or linear epitopes which are composed of a single polypeptide chain. Fragment of a sequence: A fragment of a sequence may typically be a shorter portion of a full-length sequence of e.g. a nucleic acid molecule or an amino acid sequence. Accordingly, a fragment, typically, consists of a sequence that is identical to the corresponding stretch within the full-length sequence. A preferred fragment of a sequence in the context of the present invention, consists of a continuous stretch of entities, such as nucleotides or amino acids corresponding to a continuous stretch of entities in the molecule the fragment is derived from, which represents at least 20%, preferably at least 30%, more preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, and most preferably at least 80% of the total (i.e. full- length) molecule from which the fragment is derived. G/C modified: A G/C-modified nucleic acid may typically be a nucleic acid, preferably an artificial nucleic acid molecule as defined herein, based on a modified wild- type sequence comprising a preferably increased number of guanosine and/or cytosine nucleotides as compared to the wild-type sequence. Such an increased number may be generated by substitution of codons containing adenosine or thymidine nucleotides by codons containing guanosine or cytosine nucleotides. If the enriched G/C content occurs in a coding region of DNA or RNA, it makes use of the degeneracy of the genetic code. Accordingly, the codon substitutions preferably do not alter the encoded amino acid residues, but exclusively increase the G/C content of the nucleic acid molecule.
Gene therapy: Gene therapy may typically be understood to mean a treatment of a patient's body or isolated elements of a patient's body, for example isolated tissues/cells, by nucleic acids encoding a peptide or protein. It typically may comprise at least one of the steps of a) administration of a nucleic acid, preferably an artificial nucleic acid molecule as defined herein, directly to the patient - by whatever administration route - or in vitro to isolated cells/tissues of the patient, which results in transfection of the patient's cells either in vivo/ex vivo or in vitro, b) transcription and/or translation of the introduced nucleic acid molecule; and optionally c) re-administration of isolated, transfected cells to the patient, if the nucleic acid has not been administered directly to the patient.
Genetic vaccination: Genetic vaccination may typically be understood to be vaccination by administration of a nucleic acid molecule encoding an antigen or an immunogen or fragments thereof. The nucleic acid molecule may be administered to a subject's body or to isolated cells of a subject. Upon transfection of certain cells of the body or upon transfection of the isolated cells, the antigen or immunogen may be expressed by those cells and subsequently presented to the immune system, eliciting an adaptive, i.e. antigen- specific immune response. Accordingly, genetic vaccination typically comprises at least one of the steps of a) administration of a nucleic acid, preferably an artificial nucleic acid molecule as defined herein, to a subject, preferably a patient, or to isolated cells of a subject, preferably a patient, which usually results in transfection of the subject's cells either in vivo or in vitro, b) transcription and/or translation of the introduced nucleic acid molecule; and optionally c) re-administration of isolated, transfected cells to the subject, preferably the patient, if the nucleic acid has not been administered directly to the patient. Heterologous sequence: Two sequences are typically understood to be 'heterologous' if they are not derivable from the same gene. I.e., although heterologous sequences may be derivable from the same organism, they naturally (in nature) do not occur in the same nucleic acid molecule, such as in the same mRNA.
Humoral immunity/humoral immune response: Humoral immunity refers typically to antibody production and optionally to accessory processes accompanying antibody production. A humoral immune response may be typically characterized, e.g., by Th2 activation and cytokine production, germinal center formation and isotype switching, affinity maturation and memory cell generation. Humoral immunity also typically may refer to the effector functions of antibodies, which include pathogen and toxin neutralization, classical complement activation, and opsonin promotion of phagocytosis and pathogen elimination.
Immunogen: In the context of the present invention an immunogen may be typically understood to be a compound that is able to stimulate an immune response. Preferably, an immunogen is a peptide, polypeptide, or protein. In a particularly preferred embodiment, an immunogen in the sense of the present invention is the product of translation of a provided nucleic acid molecule, preferably an artificial nucleic acid molecule as defined herein. Typically, an immunogen elicits at least an adaptive immune response.
Immunostimulatory composition: In the context of the invention, an immunostimulatory composition may be typically understood to be a composition containing at least one component which is able to induce an immune response or from which a component which is able to induce an immune response is derivable. Such immune response may be preferably an innate immune response or a combination of an adaptive and an innate immune response. Preferably, an immunostimulatory composition in the context of the invention contains at least one artificial nucleic acid molecule, more preferably an RNA, for example an mRNA molecule. The immunostimulatory component, such as the mRNA may be complexed with a suitable carrier. Thus, the immunostimulatory composition may comprise an mRNA/carrier-complex. Furthermore, the immunostimulatory composition may comprise an adjuvant and/or a suitable vehicle for the immunostimulatory component, such as the mRNA.
Immune response: An immune response may typically be a specific reaction of the adaptive immune system to a particular antigen (so called specific or adaptive immune response) or an unspecific reaction of the innate immune system (so called unspecific or innate immune response), or a combination thereof.
Immune system: The immune system may protect organisms from infection. If a pathogen succeeds in passing a physical barrier of an organism and enters this organism, the innate immune system provides an immediate, but non-specific response. If pathogens evade this innate response, vertebrates possess a second layer of protection, the adaptive immune system. Here, the immune system adapts its response during an infection to improve its recognition of the pathogen. This improved response is then retained after the pathogen has been eliminated, in the form of an immunological memory, and allows the adaptive immune system to mount faster and stronger attacks each time this pathogen is encountered. According to this, the immune system comprises the innate and the adaptive immune system. Each of these two parts typically contains so called humoral and cellular components.
Immunostimulatory RNA: An immunostimulatory RNA (isRNA) in the context of the invention may typically be an RNA that is able to induce an innate immune response. It usually does not have an open reading frame and thus does not provide a peptide-antigen or immunogen but elicits an immune response e.g. by binding to a specific kind of Toll-like- receptor (TLR) or other suitable receptors. However, of course also mRNAs having an open reading frame and coding for a peptide/protein may induce an innate immune response and, thus, may be immunostimulatory RNAs. Innate immune system: The innate immune system, also known as non-specific (or unspecific) immune system, typically comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner. This means that the cells of the innate system may recognize and respond to pathogens in a generic way, but unlike the adaptive immune system, it does not confer long-lasting or protective immunity to the host. The innate immune system may be, e.g., activated by ligands of Toll-like receptors (TLRs) or other auxiliary substances such as lipopolysaccharides, TNF-alpha, CD40 ligand, or cytokines, monokines, lymphokines, interleukins or chemokines, IL-1 , IL-2, IL-3, IL-4, IL- 5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-1 1 , IL-12, IL-13, IL-14, IL-15, IL-16, IL-1 7, IL-18, IL-19, IL- 20, IL-21 , IL-22, IL-23, IL-24, IL-25, IL-26, IL-27, IL-28, IL-29, IL-30, IL-31 , IL-32, IL-33, IFN- alpha, IFN-beta, IFN-gamma, GM-CSF, G-CSF, M-CSF, LT-beta, TNF-alpha, growth factors, and hGH, a ligand of human Toll-like receptor TLR1 , TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, a ligand of murine Toll-like receptor TLR1 , TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR1 1 , TLR12 or TLR13, a ligand of a NOD-like receptor, a ligand of a RIG-I like receptor, an immunostimulatory nucleic acid, an immunostimulatory RNA (isRNA), a CpG-DNA, an antibacterial agent, or an anti-viral agent. The pharmaceutical composition according to the present invention may comprise one or more such substances. Typically, a response of the innate immune system includes recruiting immune cells to sites of infection, through the production of chemical factors, including specialized chemical mediators, called cytokines; activation of the complement cascade; identification and removal of foreign substances present in organs, tissues, the blood and lymph, by specialized white blood cells; activation of the adaptive immune system; and/or acting as a physical and chemical barrier to infectious agents.
Cloning site: A cloning site is typically understood to be a segment of a nucleic acid molecule, which is suitable for insertion of a nucleic acid sequence, e.g., a nucleic acid sequence comprising an open reading frame. Insertion may be performed by any molecular biological method known to the one skilled in the art, e.g. by restriction and ligation. A cloning site typically comprises one or more restriction enzyme recognition sites (restriction sites). These one or more restrictions sites may be recognized by restriction enzymes which cleave the DNA at these sites. A cloning site which comprises more than one restriction site may also be termed a multiple cloning site (MCS) or a polylinker.
Nucleic acid molecule: A nucleic acid molecule is a molecule comprising, preferably consisting of nucleic acid components. The term nucleic acid molecule preferably refers to DNA or RNA molecules. It is preferably used synonymous with the term "polynucleotide". Preferably, a nucleic acid molecule is a polymer comprising or consisting of nucleotide monomers which are covalently linked to each other by phosphodiester-bonds of a sugar/phosphate-backbone. The term "nucleic acid molecule" also encompasses modified nucleic acid molecules, such as base-modified, sugar-modified or backbone-modified etc. DNA or RNA molecules.
Open reading frame: An open reading frame (ORF) in the context of the invention may typically be a sequence of several nucleotide triplets which may be translated into a peptide or protein. An open reading frame preferably contains a start codon, i.e. a combination of three subsequent nucleotides coding usually for the amino acid methionine (ATG or AUG), at its 5'-end and a subsequent region which usually exhibits a length which is a multiple of 3 nucleotides. An ORF is preferably terminated by a stop-codon (e.g., TAA, TAG, TGA). Typically, this is the only stop-codon of the open reading frame. Thus, an open reading frame in the context of the present invention is preferably a nucleotide sequence, consisting of a number of nucleotides that may be divided by three, which starts with a start codon (e.g. ATG or AUG) and which preferably terminates with a stop codon (e.g., TAA, TGA, or TAG or UAA, UAG, UGA, respectively). The open reading frame may be isolated or it may be incorporated in a longer nucleic acid sequence, for example in a vector or an mRNA. An open reading frame may also be termed 'protein coding region'.
Peptide: A peptide or polypeptide is typically a polymer of amino acid monomers, linked by peptide bonds. It typically contains less than 50 monomer units. Nevertheless, the term peptide is not a disclaimer for molecules having more than 50 monomer units. Long peptides are also called polypeptides, typically having between 50 and 600 monomeric units.
Pharmaceutically effective amount: A pharmaceutically effective amount in the context of the invention is typically understood to be an amount that is sufficient to induce a pharmaceutical effect, such as an immune response, altering a pathological level of an expressed peptide or protein, or substituting a lacking gene product, e.g., in case of a pathological situation.
Protein A protein typically comprises one or more peptides or polypeptides. A protein is typically folded into 3-dimensional form, which may be required for to protein to exert its biological function.
Pol (A) sequence: A poly(A) sequence, also called poly(A) tail or 3'-poly(A) tail, is typically understood to be a sequence of adenine nucleotides, e.g., of up to about 400 adenine nucleotides, e.g. from about 20 to about 400, preferably from about 50 to about 400, more preferably from about 50 to about 300, even more preferably from about 50 to about 250, most preferably from about 60 to about 250 adenine nucleotides. A poly(A) sequence is typically located at the 3'end of an mRNA. In the context of the present invention, a poly(A) sequence may be located within an mRNA or any other nucleic acid molecule, such as, e.g., in a vector, for example, in a vector serving as template for the generation of an RNA, preferably an mRNA, e.g., by transcription of the vector.
Polyadenylation: Polyadenylation is typically understood to be the addition of a poly(A) sequence to a nucleic acid molecule, such as an RNA molecule, e.g. to a premature mRNA. Polyadenylation may be induced by a so called polyadenylation signal. This signal is preferably located within a stretch of nucleotides at the 3'-end of a nucleic acid molecule, such as an RNA molecule, to be polyadenylated. A polyadenylation signal typically comprises a hexamer consisting of adenine and uracil/thymine nucleotides, preferably the hexamer sequence AAUAAA. Other sequences, preferably hexamer sequences, are also conceivable. Polyadenylation typically occurs during processing of a pre-mRNA (also called premature-mRNA). Typically, RNA maturation (from pre-mRNA to mature mRNA) comprises the step of polyadenylation.
Restriction site: A restriction site, also termed 'restriction enzyme recognition site', is a nucleotide sequence recognized by a restriction enzyme. A restriction site is typically a short, preferably palindromic nucleotide sequence, e.g. a sequence comprising 4 to 8 nucleotides. A restriction site is preferably specifically recognized by a restriction enzyme. The restriction enzyme typically cleaves a nucleotide sequence comprising a restriction site at this site. In a double-stranded nucleotide sequence, such as a double-stranded DNA sequence, the restriction enzyme typically cuts both strands of the nucleotide sequence.
RNA, mRNA: RNA is the usual abbreviation for ribonucleic-acid. It is a nucleic acid molecule, i.e. a polymer consisting of nucleotides. These nucleotides are usually adenosine- monophosphate, uridine-monophosphate, guanosine-monophosphate and cytidine- monophosphate monomers which are connected to each other along a so-called backbone. The backbone is formed by phosphodiester bonds between the sugar, i.e. ribose, of a first and a phosphate moiety of a second, adjacent monomer. The specific succession of the monomers is called the RNA-sequence. Usually RNA may be obtainable by transcription of a DNA-sequence, e.g., inside a cell. In eukaryotic cells, transcription is typically performed inside the nucleus or the mitochondria. In vivo, transcription of DNA usually results in the so-called premature RNA which has to be processed into so-called messenger-RNA, usually abbreviated as mRNA. Processing of the premature RNA, e.g. in eukaryotic organisms, comprises a variety of different posttranscriptional-modifications such as splicing, 5'- capping, polyadenylation, export from the nucleus or the mitochondria and the like. The sum of these processes is also called maturation of RNA. The mature messenger RNA usually provides the nucleotide sequence that may be translated into an amino acid sequence of a particular peptide or protein. Typically, a mature mRNA comprises a 5'-cap, a 5'UTR, an open reading frame, a 3'UTR and a poly(A) sequence. Aside from messenger RNA, several non-coding types of RNA exist which may be involved in regulation of transcription and/or translation. Sequence of a nucleic acid molecule: The sequence of a nucleic acid molecule is typically understood to be the particular and individual order, i.e. the succession of its nucleotides. The sequence of a protein or peptide is typically understood to be the order, i.e. the succession of its amino acids. Sequence identity: Two or more sequences are identical if they exhibit the same length and order of nucleotides or amino acids. The percentage of identity typically describes the extent to which two sequences are identical, i.e. it typically describes the percentage of nucleotides that correspond in their sequence position with identical nucleotides of a reference-sequence. For determination of the degree of identity, the sequences to be compared are considered to exhibit the same length, i.e. the length of the longest sequence of the sequences to be compared. This means that a first sequence consisting of 8 nucleotides is 80% identical to a second sequence consisting of 10 nucleotides comprising the first sequence. In other words, in the context of the present invention, identity of sequences preferably relates to the percentage of nucleotides of a sequence which have the same position in two or more sequences having the same length. Gaps are usually regarded as non-identical positions, irrespective of their actual position in an alignment.
Stabilized nucleic acid molecule: A stabilized nucleic acid molecule is a nucleic acid molecule, preferably a DNA or RNA molecule that is modified such, that it is more stable to disintegration or degradation, e.g., by environmental factors or enzymatic digest, such as by an exo- or endonuclease degradation, than the nucleic acid molecule without the modification. Preferably, a stabilized nucleic acid molecule in the context of the present invention is stabilized in a cell, such as a prokaryotic or eukaryotic cell, preferably in a mammalian cell, such as a human cell. The stabilization effect may also be exerted outside of cells, e.g. in a buffer solution etc., for example, in a manufacturing process for a pharmaceutical composition comprising the stabilized nucleic acid molecule.
Transfection: The term 'transfection' refers to the introduction of nucleic acid molecules, such as DNA or RNA (e.g. mRNA) molecules, into cells, preferably into eukaryotic cells. In the context of the present invention, the term 'transfection' encompasses any method known to the skilled person for introducing nucleic acid molecules into cells, preferably into eukaryotic cells, such as into mammalian cells. Such methods encompass, for example, electroporation, lipofection, e.g. based on cationic lipids and/or liposomes, calcium phosphate precipitation, nanoparticle based transfection, virus based transfection, or transfection based on cationic polymers, such as DEAE-dextran or polyethylenimine etc. Preferably, the introduction is non-viral.
Vaccine: A vaccine is typically understood to be a prophylactic or therapeutic material providing at least one antigen, preferably an immunogen. The antigen or immunogen may be derived from any material that is suitable for vaccination. For example, the antigen or immunogen may be derived from a pathogen, such as from bacteria or virus particles etc., or from a tumor or cancerous tissue. The antigen or immunogen stimulates the body's adaptive immune system to provide an adaptive immune response. Vector: The term 'vector' refers to a nucleic acid molecule, preferably to an artificial nucleic acid molecule. A vector in the context of the present invention is suitable for incorporating or harboring a desired nucleic acid sequence, such as a nucleic acid sequence comprising an open reading frame. Such vectors may be storage vectors, expression vectors, cloning vectors, transfer vectors etc. A storage vector is a vector which allows the convenient storage of a nucleic acid molecule, for example, of an mRNA molecule. Thus, the vector may comprise a sequence corresponding, e.g., to a desired mRNA sequence or a part thereof, such as a sequence corresponding to the open reading frame and the 3'UTR of an mRNA. An expression vector may be used for production of expression products such as RNA, e.g. mRNA, or peptides, polypeptides or proteins. For example, an expression vector may comprise sequences needed for transcription of a sequence stretch of the vector, such as a promoter sequence, e.g. an RNA promoter sequence. A cloning vector is typically a vector that contains a cloning site, which may be used to incorporate nucleic acid sequences into the vector. A cloning vector may be, e.g., a plasmid vector or a bacteriophage vector. A transfer vector may be a vector which is suitable for transferring nucleic acid molecules into cells or organisms, for example, viral vectors. A vector in the context of the present invention may be, e.g., an RNA vector or a DNA vector. Preferably, a vector is a DNA molecule. Preferably, a vector in the sense of the present application comprises a cloning site, a selection marker, such as an antibiotic resistance factor, and a sequence suitable for multiplication of the vector, such as an origin of replication. Preferably, a vector in the context of the present application is a plasmid vector. Vehicle: A vehicle is typically understood to be a material that is suitable for storing, transporting, and/or administering a compound, such as a pharmaceutically active compound. For example, it may be a physiologically acceptable liquid which is suitable for storing, transporting, and/or administering a pharmaceutically active compound. 3'-untranslated region (3'UTR): A 3'UTR is typically the part of an mRNA which is located between the protein coding region (i.e. the open reading frame) and the poly(A) sequence of the mRNA. A 3'UTR of the mRNA is not translated into an amino acid sequence. The 3'UTR sequence is generally encoded by the gene which is transcribed into the respective mRNA during the gene expression process. The genomic sequence is first transcribed into pre-mature mRNA, which comprises optional introns. The pre-mature mRNA is then further processed into mature mRNA in a maturation process. This maturation process comprises the steps of 5'capping, splicing the pre-mature mRNA to excise optional introns and modifications of the 3'-end, such as polyadenylation of the 3'-end of the premature mRNA and optional endo- or exonuclease cleavages etc. In the context of the present invention, a 3'UTR corresponds to the sequence of a mature mRNA which is located 3' to the stop codon of the protein coding region, preferably immediately 3' to the stop codon of the protein coding region, and which extends to the 5'-side of the poly(A) sequence, preferably to the nucleotide immediately 5' to the poly(A) sequence. The term "corresponds to" means that the 3'UTR sequence may be an RNA sequence, such as in the mRNA sequence used for defining the 3'UTR sequence, or a DNA sequence which corresponds to such RNA sequence. In the context of the present invention, the term "a 3'UTR of a gene", such as "a 3'UTR of an albumin gene", is the sequence which corresponds to the 3'UTR of the mature mRNA derived from this gene, i.e. the mRNA obtained by transcription of the gene and maturation of the pre-mature mRNA. The term "3'UTR of a gene" encompasses the DNA sequence and the RNA sequence of the 3'UTR.
5'-untranslated region (5'UTR): A 5'UTR is typically understood to be a particular section of messenger RNA (mRNA). It is located 5' of the open reading frame of the mRNA. Typically, the 5'UTR starts with the transcriptional start site and ends one nucleotide before the start codon of the open reading frame. The 5'UTR may comprise elements for controlling gene expression, also called regulatory elements. Such regulatory elements may be, for example, ribosomal binding sites or a 5'-Terminal Oligopyrimidine Tract. The 5'UTR may be posttranscriptionally modified, for example by addition of a 5'-cap. In the context of the present invention, a 5'UTR corresponds to the sequence of a mature mRNA which is located between the 5'cap and the start codon. Preferably, the 5'UTR corresponds to the sequence which extends from a nucleotide located 3' to the 5'-cap, preferably from the nucleotide located immediately 3' to the 5'cap, to a nucleotide located 5' to the start codon of the protein coding region, preferably to the nucleotide located immediately 5' to the start codon of the protein coding region. The nucleotide located immediately 3' to the 5'cap of a mature mRNA typically corresponds to the transcriptional start site. The term "corresponds to" means that the 5'UTR sequence may be an RNA sequence, such as in the mRNA sequence used for defining the 5'UTR sequence, or a DNA sequence which corresponds to such RNA sequence. In the context of the present invention, the term "a 5'UTR of a gene", such as "a 5'UTR of a TOP gene", is the sequence which corresponds to the 5'UTR of the mature mRNA derived from this gene, i.e. the mRNA obtained by transcription of the gene and maturation of the pre-mature mRNA. The term "5'UTR of a gene" encompasses the DNA sequence and the RNA sequence of the 5'UTR.
5'Terminal Oligopyrimidine Tract (TOP): The 5'terminal oligopyrimidine tract (TOP) is typically a stretch of pyrimidine nucleotides located at the 5' terminal region of a nucleic acid molecule, such as the 5' terminal region of certain mRNA molecules or the 5' terminal region of a functional entity, e.g. the transcribed region, of certain genes. The sequence starts with a cytidine, which usually corresponds to the transcriptional start site, and is followed by a stretch of usually about 3 to 30 pyrimidine nucleotides, more often 3 to 1 5 pyrimidine nucleotides. For example, the TOP may comprise 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 1 6, 1 7, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30 or even more nucleotides. The pyrimidine stretch and thus the 5' TOP ends one nucleotide 5' to the first purine nucleotide located downstream of the TOP. Messenger RNA that contains a 5'-terminal oligopyrimidine tract is often referred to as TOP mRNA. Accordingly, genes that provide such messenger RNAs are referred to as TOP genes. TOP sequences have, for example, been found in genes and mRNAs encoding peptide elongation factors and ribosomal proteins.
TOP motif: In the context of the present invention, a TOP motif is a nucleic acid sequence which corresponds to a 5'TOP as defined above. Thus, a TOP motif in the context of the present invention is preferably a stretch of pyrimidine nucleotides having a length of 3-30 nucleotides. Preferably, the TOP-motif consists of at least 3 pyrimidine nucleotides, preferably at least 4 pyrimidine nucleotides, preferably at least 5 pyrimidine nucleotides, more preferably at least 6 nucleotides, more preferably at least 7 nucleotides, most preferably at least 8 pyrimidine nucleotides, wherein the stretch of pyrimidine nucleotides prefera- bly starts at its 5'end with a cytosine nucleotide. In TOP genes and TOP mRNAs, the TOP- motif preferably starts at its 5'end with the transcriptional start site and ends one nucleotide 5' to the first purin residue in said gene or mRNA. A TOP motif in the sense of the present invention is preferably located at the 5'end of a sequence which represents a 5'UTR or at the 5'end of a sequence which codes for a 5'UTR. Thus, preferably, a stretch of 3 or more pyrimidine nucleotides is called "TOP motif" in the sense of the present invention if this stretch is located at the 5'end of a respective sequence, such as the artificial nucleic acid molecule according to the present invention, the 5'UTR element of the artificial nucleic acid molecule according to the present invention, or the nucleic acid sequence which is derived from the 5'UTR of a TOP gene as described herein. In other words, a stretch of 3 or more pyrimidine nucleotides which is not located at the 5'-end of a 5'UTR or a 5'UTR element but anywhere within a 5'UTR or a 5'UTR element is preferably not referred to as "TOP motif".
TOP gene: TOP genes are typically characterised by the presence of a 5' terminal oli- gopyrimidine tract. Furthermore, most TOP genes are characterized by a growth -associated translational regulation. However, also TOP genes with a tissue specific translational regulation are known. As defined above, the 5'UTR of a TOP gene corresponds to the sequence of a 5'UTR of a mature mRNA derived from a TOP gene, which preferably extends from the nucleotide located 3' to the 5'cap to the nucleotide located 5' to the start codon. A 5'UTR of a TOP gene typically does not comprise any start codons, preferably no upstream AUGs (uAUGs) or upstream open reading frames (uORFs). Therein, upstream AUGs and upstream open reading frames are typically understood to be AUGs and open reading frames that occur 5' of the start codon (AUG) of the open reading frame that should be translated. The 5'UTRs of TOP genes are generally rather short. The lengths of 5'UTRs of TOP genes may vary between 20 nucleotides up to 500 nucleotides, and are typically less than about 200 nucleotides, preferably less than about 150 nucleotides, more preferably less than about 100 nucleotides. Exemplary 5'UTRs of TOP genes in the sense of the present invention are the nucleic acid sequences extending from the nucleotide at position 5 to the nucleotide located immediately 5' to the start codon (e.g. the ATG) in the sequences according to SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 and SEQ ID NO. 1422.
In a first aspect, the present invention relates to an artificial nucleic acid molecule comprising a. at least one 5'-untranslated region element (5'UTR element) which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a TOP gene or which is derived from a variant of the 5'UTR of a TOP gene; and b. at least one open reading frame (ORF). Such an artificial nucleic acid molecule may be DNA or RNA. In case the artificial nucleic acid molecule is DNA it may be used for providing RNA, preferably an mRNA with a corresponding sequence as is described further below. The inventive artificial nucleic acid molecule is particularly useful in gene therapy and genetic vaccination because it may provide increased and/or prolonged protein production of the protein encoded by the open reading frame. It is preferred, if the components (a) and (b) are heterologous, such that the inventive nucleic acid molecule does not occur naturally, but is an artificial chimeric recombinant nucleic acid molecule.
In this context, the term '5'UTR element' preferably refers to a nucleic acid sequence which represents a 5'UTR of an artificial nucleic acid sequence, such as an artificial mRNA, or which codes for a 5'UTR of an artificial nucleic acid molecule. Thus, preferably, a 5'UTR element may be the 5'UTR of an mRNA, preferably of an artificial mRNA, or it may be the transcription template for a 5'UTR of an mRNA. Thus, a 5'UTR element preferably is a nucleic acid sequence which corresponds to the 5'UTR of an mRNA, preferably to the 5'UTR of an artificial mRNA, such as an mRNA obtained by transcription of a genetically engineered vector construct. Preferably, a 5'UTR element in the sense of the present invention functions as a 5'UTR or codes for a nucleotide sequence that fulfils the function of a 5'UTR. The term '5'UTR element' may also refer to a fragment or part of a 5'UTR of an artificial nucleic acid sequence, such as an artificial mRNA, or which codes for a part or fragment of a 5'UTR of an artificial nucleic acid molecule. This means that the 5'UTR element in the sense of the present invention may be comprised in the 5'UTR of an artificial nucleic acid sequence, such as an artificial mRNA, or which codes for a 5'UTR of an artificial nucleic acid molecule.
According to the invention, the 5'UTR element comprises or consists of a nucleic acid sequence that is derived from the 5'UTR of a TOP gene or from a variant of the 5'UTR of a TOP gene.
The term 'a nucleic acid sequence which is derived from the 5'UTR of a TOP gene' preferably refers to a nucleic acid sequence which is based on the 5'UTR sequence of a TOP gene or on a fragment thereof. This term includes sequences corresponding to the entire 5'UTR sequence, i.e. the full length 5'UTR sequence of a TOP gene, and sequences corresponding to a fragment of the 5'UTR sequence of a TOP gene. Preferably, a fragment of a 5'UTR of a TOP gene consists of a continuous stretch of nucleotides corresponding to a continuous stretch of nucleotides in the full-length 5'UTR of a TOP gene, which represents at least 20%, preferably at least 30%, more preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, and most preferably at least 90% of the full-length 5'UTR of a TOP gene. Such a fragment, in the sense of the present invention, is preferably a functional fragment as described herein. A particularly preferred fragment of a 5'UTR of a TOP gene is a 5'UTR of a TOP gene lacking the 5'TOP motif, which typically corresponds to a pyrimidine stretch of 3 to 30 pyrimidine nucleotides at the 5' terminus of the 5'UTR of a TOP gene. For the above preferred embodiment of the invention employing a 5'UTR of a TOP gene, the 5'UTR (comprised by the inventive nucleic acid molecule) starts with the first nucleotide following the most 3'-terminal nucleotide of the 5'TOP motif. In case the 5'TOP motif does not correspond to the 5'terminal part of the 5'UTR of the TOP gene, the 5' UTR (of the TOP gene) employed in the inventive nucleic acid may consist of the nucleotide sequence located upstream of the 5'terminus of the 5'TOP motif and/or of the nucleotide sequence located downstream of the 3'terminus of the 5'TOP motif. In an alternative embodiment, the 5' motif of a 5'UTR of a TOP gene may be rendered dysfunctional by e.g. introducing one or more purine nucleotides, which interupt the monotonic pyrimidine nucleotide stretch of the 5'TOP motif such that the modified (interrupted) 5'TOP motif sequence cannot exert its regulatory function any longer, in particular cannot exert its function as an element for translational control. Another way of rendering the 5' TOP motif dysfunctional is the deletion of one or more pyrimidine nucleotides of the 5'TOP motif sequence (either at the termini and/or within the 5'TOP motif).
In one embodiment, the 5'UT of a TOP gene will not be derived from the 5'UTR of ribosomal proteins (rp) mRNA (in particular not from mammalian 5'UTR of rp mRNA, more specifically not from rpP2 (e.g. rat rpP2), rpL32, rpL30, rpL13a (e.g. mouse transplantation antigen P198), rpS20, rpS6, rpLI 2 or rpS1 6 mRNA or not from an rpS19 mRNA (e.g. from Xenopus). In anotther embodiment, the 5'UTR of a TOP gene is not derived from the 5'UTR of a EF1 alpha or (hamster) EF2 mRNA. The 5'UTRs of these afore-mentioned rp mRNAs are specifically not used, if they are linked to reporter genes in the ORF of the inventive nucleic acid. If e.g. the 5'UTR of rpS1 6 mRNA is used for the inventive nucleic acid, that 5'UTR will either not contain the 5'TOP motif sequence (composed ot the oligonucleotide (CCTTTTCC or CCUUUUCC) or will contain a dysfunctional variant therof by e.g. interruption of the oligopyrimidine sequence by purine nucleotides or by deltion of one or more pyrimidine nucleotides of that 5'TOP motif. Accordingly, the dysfunctional mutants may e.g. contain one or more purine nucleotides within the 5'TOP motif sequence thereby lacking the translational control function exerted by the 5'TOP motif, e.g. by abolishing its interaction with other regulatory compounds, e.g. miRNA or interaction with granule-associated proteins TIA-1 and TIAR.
The term '5'UTR of a TOP gene' preferably refers to the 5'UTR of a naturally occurring TOP gene.
The terms 'variant of the 5'UTR of a TOP gene' and 'variant thereof in the context of a 5'UTR of a TOP gene refers to a variant of the 5'UTR of a naturally occurring TOP gene, preferably to a variant of the 5'UTR of a vertebrate TOP gene, preferably to a variant of the 5'UTR of a mammalian TOP gene, more preferably to a variant of the 5'UTR of a human TOP gene. Such variant may be a modified 5'UTR of a TOP gene. For example, a variant 5'UTR may exhibit one or more nucleotide deletions, insertions, additions and/or substitutions compared to the naturally occurring 5'UTR from which the variant is derived. Preferably, a variant of a 5'UTR of a TOP gene is at least 40%, preferably at least 50%, more preferably at least 60%, more preferably at least 70%, even more preferably at least 80%, even more preferably at least 90%, most preferably at least 95% identical to the naturally occurring 5'UTR the variant is derived from. Preferably, the variant is a functional variant as described herein.
The term "a nucleic acid sequence that is derived from a variant of the 5'UTR of a TOP gene" preferably refers to a nucleic acid sequence which is based on a variant of a 5'UTR sequence of a TOP gene or on a fragment thereof. This term includes sequences corresponding to the entire variant 5'UTR sequence, i.e. the full length variant 5'UTR sequence of a TOP gene, and sequences corresponding to a fragment of the variant 5'UTR sequence of a TOP gene. Preferably, a fragment of a variant of the 5'UTR of a TOP gene consists of a continuous stretch of nucleotides corresponding to a continuous stretch of nucleotides in the full-length variant 5'UTR of a TOP gene, which represents at least 20%, preferably at least 30%, more preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, and most preferably at least 90% of the full-length variant 5'UTR of a TOP gene. Such a fragment of a variant, in the sense of the present invention, is preferably a functional fragment as described herein.
Thus, the 5'UTR element of the artificial nucleic acid molecule may comprise or consist of a fragment of the 5'UTR of a TOP gene or of a fragment of a variant of the 5'UTR of a TOP gene or may comprise or consist of the entire 5'UTR of a TOP gene or may comprise or consist of a variant of the 5'UTR of a TOP gene.
The 5'UTR element is preferably suitable for increasing protein production from the artificial nucleic acid molecule.
Preferably, the at least one 5'UTR element is functionally linked to the ORF. This means preferably that the 5'UTR element is associated with the ORF such that it may exert a function, such as a protein production increasing function for the protein encoded by the ORF or a stabilizing function on the artificial nucleic acid molecule. Preferably, the 5'UTR element and the ORF are associated in 5'- 3' direction. Thus, preferably, the artificial nucleic acid molecule comprises the structure 5'-5'UTR element-(optional)linker-ORF-3', wherein the linker may be present or absent. For example, the linker may be one or more nucleotides, such as a stretch of 1 -50 or 1 -20 nucleotides, e.g., comprising or consisting of one or more restriction enzyme recognition sites (restriction sites).
Preferably, the 5'UTR element and the at least one open reading frame are heterologous. The term 'heterologous' in this context means that the open reading frame and the 5'UTR element are not occurring naturally (in nature) in this combination. Preferably, the 5'UTR element is derived from a different gene than the open reading frame. For example, the ORF may be derived from a different gene than the 5'UTR element, e.g. encoding a different protein or the same protein but of a different species etc. For example, the ORF does not encode the protein which is encoded by the gene from which the 5'UTR element is derived.
In a preferred embodiment, the 5'UTR element, preferably the artificial nucleic acid molecule, does not comprise a complete TOP-motif or 5'TOP sequence. Thus, preferably, the 5'UTR element, preferably the artificial nucleic acid molecule, does not comprise the complete TOP-motif of the TOP gene from which the nucleic acid sequence of the 5'UTR element is derived. For example, the 5'UTR element or the artificial nucleic acid molecule according to the present invention may comprise 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more pyrimidine residues of the TOP-motif or 5'TOP, preferably 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10 or more pyrimidine residues of the TOP-motif located at the 3'side of the TOP-motif or 5'TOP. For example, the 5'UTR element may comprise or consist of a nucleic acid sequence which starts at its 5'end with a pyrimidine residue that corresponds to residue 2, 3, 4, 5, 6, 7, 8, 9, 10 etc. of the TOP-motif or 5'TOP of the TOP gene from which the nucleic acid sequence of the 5'UTR element is derived. It is particularly preferred that the 5'UTR element, preferably the artificial nucleic acid molecule according to the present invention, does not comprise a TOP-motif or a 5'TOP. For example, the nucleic acid sequence of the 5'UTR element which is derived from a 5'UTR of a TOP gene starts at its 5'-end with a nucleotide located at position 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 downstream of the 5'terminal oligopyrimidine tract (TOP) of the 5'UTR of a TOP gene. Position 1 downstream of the 5'terminal oligopyrimidine tract (TOP) is the first purine based nucleotide 3' of the TOP-motif or the 5'TOP. Accordingly, position 1 downstream of the 5'terminal oligopyrimidine tract is the first nucleotide following the 3'- end of the 5'terminal oligopyrimidine tract in 5'-3'-direction. Likewise, position 2 downstream of the 5'TOP is the second nucleotide following the end of the 5'terminal oligopyrimidine tract, position 3 the third nucleotide and so on.
Therefore, the 5'UTR element preferably starts 5, 10, 15, 20, 25, 30, 40 or 50 nucleotides downstream of the transcriptional start site of the 5'UTR of a TOP gene.
In some embodiments, the nucleic acid sequence of the 5'UTR element which is derived from a 5'UTR of a TOP gene terminates at its 3'-end with a nucleotide located at position 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 upstream of the start codon (e.g. A(U/T)G) of the gene or mRNA it is derived from. Thus, the 5'UTR element does not comprise any part of the protein coding region. Thus, preferably, the only protein coding part of the inventive artificial nucleic acid molecule is provided by the open reading frame. However, the open reading frame is preferably derived - as said above - from a gene that is different to the gene the 5'UTR element is derived from.
It is particularly preferred that the 5'UTR element does not comprise a start codon, such as the nucleotide sequence A(U/T)G. Thus, preferably, the artificial nucleic acid molecule will not comprise any upstream AUGs (or upstream ATGs in case it is a DNA molecule). In other words, in some embodiments, it may be preferred that the AUG or ATG, respectively, of the open reading frame is the only start codon of the artificial nucleic acid molecule.
Additionally, it is preferred that the 5'UTR element does not comprise an open reading frame. Thus, preferably, the artificial nucleic acid molecule will not comprise any upstream open reading frames.
The nucleic acid sequence which is derived from the 5'UTR of a TOP gene is derived from a eukaryotic TOP gene, preferably a plant or animal TOP gene, more preferably a chordate TOP gene, even more preferably a vertebrate TOP gene, most preferably a mammalian TOP gene, such as a human or mouse TOP gene.
Preferably, the artificial nucleic acid molecule according to the present invention comprises a 5'UTR element which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a TOP gene or which is derived from a variant of the 5'UTR of a TOP gene, wherein the TOP gene is a plant or animal TOP gene, more preferably a chordate TOP gene, even more preferably a vertebrate TOP gene, most preferably a mammalian TOP gene, such as a human or mouse TOP gene and which optionally does not comprise the nucleotide sequence A(U/T)C and optionally does not comprise an open reading frame; at least one open reading frame (ORF); wherein optionally the 5'UTR element does not comprise a TOP motif and wherein optionally the 5'UTR element starts at its 5'-end with a nucleotide located at position 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 downstream of the 5'terminal oligopyrimidine tract (TOP) of the 5'UTR of a TOP gene and wherein further optionally the 5'UTR element which is derived from a 5'UTR of a TOP gene terminates at its 3'-end with a nucleotide located at position 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 upstream of the start codon (A(U/T)G) of the gene or mRNA it is derived from.
For example, the 5'UTR element comprises or consists of a nucleic acid sequence which is derived from a nucleic acid sequence selected from the group consisting of SEQ ID NOs. 1 - 1363, SEQ ID NO. 1395, SEQ ID NO. 1421 and SEQ ID NO. 1422, from the homologs of SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 and SEQ ID NO. 1422, from a variant thereof, or a corresponding RNA sequence. The term "homologs of SEQ ID NOs. 1 - 1363, SEQ ID NO. 1395, SEQ ID NO. 1421 and SEQ ID NO. 1422" refers to sequences of other species, e.g. other species than Homo sapiens (human) or Mus musculus (mouse), which are homologous to the sequences according to SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 or SEQ ID NO. 1422. For example, SEQ ID NO. 1 relates to a sequence comprising the 5'UTR of Homo sapiens alpha 2 macroglobuiin (A2M). A homolog of SEQ ID NO. 1 in the context of the present invention is any such sequence derived from an alpha 2 macroglobuiin (A2M) gene or mRNA of another species than Homo sapiens, such as any vertebrate, preferably any mammalian alpha 2 macroglobuiin (A2M) gene other than the human alpha 2 macroglobuiin (A2M) gene, such as a mouse, rat, rabbit, monkey etc. alpha 2 macroglobuiin (A2M) gene.
In a preferred embodiment, the 5'UTR element comprises or consists of a nucleic acid sequence which is derived from a nucleic acid sequence extending from nucleotide position 5 (i.e. the nucleotide that is located at position 5 in the sequence) to the nucleotide position immediately 5' to the start codon (located at the 3' end of the sequences), e.g. the nucleotide position immediately 5' to the ATG sequence, of a nucleic acid sequence selected from SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 or SEQ ID NO. 1422, from the homologs of SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 or SEQ ID NO. 1422, from a variant thereof, or a corresponding RNA sequence. It is particularly preferred that the 5' UTR element is derived from a nucleic acid sequence extending from the nucleotide position immediately 3' to the 5'TOP to the nucleotide position immediately 5' to the start codon (located at the 3' end of the sequences), e.g. the nucleotide position immediately 5' to the ATG sequence, of a nucleic acid sequence selected from SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 or SEQ ID NO. 1422, from the homologs of SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 or SEQ ID NO. 1422, from a variant thereof, or a corresponding RNA sequence. In a preferred embodiment, the 5'UTR element comprises or consists of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to a nucleic acid sequence extending from nucleotide position 5 to the nucleotide position immediately 5' to the start codon (located at the 3' end of the sequences), e.g. the nucleotide position immediately 5' to the ATG sequence of a nucleic acid sequence selected from SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 or SEQ ID NO. 1422,or a corresponding RNA sequence, or wherein the at least one 5'UTR element comprises or consists of a fragment of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to a nucleic acid sequence extending from nucleotide position 5 to the nucleotide position immediately 5' to the start codon (located at the 3' end of the sequences), e.g. the nucleotide position immediately 5' to the ATG sequence of a nucleic acid sequence, selected from SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 or SEQ ID NO. 1422, or a corresponding RNA sequence, wherein, preferably, the fragment is as described above, i.e. being a continuous stretch of nucleotides representing at least 20% etc. of the full-length 5'UTR the fragment is derived from.
Preferably, the 5'UTR element comprises or consists of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to a nucleic acid sequence extending from the nucleotide position immediately 3' to the 5'TOP to the nucleotide position immediately 5' to the start codon (located at the 3' end of the sequences), e.g. the nucleotide position immediately 5' to the ATG sequence, of a nucleic acid sequence selected from SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 or SEQ ID NO. 1422, or a corresponding RNA sequence, or wherein the at least one 5'UTR element comprises or consists of a fragment of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to a nucleic acid sequence extending from the nucleotide position immediately 3' to the 5'TOP to the nucleotide position immediately 5' to the start codon (located at the 3' end of the sequences), e.g. the nucleotide position immediately 5' to the ATG sequence, of a nucleic acid sequence selected from SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 or SEQ ID NO. 1422, or a corresponding RNA sequence, wherein, preferably, the fragment is as described above, i.e. being a continuous stretch of nucleotides representing at least 20% etc. of the full-length 5'UTR the fragment is derived from.
Preferably, the above defined fragments and variants (e.g. exhibiting at least 40% identity) of the sequences according to SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 or SEQ ID NO. 1422, are functional fragments and variants as described herein. Furthermore, the artificial nucleic acid molecule according to the present invention may comprise more than one 5'UTR elements as described above. For example, the artificial nucleic acid molecule according to the present invention may comprise one, two, three, four or more 5'UTR elements, wherein the individual 5'UTR elements may be the same or they may be different. For example, the artificial nucleic acid molecule according to the present invention may comprise two essentially identical 5'UTR elements as described above, e.g. two 5'UTR elements comprising or consisting of a nucleic acid sequence which is derived from a nucleic acid sequence selected from the group consisting of SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 and SEQ ID NO. 1422, from the homologs of SEQ ID NOs. 1 -1363, SEQ ID NO. 1395, SEQ ID NO. 1421 and SEQ ID NO. 1422, from a variant thereof, or a corresponding RNA sequence or from functional variants thereof, functional fragments thereof, or functional variant fragments thereof as described above. In a particularly preferred embodiment, the 5'UTR element comprises or consists of a nucleic acid sequence which is derived from a 5'UTR of a TOP gene encoding a ribosomal protein or from a variant of a 5'UTR of a TOP gene encoding a ribosomal protein. Particularly preferred 5'UTR elements comprise or consist of a nucleic acid sequence which are derived from a 5' UTR of a TOP gene coding for a ribosomal protein se- lected from RPSA, RPS2, RPS3, RPS3A, RPS4, RPS5, RPS6, RPS7, RPS8, RPS9, RPS10, RPS1 1 , RPS12, RPS13, RPS14, RPS1 5, RPS15A, RPS1 6, RPS1 7, RPS1 8, RPS19, RPS20, RPS21 , RPS23, RPS24, RPS25, RPS26, RPS27, RPS27A, RPS28, RPS29, RPS30, RPL3, RPL4, RPL5, RPL6, RPL7, RPL7A, RPL8, RPL9, RPL10, RPL10A, RPL1 1 , RPL12, RPL13, RPL13A, RPL14, RPL15, RPL1 7, RPL18, RPL18A, RPL19, RPL21 , RPL22, RPL23, RPL23A, RPL24, RPL26, RPL27, RPL27A, RPL28, RPL29, RPL30, RPL31 , RPL32, RPL34, RPL35, RPL35A, RPL36, RPL36A, RPL37, RPL37A, RPL38, RPL39, RPL40, RPL41 , RPLPO, RPLP1 , RPLP2, RPLP3, UBA52. Particularly preferred are nucleic acid sequences which are derived from a 5' UTR of TOP genes vertebrate coding for ribosomal proteins, such as mammalian ribosomal proteins e.g. human or mouse ribosomal proteins.
For example, the 5'UTR element comprises or consists of a nucleic acid sequence which is derived from a 5'UTR of a nucleic acid sequence according to any of SEQ ID NOs: 1 70, 232, 244, 259, 1284, 1285, 1286, 1287, 1288, 1289, 1290, 1291 , 1292, 1293, 1294, 1295, 1296, 1297, 1298, 1299, 1300, 1301 , 1302, 1303, 1304, 1305, 1306, 1307, 1308, 1309, 1310, 131 1 , 1312, 1313, 1314, 1315, 131 6, 131 7, 1318, 1319, 1320, 1 321 , 1322, 1323, 1324, 1325, 1326, 1327, 1328, 1329, 1330, 1331 , 1332, 1333, 1334, 1 335, 1336, 1337, 1338, 1339, 1340, 1341 , 1342, 1343, 1344, 1346, 1347, 1348, 1349, 1 350, 1351 , 1352, 1353, 1354, 1355, 1356, 1357, 1358, 1359, or 1360; a corresponding RNA sequence, a homolog thereof, or a variant thereof as described herein, preferably lacking the 5'TOP motif. As described above, the sequence extending from position 5 to the nucleotide immediately 5' to the ATG (which is located at the 3'end of the sequences) corresponds to the 5'UTR of said sequences. Preferably, the 5'UTR element comprises or consists of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to the 5'UTR of a nucleic acid sequence according to any of SEQ ID NOs.: 1 70, 232, 244, 259, 1284, 1285, 1286, 1287, 1288, 1289, 1290, 1291 ,
1292, 1293, 1294, 1295, 1296, 1297, 1298, 1299, 1 300, 1301 , 1302, 1 303, 1304, 1 305, 1306, 1307, 1308, 1309, 1310, 131 1 , 1312, 1313, 1 314, 1315, 131 6, 131 7, 1318, 1 31 9,
1320, 1321 , 1322, 1323, 1324, 1325, 1326, 1327, 1 328, 1329, 1330, 1331 , 1332, 1 333, 1334, 1335, 1336, 1337, 1338, 1339, 1340, 1341 , 1342, 1343, 1344, 1346, 1347, 1 348,
1349, 1350, 1351 , 1352, 1353, 1354, 1355, 1356, 1357, 1358, 1359, or 1360; or a corresponding RNA sequence, preferably lacking the 5'TOP motif, or wherein the at least one 5'UTR element comprises or consists of a fragment of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to the 5'UTR of a nucleic acid sequence according to SEQ ID NOs: 1 70, 232, 244, 259, 1284, 1285, 1286, 1287, 1288, 1289, 1290, 1291 , 1292,
1293, 1294, 1295, 1296, 1297, 1298, 1299, 1300, 1301 , 1302, 1303, 1304, 1305, 1306, 1307, 1308, 1309, 1310, 131 1 , 1312, 1313, 1314, 1315, 1316, 1 31 7, 1318, 1319, 1320,
1321 , 1322, 1323, 1324, 1325, 1326, 1327, 1328, 1329, 1330, 1331 , 1332, 1 333, 1334, 1335, 1336, 1337, 1338, 1339, 1340, 1341 , 1342, 1343, 1344, 1346, 1347, 1 348, 1349,
1350, 1351 , 1352, 1353, 1354, 1355, 1356, 1357, 1358, 1359, or 1360; or a corresponding RNA sequence, wherein, preferably, the fragment is as described above, i.e. being a continuous stretch of nucleotides representing at least 20% etc. of the full-length 5'UTR, preferably lacking the 5'TOP motif. Preferably, the fragment exhibits a length of at least about 20 nucleotides or more, preferably of at least about 30 nucleotides or more, more preferably of at least about 40 nucleotides or more. Preferably, the fragment is a functional fragment as described herein.
Preferably, the 5'UTR element comprises or consists of a nucleic acid sequence which is derived from a 5'UTR of a TOP gene encoding a ribosomai Large protein (RPL) or from a variant of a 5'UTR of a TOP gene encoding a ribosomai Large protein (RPL). For example, the 5'UTR element comprises or consists of a nucleic acid sequence which is derived from a 5'UTR of a nucleic acid sequence according to any of SEQ ID NOs: 67, 259, 1284-1318, 1344, 1346, 1348-1354, 1357, 1358, 1421 and 1422, a corresponding RNA sequence, a homolog thereof, or a variant thereof as described herein, preferably lacking the 5'TOP motif.
Preferably, the 5'UTR element comprises or consists of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to the 5'UTR of a nucleic acid sequence according to any of SEQ ID NOs. 67, 259, 1284-1318, 1344, .1346, 1348-1354, 1357, 1358, 1421 and 1422 or a corresponding RNA sequence, preferably lacking the 5'TOP motif, or wherein the at least one 5'UTR element comprises or consists of a fragment of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to the 5'UTR of a nucleic acid sequence according to SEQ ID NOs: 67, 259, 1284-1318, 1344, 1346, 1348-1354, 1357, 1358, 1421 and 1422 or a corresponding RNA sequence, wherein, preferably, the fragment is as described above, i.e. being a continuous stretch of nucleotides representing at least 20% etc. of the full-length 5'UTR, preferably lacking the 5'TOP motif. Preferably, the fragment exhibits a length of at least about 20 nucleotides or more, preferably of at least about 30 nucleotides or more, more preferably of at least about 40 nucleotides or more. Preferably, the fragment is a functional fragment as described herein.
In a particularly preferred embodiment, the 5'UTR element comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a ribosomal protein Large 32 gene (RPL32), a ribosomal protein Large 35 gene (RPL35), a ribosomal protein Large 21 gene (RPL21 ), an ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 , cardiac muscle (ATP5A1 ) gene, an hydroxysteroid (1 7-beta) dehydrogenase 4 gene (HSD1 7B4), an androgen-induced 1 gene (Aid ), cytochrome c oxidase subunit Vic gene (COX6C), or a N-acylsphingosine amidohydrolase (acid ceramidase) 1 gene (ASAH1 ) or from a variant thereof, preferably from a vertebrate ribosomal protein Large 32 gene (RPL32), a vertebrate ribosomal protein Large 35 gene (RPL35), a vertebrate ribosomal protein Large 21 gene (RPL21 ), a vertebrate ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 , cardiac muscle (ATP5A1 ) gene, a vertebrate hydroxysteroid (1 7- beta) dehydrogenase 4 gene (HSD1 7B4), a vertebrate androgen-induced 1 gene (A1G1 ), a vertebrate cytochrome c oxidase subunit Vic gene (COX6C), or a vertebrate N- acylsphingosine amidohydrolase (acid ceramidase) 1 gene (ASAH1 ) or from a variant thereof, more preferably from a mammalian ribosomal protein Large 32 gene (RPL32), a ribosomal protein Large 35 gene (RPL35), a ribosomal protein Large 21 gene (RPL21 ), a mammalian ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 , cardiac muscle (ATP5A1 ) gene, a mammalian hydroxysteroid (1 7-beta) dehydrogenase 4 gene (HSD1 7B4), a mammalian androgen-induced 1 gene (AIG1 ), a mammalian cytochrome c oxidase subunit Vic gene (COX6C), or a mammalian N-acylsphingosine amidohydrolase (acid ceramidase) 1 gene (ASAH1 ) or from a variant thereof, most preferably from a human ribosomal protein Large 32 gene (RPL32), a human ribosomal protein Large 35 gene (RPL35), a human ribosomal protein Large 21 gene (RPL21 ), a human ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 , cardiac muscle (ATP5A1 ) gene, a human hydroxysteroid (1 7-beta) dehydrogenase 4 gene (HSD1 7B4), a human androgen-induced 1 gene (AIG1 ), a human cytochrome c oxidase subunit Vic gene (COX6C), or a human N-acylsphingosine amidohydrolase (acid ceramidase) 1 gene (ASAH1 ) or from a variant thereof, wherein preferably the 5'UTR element does not comprise the 5'TOP of said gene.
Accordingly, in a particularly preferred embodiment, the 5'UTR element comprises or consists of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to the nucleic acid sequence according to SEQ ID No. 1368, or SEQ ID NOs 1412-1420, or a corresponding RNA sequence, or wherein the at least one 5'UTR element comprises or consists of a fragment of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to the nucleic acid sequence according to SEQ ID No. 1368, or SEQ ID NOs 1412- 1420, wherein, preferably, the fragment is as described above, i.e. being a continuous stretch of nucleotides representing at least 20% etc. of the full-length 5'UTR. Preferably, the fragment exhibits a length of at least about 20 nucleotides or more, preferably of at least about 30 nucleotides or more, more preferably of at least about 40 nucleotides or more. Preferably, the fragment is a functional fragment as described herein. Preferably, the at least one 5'UTR element exhibits a length of at least about 20 nucleotides or more, preferably of at least about 30 nucleotides or more, more preferably of at least about 40 nucleotides or more. However, it may be preferred if the 5'UTR element of the artificial nucleic acid molecule is rather short. Accordingly, it may have a length of less than about 200, preferably less than 150, more preferably less than 100 nucleotides. For example, the 5'UTR may have a length of less than about 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200 nucleotides Preferably, the 5'UTR element may have a length of about 20-25, 26-30, 31-35, 36-40, 41-45, 46-50, 51-55, 56-60, 61-65, 66-70, 71- 80, 81-85, 86-90, 91-95, 96-100, 101-105, 106-110, 111-115, 116-120, 121-125, 126- 130, 131-135, 136-140, 141-145, 146-150, 151-155, 156-160, 161-165, 166-170, 171-
175, 176-180, 181 -185, 186-190, 191 -195, 196-200 or more nucleotides. For example, the 5'UTR element may have a length of about 20, 26, 31, 36, 41, 46, 51, 56, 61, 66, 71, 81, 86, 91, 96, 101, 106, 111, 116, 121, 126, 131, 136, 141, 146, 151, 156, 161, 166, 171,
176, 181, 186, 191 or 196 nucleotides. Preferably, the 5'UTR element may have a length from about 20, 30, 40 or more to less than about 200 nucleotides, more preferably from about 20, 30, 40 or more to less than about 150 nucleotides, most preferably from about 20, 30, 40 or more to less than about 100 nucleotides.
Preferred 5'UTR elements are derived from a 5' UTR of a TOP gene selected from RPSA, RPS2, RPS3, RPS3A, RPS4, RPS5, RPS6, RPS7, RPS8, RPS9, RPS10, RPS11, RPS12, RPS13, RPS14, RPS15, RPS15A, RPS16, RPS17, RPS18, RPS19, RPS20, RPS21, RPS23, RPS24, RPS25, RPS26, RPS27, RPS27A, RPS28, RPS29, RPS30, RPL3, RPL4, RPL5, RPL6, RPL7, RPL7A, RPL8, RPL9, RPL10, RPL10A, RPL11, RPL12, RPL13, RPL13A, RPL14, RPL15, RPL17, RPL18, RPL18A, RPL19, RPL21, RPL22, RPL23, RPL23A, RPL24, RPL26, RPL27, RPL27A, RPL28, RPL29, RPL30, RPL31 , RPL32, RPL34, RPL35, RPL35A, RPL36, RPL36A, RPL37, RPL37A, RPL38, RPL39, RPL40, RPL41 , RPLPO, RPLP1 , RPLP2, RPLP3, RPLPO, RPLP1 , RPLP2, EEF1 A1 , EEF1 B2, EEF1 D, EEF1 G, EEF2, EIF3E, EIF3F, EIF3H, EIF2S3, EIF3C, EIF3K, EIF3EIP, EIF4A2, PABPC1 , HNRNPA1 , TPT1 , TUBB1 , UBA52, NPM1 , ATP5G2, GNB2L1 , NME2, UQCRB or from a variant thereof.
In some embodiments, the artificial nucleic acid molecule comprises a 5'UTR element which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a vertebrate TOP gene, such as a mammalian, e.g. a human TOP gene, selected from RPSA, RPS2, RPS3, RPS3A, RPS4, RPS5, RPS6, RPS7, RPS8, RPS9, RPS10, RPS1 1 , RPS12, RPS13, RPS14, RPS15, RPS15A, RPS16, RPS1 7, RPS18, RPS19, RPS20, RPS21 , RPS23, RPS24, RPS25, RPS26, RPS27, RPS27A, RPS28, RPS29, RPS30, RPL3, RPL4, RPL5, RPL6, RPL7, RPL7A, RPL8, RPL9, RPL10, RPL10A, RPL1 1 , RPL12, RPL13, RPL13A, RPL14, RPL15, RPL1 7, RPL18, RPL18A, RPL19, RPL21 , RPL22, RPL23, RPL23A, RPL24, RPL26, RPL27, RPL27A, RPL28, RPL29, RPL30, RPL31 , RPL32, RPL34, RPL35, RPL35A, RPL36, RPL36A, RPL37, RPL37A, RPL38, RPL39, RPL40, RPL41 , RPLPO, RPLP1 , RPLP2, RPLP3, RPLPO, RPLP1 , RPLP2, EEF1 A1 , EEF1 B2, EEF1 D, EEF1 G, EEF2, EIF3E, EIF3F, EIF3H, EIF2S3, EIF3C, EIF3K, EIF3EIP, EIF4A2, PABPC1 , HNRNPA1 , TPT1 , TUBB1 , UBA52, NPM1 , ATP5G2, GNB2L1 , NME2, UQCRB, or from a variant thereof, wherein preferably the 5'UTR element does not comprise a TOP-motif or the 5'TOP of said genes, and wherein optionally the 5'UTR element starts at its 5'-end with a nucleotide located at position 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 downstream of the 5'terminal oligopyrimidine tract (TOP) and wherein further optionally the 5'UTR element which is derived from a 5'UTR of a TOP gene terminates at its 3'-end with a nucleotide located at position 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 upstream of the start codon (A(U/T)G) of the gene it is derived from.
In a preferred embodiment, the artificial nucleic acid molecule according to the present invention further comprises c. at least one 3'UTR element which comprises or consists of a nucleic acid sequence derived from the 3'UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene, or from a variant of the 3'UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene.
The term '3'UTR element' refers to a nucleic acid sequence which comprises or consists of a nucleic acid sequence that is derived from a 3'UTR or from a variant of a 3'UTR. A 3'UTR element in the sense of the present invention may represent the 3'UTR of an mRNA, e.g., in the event that the artificial nucleic acid molecule is an mRNA, or it may represent a sequence in a nucleic acid construct, such as a vector construct, that when transcribed represents the 3'UTR of the transcription product, such as the mRNA. Thus, in the sense of the present invention, preferably, a 3'UTR element may be the 3'UTR of an mRNA, preferably of an artificial mRNA, or it may be the transcription template for a 3'UTR of an mRNA. Thus, a 3'UTR element preferably is a nucleic acid sequence which corresponds to the 3'UTR of an mRNA, preferably to the 3'UTR of an artificial mRNA, such as an mRNA obtained by transcription of a genetically engineered vector construct. Preferably, the 3'UTR element fulfils the function of a 3'UTR or encodes a sequence which fulfils the function of a 3'UTR. The term '3UTR element' furthermore refers to a fragment or part of a 3'UTR of an artificial nucleic acid sequence, such as an artificial mRNA, or which codes for a part or fragment of a 3'UTR of an artificial nucleic acid molecule. This means that the 3'UTR element in the sense of the present invention may be comprised in the 3'UTR of an artificial nucleic acid sequence, such as an artificial mRNA, or which codes for a 3'UTR of an artificial nucleic acid molecule.
Preferably, the 3'UTR element and the at least one open reading frame are heterologous. For example, the artificial nucleic acid molecule may consist of at least two sequence parts that are derivable from two different genes, the 5'UTR element which is derivable from a TOP gene and the open reading frame and the 3'UTR which may be derivable from the gene encoding the desired protein product. More preferably, the artificial nucleic molecule consist of three sequence parts that are derivable from three different genes: the 5'UTR element which is derivable from a TOP gene, the open reading frame which is derivable from the gene encoding the desired gene product and the 3'UTR element which may be derivable from a gene that relates to an mRNA with an enhanced half-life, for example a 3'UTR element as defined and described below. Preferably, the at least one 3'UTR element is functionally linked to the ORF. This means preferably that the 3'UTR element is associated with the ORF such that it may exert a function, such as a stabilizing function on the expression of the ORF or a stabilizing function on the artificial nucleic acid molecule. Preferably, the ORF and the 3'UTR element are associated in 5'- 3' direction. Thus, preferably, the artificial nucleic acid molecule comprises the structure 5'-ORF-(optional)linker-3'UTR element-3', wherein the linker may be present or absent. For example, the linker may be one or more nucleotides, such as a stretch of 1 -50 or 1 -20 nucleotides, e.g., comprising or consisting of one or more restriction enzyme recognition sites (restriction sites).
Preferably, the at least one 5'UTR element and the at least one 3'UTR element are functionally linked to the ORF. This means preferably that the 5'UTR element and the 3'UTR element are associated with the ORF such that they may exert a function, preferably in an additive, more preferably in a synergistic manner, such as a stabilizing function on the expression of the ORF, a protein production increasing function for the protein encoded by the ORF, or a stabilizing function on the artificial nucleic acid molecule. Preferably, the 5'UTR element, the ORF, and the 3'UTR element are associated in 5'->3' direction. Thus, preferably, the artificial nucleic acid molecule comprises the structure 5'-5'UTR element- (optional)linker-ORF-(optional)linker-3'UTR element-3', wherein the linker may be present or absent. For example, the linker may be one or more nucleotides, such as a stretch of 1 -50 or 1 -20 nucleotides, e.g., comprising or consisting of one or more restriction enzyme recognition sites (restriction sites). In a particularly preferred embodiment, the 5'UTR element and the 3'UTR element are heterologous, e.g. preferably the 5'UTR and the 3'UTR are derived from different genes of the same or of different species. Preferably, the 3'UTR is not derived from the TOP gene the 5'UTR is derived from. In a preferred embodiment, the 3'UTR element is chosen such that it exerts at least an additive, preferably a synergistic function with the 5'UTR element on the protein production from the ORF of the artificial nucleic acid molecule. Preferably, the protein production is increased in at least an additive, preferably a synergistic way by the 3'UTR element and the 5'UTR element. Thus, the protein amount of the protein encoded by the ORF, such as a reporter protein, e.g. luciferase, at a certain time point after initiation of expression of the ORF, e.g. after transfection of a test cell or cell line, is preferably at least the same, preferably higher than what would be expected if the protein production increasing effects of the 3'UTR element and the 5'UTR element were purely additive. The additive, preferably the synergistic effect may, for example, be determined by the following assay. Four artificial nucleic acid molecules, e.g. mRNAs, comprising an ORF encoding, e.g. a reporter protein such as luciferase, are generated, i.e. (i) lacking UTR elements (E0), (ii) containing a 5'UTR element derived from a 5'UTR of a TOP gene or of a variant thereof (E1 ), (iii) containing a test 3'UTR element (E2), and (iv) containing both the 5'UTR element and the test 3'UTR element (E1 E2). Expression of the ORF contained in the artificial nucleic acid molecules is initiated, for example, by transfecting a test cell line, such as a mammalian cell line, e.g. HELA cells, or primary cells, e.g. HDF cells. Samples are taken at specific time points after initiation of expression, for example, after 6 hours, 24 hours, 48 hours, and 72 hours and the amount of protein produced by expression of the ORF contained in the artificial nucleic acid molecules is measured, for example, by an ELISA assay or a luciferase test, depending on the type of protein encoded by the ORF. The predicted amount of protein at a certain time point after initiation of expression obtained by construct E1 E2 if the effects of the 3'UTR element and the 5'UTR element were purely additive (PPA) may be calculated as follows:
PPAX = (E1 X - E0X) + (E2X - E0X) + E0X,
E0 is the amount of protein obtained for the construct E0 (lacking UTRs), E1 is the amount of protein obtained for the construct E1 , E2 is the protein amount obtained for the construct E2, and x is the time point after initiation of expression. The effect on increasing protein production is additive if E1 E2X = PPAX and synergistic in the sense of the present invention if E1 E2X > PPAX, wherein E1 E2X is the amount of protein obtained from construct E1 E2 at time point x. Preferably, E1 E2 is at least 1 .0, preferably at least 1 .1 , more preferably at least 1 .3, more preferably at least 1 .5, even more preferably at least 1.75 times PPA at a given time point post initiation of expression, such as 24 hours, 48 hours or 72 hours post initiation of expression. Thus, in a preferred embodiment, the present invention provides an artificial nucleic acid molecule comprising (a.) at least one 5'UTR element which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a TOP gene or which is derived from a variant of the 5'UTR of a TOP gene; (b.) at least one open reading frame (ORF); and (c.) at least one 3'UTR element, wherein the 3'UTR element and the 5'UTR element act at least additively, preferably synergistically to increase protein production from the ORF, preferably wherein El E2 > PPA, preferably E1 E2 is at least 1 .0 times PPA, preferably El E2 is at least 1 .1 times PPA, more preferably E1 E2 is at least 1.3 times PPA, even more preferably El E2 is at least 1 .5 times PPA at a given time point post initiation of expression of the ORF, for example 24 hours, preferably 48 hours post initiation of expression, such as post transfection, wherein El E2 and PPA are as described above.
Furthermore, it is preferred that the 3'UTR element and the 5'UTR element have at least an additive, preferably a synergistic effect on the total protein production from the artificial nucleic acid molecule in a certain time span, such as within 24 hours, 48 hours, or 72 hours post initiation of expression. The additive or the synergistic effect may be determined as described above, with the difference that the area under the curve (AUC) for the amount of protein over time predicted for E1 E2 if the effects were purely additive is compared to the actual AUC measured for E1 E2.
In a preferred embodiment, the 3'UTR element comprises or consists of a nucleic acid sequence which is derived from the 3'UTR of a stable mRNA or from a variant of the 3'UTR of a stable mRNA. Thus, in a preferred embodiment, the 3'UTR element comprises or consists of a sequence which is derived from a gene providing a stable mRNA or from a variant of a 3'UTR of a gene providing a stable mRNA. The term "stable mRNA", preferably refers to mRNAs which exhibit a longer half-life in mammalian cells than the average half- life of mRNA molecules in mammalian cells. Preferably, a stable mRNA in the sense of the present application refers to an mRNA which exhibits a half-life of more than 5 hours, preferably more than 8 hours, in a mammalian cell, such as in a mammalian cell line, e.g. in HELA cells, or in primary cells, e.g. in HDF cells, preferably determined by using a transcription inhibitor such as actinomycin D. For example, the half-life of an mRNA in mammalian cells, such as HELA or HDF cells, may be determined by culturing the cells in presence of a transcription inhibitor, e.g. actinomycin D, 5,6-dichloro-1-P-D-ribofuranosylbenzimidazole (DRB), or oc-amanitin, harvesting the cells at different time points after inhibition of transcription, and determining the amount of the mRNA present in the cell samples by methods well known to the person skilled in the art, e.g. by quantitative RT-PCR. The half-life of a particular mRNA may be calculated based on the amounts of the particular mRNA measured at the different time points post inhibition of transcription. Alternatively, pulse-chase methods, e.g. using radioactively labelled nucleotides, or constructs comprising inducible promoters may be used for determining the half-life of an mRNA in mammalian cells.
It is particularly preferred that the enhanced stability of a stable mRNA in the sense of the present invention is affected by its 3'UTR. Thus, preferably, the 3'UTR element comprises or consists of a nucleic acid sequence which is derived from the 3'UTR of a stable mRNA which exhibits a half-life of more than 5 hours, preferably more than 8 hours, in a mammalian cell, such as in a mammalian cell line, e.g. in HeLa cells, or in mammalian primary cells, e.g. in HDF cells, preferably determined by using a transcription inhibitor such as actinomycin D, wherein the enhanced stability of said stable mRNA is effected by its 3'UTR. The ability of a 3'UTR for enhancing stability may be tested as described herein, e.g. by using a reporter open reading frame such as a luciferase encoding open reading frame. Alternatively, an artificial construct encoding the test stable mRNA may be generated, wherein the 3'UTR of the stable mRNA is replaced with a reference 3'UTR, such as a 3'UTR of a short lived mRNA, e.g. a Myc 3'UTR. The stability of the wild type stable mRNA and the 3'UTR modified mRNA may be determined as described above. In the event the 3'UTR modified mRNA exhibits a shorter half-life than the wild type stable mRNA, it may be concluded that a stability enhancing effect is exerted by the 3'UTR of the stable mRNA.
In a particularly preferred embodiment, the 3'UTR element comprises or consists of a nucleic acid sequence which is derived from a 3'UTR of a gene selected from the group consisting of an albumin gene, an a-globin gene, a β-globin gene, a tyrosine hydroxylase gene, a lipoxygenase gene, and a collagen alpha gene, such as a collagen alpha 1 (1) gene, or from a variant of a 3'UTR of a gene selected from the group consisting of an albumin gene, an a-globin gene, a β-globin gene, a tyrosine hydroxylase gene, a lipoxygenase gene, and a collagen alpha gene, such as a collagen alpha 1 (1) gene. In a particularly preferred embodiment, the 3'UTR element comprises or consists of a nucleic acid sequence which is derived from a 3'UTR of an albumin gene, preferably a vertebrate albumin gene, more preferably a mammalian albumin gene, most preferably a human albumin gene. In another particularly preferred embodiment, the 3'UTR element comprises or consists of a nucleic acid sequence which is derived from a 3'UTR of an α-globin gene, preferably a vertebrate α-globin gene, more preferably a mammalian α-globin gene, most preferably a human a- globin gene. For example, the 3'UTR element may comprise or consist of the center, a- complex-binding portion of the 3'UTR of an α-globin gene, such as of a human a-globin gene.
Preferably, the at least one 3'UTR element comprises or consists of a nucleic acid sequence which is derived from the 3'UTR of a vertebrate albumin gene, a vertebrate α-globin gene, a vertebrate β-globin gene, a vertebrate tyrosine hydroxylase gene, a vertebrate lipoxygenase gene, and a vertebrate collagen alpha gene, such as a vertebrate collagen alpha 1 (1) gene, or from a variant thereof, preferably from the 3'UTR of a mammalian albumin gene, a mammalian α-globin gene, a mammalian β-globin gene, a mammalian tyrosine hydroxylase gene, a mammalian lipoxygenase gene, and a mammalian collagen alpha gene, such as a mammalian collagen alpha 1 (I) gene, or from a variant thereof, more preferably from the 3'UTR of a human albumin gene, a human α-globin gene, a human β-globin gene, a human tyrosine hydroxylase gene, a human lipoxygenase gene, and a human collagen alpha gene, such as a human collagen alpha 1 (1) gene, or from a variant thereof, even more preferably from the 3'UTR of the human albumin gene according to GenBank Accession number NM_000477.5 or from a variant thereof. In a preferred embodiment, the 3'UTR element is not derived from the 3'UTR of a Xenopus albumin gene. Preferably, the 3'UTR element does not comprise a poly(A) limiting element B (PLEB) of a 3'UTR from a Xenopus albumin gene. Preferably, the 3'UTR element does not consist of a PLEB of a 3'UTR from a Xenopus albumin gene.
Preferably, the 3'UTR element and the at least one open reading frame are heterologous, e.g. preferably the 3'UTR element and the ORF are derived from different genes of the same or of different species. Preferably, the ORF does not encode an α-globin protein if the 3'UTR element is derived from an cc-globin gene. Preferably, the ORF does not encode a β- globin protein if the 3'UTR element is derived from a β-globin gene. Preferably, the ORF does not encode an albumin protein if the 3'UTR element is derived from an albumin gene. Preferably, the ORF does not encode a tyrosine hydroxylase protein if the 3'UTR element is derived from a tyrosine hydroxylase gene. Preferably, the ORF does not encode a lipoxygenase protein if the 3'UTR element is derived from a lipoxygenase gene. Preferably, the ORF does not encode a collagen alpha protein if the 3'UTR element is derived from a collagene alpha gene. Preferably, the ORF does not code for a protein selected from the group consisting of albumin proteins, growth hormones, e.g. human growth hormone (hGH), a-globin proteins, β-globin proteins, tyrosine hydroxylase proteins, lipoxygenase proteins, and collagen alpha proteins. Furthermore, it is preferred that the open reading frame does not code for a reporter protein, e.g., selected from the group consisting of globin proteins, in particular beta-globin,, luciferase protein, GFP proteins, e.g. EGFP, or variants thereof, for example, variants exhibiting at least 70% sequence identity to a globin protein, a luciferase protein, or a GFP protein.
The term 'a nucleic acid sequence which is derived from the 3'UTR of a [...] gene' preferably refers to a nucleic acid sequence which is based on the 3'UTR sequence of a [...] gene or on a part thereof, such as on the 3'UTR of an albumin gene, an a-globin gene, a β- globin gene, a tyrosine hydroxylase gene, a lipoxygenase gene, or a collagen alpha gene, such as a collagen alpha 1 (1) gene, preferably of an albumin gene or on a part thereof. This term includes sequences corresponding to the entire 3'UTR sequence, i.e. the full length 3'UTR sequence of a gene, and sequences corresponding to a fragment of the 3'UTR sequence of a gene, such as an albumin gene, α-globin gene, β-globin gene, tyrosine hydroxylase gene, lipoxygenase gene, or collagen alpha gene, such as a collagen alpha 1 (1) gene, preferably of an albumin gene. A fragment in this context preferably consists of a continuous stretch of nucleotides corresponding to a continuous stretch of nucleotides in the full-length 3'UTR, which represents at least 20%, preferably at least 30%, more preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, and most preferably at least 90% of the full-length 3'UTR. Such a fragment, in the sense of the present invention, is preferably a functional fragment as described herein. The term '3'UTR of a [...] gene' preferably refers to the 3'UTR of a naturally occurring gene, such as of a naturally occurring albumin gene, oc-globin gene, β-globin gene, tyrosine hydroxylase gene, lipoxygenase gene, or collagen alpha gene, such as a collagen alpha 1 (1) gene, preferably of a naturally occurring albumin gene. The terms 'variant of the 3'UTR of a [...] gene' and 'variant thereof in the context of a 3'UTR refers to a variant of the 3'UTR of a naturally occurring gene, such as a naturally occurring albumin gene, a naturally occurring a-globin gene, a naturally occurring β-globin gene, a naturally occurring tyrosine hydroxylase gene, a naturally occurring lipoxygenase gene, or a naturally occurring collagen alpha gene, such as a naturally occurring collagen alpha 1 (1) gene, preferably to a variant of the 3'UTR of a vertebrate albumin gene, a vertebrate a-globin gene, a vertebrate β-globin gene, a vertebrate tyrosine hydroxylase gene, a vertebrate lipoxygenase gene, and a vertebrate collagen alpha gene, such as a vertebrate collagen alpha 1 (1) gene, preferably to a variant of the 3'UTR of a mammalian albumin gene, a mammalian α-globin gene, a mammalian β-globin gene, a mammalian tyrosine hydroxylase gene, a mammalian lipoxygenase gene, and a mammalian collagen alpha gene, such as a mammalian collagen alpha 1 (1) gene, more preferably to a variant of the 3'UTR of a human albumin gene, a human α-globin gene, a human β-globin gene, a human tyrosine hydroxylase gene, a human lipoxygenase gene, and a human collagen alpha gene, such as a human collagen alpha 1 (1) gene. Such variant may be a modified 3'UTR of a gene. For example, a variant 3'UTR may exhibit one or more nucleotide deletions, insertions, additions and/or substitutions compared to the naturally occurring 3'UTR from which the variant is derived. Preferably, a variant of a 3'UTR is at least 40%, preferably at least 50%, more preferably at least 60%, more preferably at least 70%, even more preferably at least 80%, even more preferably at least 90%, most preferably at least 95% identical to the naturally occurring 3'UTR the variant is derived from. Preferably, the variant is a functional variant as described herein.
The term 'a nucleic acid sequence which is derived from a variant of the 3'UTR of a [...] gene' preferably refers to a nucleic acid sequence which is based on a variant of the 3'UTR sequence of a gene, such as on a variant of the 3'UTR of an albumin gene, an a-globin gene, a β-globin gene, a tyrosine hydroxylase gene, a lipoxygenase gene, or a collagen alpha gene, such as a collagen alpha 1 (I) gene, or on a part thereof as described above. This term includes sequences corresponding to the entire sequence of the variant of the 3'UTR of a gene, i.e. the full length variant 3'UTR sequence of a gene, and sequences corresponding to a fragment of the variant 3'UTR sequence of a gene. A fragment in this context preferably consists of a continuous stretch of nucleotides corresponding to a continuous stretch of nucleotides in the full-length variant 3'UTR, which represents at least 20%, preferably at least 30%, more preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, and most preferably at least 90% of the full-length variant 3'UTR. Such a fragment of a variant, in the sense of the present invention, is preferably a functional fragment of a variant as described herein.
The terms 'functional variant', 'functional fragment', and 'functional fragment of a variant' (also termed 'functional variant fragment') in the context of the present invention, mean that the fragment of the 5'UTR or the 3'UTR, the variant of the 5'UTR or the 3'UTR, or the fragment of a variant of the 5'UTR or the 3'UTR of a gene fulfils at least one, preferably more than one, function of the naturally occurring 5'UTR or 3'UTR of the gene of which the variant, the fragment, or the fragment of a variant is derived. Such function may be, for example, stabilizing mRNA and/or stabilizing and/or prolonging protein production from an mRNA and/or increasing protein production from an mRNA, preferably in a mammalian cell, such as in a human cell. It is particularly preferred that the variant, the fragment, and the variant fragment in the context of the present invention fulfil the function of stabilizing an mRNA, preferably in a mammalian cell, such as a human cell, compared to an mRNA comprising a reference 5'UTR and/or a reference 3'UTR or lacking a 5'UTR and/or a 3'UTR, and/or the function of stabilizing and/or prolonging protein production from an mRNA, preferably in a mammalian cell, such as in a human cell, compared to an mRNA comprising a reference 5'UTR and/or a reference 3'UTR or lacking a 5'UTR and/or a 3'UTR, and/or the function of increasing protein production from an mRNA, preferably in a mammalian cell, such as in a human cell, compared to an mRNA comprising a reference 5'UTR and/or a reference 3'UTR or lacking a 5'UTR and/or a 3'UTR. A reference 3'UTR may be, for example, a 3'UTR naturally occurring in combination with the ORF. Furthermore, a functional variant, a functional fragment, or a functional variant fragment of a 5'UTR or of a 3'UTR of a gene preferably does not have a substantially diminishing effect on the efficiency of translation of the mRNA which comprises such variant of a 5'UTR and/or such variant of a 3'UTR compared to the wild type 5'UTR and/or 3'UTR from which the variant is derived. A particularly preferred function of a "functional fragment", a "functional variant" or a "functional fragment of a variant" of the 3'UTR of a gene, such as an albumin gene, a-globin gene, β-globin gene, tyrosine hydroxylase gene, lipoxygenase gene, or collagen alpha gene, such as a collagen alpha 1 (1) gene, in the context of the present invention is the stabilization and/or prolongation of protein production by expression of an mRNA carrying the functional fragment, functional variant or functional fragment of a variant as described above. A particularly preferred function of a "functional fragment", a "functional variant" or a "functional fragment of a variant" of the 5'UTR in the context of the present invention is the protein production increasing function.
Preferably, the efficiency of the one or more functions exerted by the functional variant, the functional fragment, or the functional variant fragment, such as mRNA and/or protein production stabilizing efficiency and/or the protein production increasing efficiency, is at least 40%, more preferably at least 50%, more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, most preferably at least 90% of the mRNA and/or protein production stabilizing efficiency and/or the protein production increasing efficiency exhibited by the naturally occurring 5'UTR and/or 3'UTR of which the variant, the fragment or the variant fragment is derived. In the context of the present invention, a fragment or part of the 3'UTR of a gene, such as an albumin gene, a-globin gene, β-globin gene, tyrosine hydroxylase gene, lipoxygenase gene, or collagen alpha gene, such as a collagen alpha 1 (I) gene, or of a variant thereof preferably exhibits a length of at least about 40 nucleotides, preferably of at least about 50 nucleotides, preferably of at least about 75 nucleotides, more preferably of at least about 100 nucleotides, even more preferably of at least about 125 nucleotides, most preferably of at least about 150 nucleotides. Preferably, such fragment of the 3'UTR of a gene or of a variant of the 3'UTR of a gene is a functional fragment as described above.
In the context of the present invention, a fragment or part of the 5'UTR of a TOP gene or of a variant thereof preferably exhibits a length of at least about 20 nucleotides, preferably of at least about 30 nucleotides, more preferably of at least about 50 nucleotides. Preferably, such fragment of the 5'UTR of a TOP gene or of a variant of the 5'UTR of a TOP gene is a functional fragment as described above. In some embodiments, the at least one 3'UTR element of the artificial nucleic acid molecule according to the present invention comprises or consists of a "functional fragment", a "functional variant" or a "functional fragment of a variant" of the 3'UTR of a gene, such as of an albumin gene, cc-globin gene, β-globin gene, tyrosine hydroxylase gene, lipoxygenase gene, or collagen alpha gene, such as a collagen alpha 1 (I) gene, or of a variant thereof.
In some embodiments, the at least one 5'UTR element of the artificial nucleic acid molecule according to the present invention comprises or consists of a "functional fragment", a "functional variant" or a "functional fragment of a variant" of the 5'UTR of a TOP gene.
Preferably, the at least one 3'UTR element of the artificial nucleic acid molecule according to the present invention increases the stability of the artificial nucleic acid molecule, e.g. increases the stability of an mRNA according to the present invention, compared to a respective mRNA (reference mRNA) lacking a 3'UTR element or comprising a reference 3'UTR element, such as a 3'UTR naturally occurring in combination with the ORF. Preferably, the at least one 3'UTR element of the artificial nucleic acid molecule according to the present invention increases the stability of protein production from the artificial nucleic acid molecule according to the present invention, e.g. from an mRNA according to the present invention, compared to a respective mRNA lacking a 3'UTR element or comprising a reference 3'UTR element, such as a 3'UTR naturally occurring in combination with the ORF. Preferably, the at least one 3'UTR element of the artificial nucleic acid molecule according to the present invention prolongs protein production from the artificial nucleic acid molecule according to the present invention, e.g. from an mRNA according to the present invention, compared to a respective mRNA lacking a 3'UTR element or comprising a reference 3'UTR element, such as a 3'UTR naturally occurring in combination with the ORF. Preferably, the at least one 3'UTR element of the artificial nucleic acid molecule according to the present invention increases the protein production from the artificial nucleic acid molecule according to the present invention, e.g. from an mRNA according to the present invention, compared to a respective mRNA lacking a 3'UTR element or comprising a reference 3'UTR element, such as a 3'UTR naturally occurring in combination with the ORF. Preferably, the at least one 3'UTR element of the artificial nucleic acid molecule according to the present invention does not negatively influence translational efficiency of an mRNA compared to the translational efficiency of a respective mRNA lacking a 3'UTR element or comprising a reference 3'UTR element, such as a 3'UTR naturally occurring in combination with the ORF. The term 'respective mRNA' in this context means that - apart from the different 3'UTR - the reference mRNA is comparable, preferably identical, to the mRNA comprising the 3'UTR element.
Preferably, the at least one 5'UTR element of the artificial nucleic acid molecule according to the present invention increases the stability of the artificial nucleic acid molecule, e.g. increases the stability of an mRNA according to the present invention, compared to a respective mRNA (reference mRNA) lacking a 5'UTR element or comprising a reference 5'UTR element, such as a 5'UTR naturally occurring in combination with the ORF. Preferably, the at least one 5'UTR element of the artificial nucleic acid molecule according to the present invention increases protein production from the artificial nucleic acid molecule according to the present invention, e.g. from an mRNA according to the present invention, compared to a respective mRNA lacking a 5'UTR element or comprising a reference 5'UTR element, such as a 5'UTR naturally occurring in combination with the ORF. The term 'respective mRNA' in this context means that - apart from the different 5'UTR - the reference mRNA is comparable, preferably identical, to the mRNA comprising the inventive 5'UTR element.
Preferably, the at least one 5'UTR element and the at least one 3'UTR element act synergistically to increase protein production from the artificial nucleic acid molecule according to the present invention, e.g. from an mRNA according to the present invention, as described above.
The term 'stabilizing and/or prolonging protein production from an mRNA' preferably means that the protein production from the mRNA is stabilized and/or prolonged compared to the protein production from a reference mRNA, e.g. comprising a reference 3'UTR element or lacking a 3'UTR element.
'Stabilized protein expression' in this context preferably means that there is more uniform protein production from the artificial nucleic acid molecule according to the present invention over a predetermined period of time, such as over 24 hours, more preferably over 48 hours, even more preferably over 72 hours, when compared to a reference nucleic acid molecule, for example, an mRNA comprising a reference 3'UTR element or lacking a 3'UTR element. Thus, the level of protein production, e.g. in a mammalian system, from the artificial nucleic acid molecule comprising a 3'UTR element according to the present invention, e.g. from an mRNA according to the present invention, preferably does not drop to the extent observed for a reference nucleic acid molecule, such as a reference mRNA as described above. For example, the amount of a protein (encoded by the ORF) observed 6 hours after initiation of expression, e.g. 6 hours post transfection of the artificial nucleic acid molecule according to the present invention into a cell, such as a mammalian cell, may be comparable to the amount of protein observed 48 hours after initiation of expression, e.g. 48 hours post transfection. Thus, the ratio of the amount of protein encoded by the ORF, such as of a reporter protein, e.g., luciferase, observed at 48 hours post initiation of expression, e.g. 48 hours post transfection, to the amount of protein observed 6 hours after initiation of expression, e.g. 6 hours post transfection, is preferably above 0.4, preferably above 0.5, more preferably above 0.6, even more preferably above 0.7, e.g. between about 0.4 and about 4, preferably between about 0.65 and about 3, more preferably between about 0.7 and about 2 for a nucleic acid molecule according to the present invention. For a respective reference nucleic acid molecule, e.g. an mRNA comprising a reference 3'UTR element or lacking a 3'UTR element, said ratio may be, e.g. between about 0.05 and about 0.3. Thus, the present invention provides an artificial nucleic acid molecule comprising an ORF and a 3'UTR element as described above, wherein the ratio of the (reporter) protein amount observed 48 hours after initiation of expression to the (reporter) protein amount observed 6 hours after initiation of expression, preferably in a mammalian expression system, such as in mammalian cells, is preferably above 0.4, preferably above 0.5, more preferably above 0.6, even more preferably above 0.7, e.g. between about 0.4 and about 4, preferably between about 0.65 and about 3, more preferably between about 0.7 and about 2.
'Increased protein expression' in the context of the present invention may refer to increased protein expression at one time point after initiation of expression compared to a reference molecule or to an increased total protein production within a certain time period after initiation of expression. Thus, the protein level observed at a certain time point after initiation of expression, e.g. after transfection, of the artificial nucleic acid molecule according to the present invention, e.g. after transfection of an mRNA according to the present invention, for example, 24, 48, or 72 hours post transfection, or the total protein produced in a time span of, e.g. 24, 48 or 72 hours, is preferably higher than the protein level observed at the same time point after initiation of expression, e.g. after transfection, or the total protein produced within the same time span, for a reference nucleic acid molecule, such as a reference mRNA comprising a reference 5' and/or a reference 3'UTR or lacking a 5'UTR element and/or 3'UTR element. As set forth above, it is a particularly preferred function of the 5'UTR element to affect the increase in protein production from the artificial nucleic acid molecule. Preferably, the increase in protein production effected by the 5'UTR element compared to a reference nucleic acid molecule lacking such 5'UTR element at a given time point post initiation of expression is at least 1 .5-fold, more preferably at least 2- fold, more preferably at least 3-fold, even more preferably at least 4-fold, most preferably at least 5-fold of the protein production observed for a reference nucleic acid molecule lacking the 5'UTR element. The same holds preferably for the total protein production in a given time period, for example in a time period of 24, 48 or 72 hours post initiation of expression.
Said increase in stability of the artificial nucleic acid molecule, said increase in stability of protein production, said prolongation of protein production and/or said increase in protein production is preferably determined by comparison with a respective reference nucleic acid molecule lacking a 5'UTR element and/or a 3'UTR element, e.g. an mRNA lacking a 5'UTR element and/or a 3'UTR element, or a reference nucleic acid molecule comprising a reference 5'UTR element and/or a reference 3'UTR element, such as a 3'UTR and/or a 5'UTR naturally occurring with the ORF or a 5'UTR and/or a 3'UTR of a reference gene.
The mRNA and/or protein production stabilizing effect and efficiency and/or the protein production increasing effect and efficiency of the variants, fragments and/or variant fragments of the 3'UTR of an albumin gene as well as the mRNA and/or protein production stabilizing effect and efficiency and/or the protein production increasing effect and efficiency of the at least one 3'UTR element, the at least one 5'UTR element, or the at least one 3'UTR element and the at least one 5'UTR element of the artificial nucleic acid molecule according to the present invention may be determined by any method suitable for this purpose known to the skilled person. For example, artificial mRNA molecules may be generated comprising a coding sequence for a reporter protein, such as luciferase, and no 3'UTR and/or no 5'UTR, a 5'UTR element derived from a TOP gene and/or a 3'UTR elem,ent derived from a gene as described above, a 5'UTR element derived from a reference gene and/or a 3'UTR derived derived from a reference gene (i.e., a reference 3'UTR element or a reference 5'UTR element, such as a 5'UTR or a 3'UTR naturally occurring with the ORF), as 3'UTR a variant of a 3'UTR of a gene as described above, as 3'UTR a fragment of a 3'UTR of a gene as described above, or as 3'UTR a fragment of a variant of a 3'UTR of a gene as described above, as 5'UTR a variant of a 5'UTR of a TOP gene, as 5'UTR a fragment of a 5'UTR of a TOP gene, or as 5'UTR a fragment of a variant of a 5'UTR of a TOP gene. Such mRNAs may be generated, for example, by in vitro transcription of respective vectors such as plasmid vectors, e.g. comprising a T7 promoter and a sequence encoding the respective mRNA sequences. The generated mRNA molecules may be transfected into cells by any transfection method suitable for transfecting mRNA, for example they may be electroporated into mammalian cells, such as HELA or HDF cells, and samples may be analyzed certain time points after transfection, for example, 6 hours, 24 hours, 48 hours, and 72 hours post transfection. Said samples may be analyzed for mRNA quantities and/or protein quantities by methods well known to the skilled person. For example, the quantities of reporter mRNA present in the cells at the sample time points may be determined by quantitative PCR methods. The quantities of reporter protein encoded by the respective mRNAs may be determined, e.g., by ELISA assays or reporter assays such as luciferase assays depending on the reporter protein used. The effect of stabilizing protein expression and/or prolonging protein expression may be, for example, analyzed by determining the ratio of the protein level observed 48 hours post transfection and the protein level observed 6 hours post transfection. The closer said value is to 1 , the more stable the protein expression is within this time period. Said value may also be above 1 if the protein level is higher at the later time point. Such measurements may of course also be performed at 72 or more hours and the ratio of the protein level observed 72 hours post transfection and the protein level observed 6 hours post transfection may be determined to determine stability of protein expression.
Preferably, the at least one 3'UTR element of the artificial nucleic acid molecule according to the present invention comprises or consists of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99%, most preferably of 100% to a nucleic acid sequence selected from SEQ ID No. 1369-1377, 1391 , 1392, and 1393 and wherein the variants of the sequences according to SEQ ID No. 1369-1377, 1391 , 1 392 and 1393 are preferably functional variants as described above.
The at least one 3'UTR element of the artificial nucleic acid molecule according to the present invention may also comprise or consist of a fragment of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99%, most preferably of 100% to the nucleic acid sequence according to SEQ ID No. 1369-1377, 1391 , 1392, or 1393 wherein the fragment is preferably a functional fragment or a functional variant fragment as described above. Preferably, the fragment is as described above, i.e. being a continuous stretch of nucleotides representing at least 20% etc. of the full-length 3'UTR the fragment is derived from. Such fragment preferably exhibits a length of at least about 40 nucleotides, preferably of at least about 50 nucleotides, preferably of at least about 75 nucleotides, more preferably of at least about 100 nucleotides, even more preferably of at least about 125 nucleotides, most preferably of at least about 150 nucleotides.
For example, such fragment may exhibit a nucleic acid sequence according to SEQ ID Nos. 1378-1390, such as
AAAAGCATCT CAGCCTACCA TGAGAATAAG AGAAAGAAAA TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT TGCCTCTTTT CTCTGTGCTT CAATT (SEQ ID No. 1378) CATCACATTT AAAAGCATCT CAGCCTACCA TGAGAATAAG AGAAAGAAAA TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG (SEQ ID No. 1379) AAAAGCATCT CAGCCTACCA TGAGAATAAG AGAAAGAAAA TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC (SEQ ID No. 1380) CAGCCTACCA TGAGAATAAG AGAAAGAAAA TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT (SEQ ID No. 1381 )
TGAGAATAAG AGAAAGAAAA TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT (SEQ ID No. 1382)
AGAAAGAAAA TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT TGCCTCTTTT (SEQ ID No. 1383)
TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG
TCTAAAAAAC ATAAATTTCT TTAATCATTT TGCCTCTTTT CTCTGTGCTT (SEQ ID No. 1384)
AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC
ATAAATTTCT TTAATCATTT TGCCTCTTTT CTCTGTGCTT CAATTAATAA (SEQ ID No. 1385) ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT
TTAATCATTT TGCCTCTTTT CTCTGTGCTT CAATTAATAA AAAATGGAAA (SEQ ID No. 1386)
CAGCCTACCA TGAGAATAAG AGAAAGAAAA TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT
TGCCTCTTTT CTCTGTGCTT CAATTAATAA A (SEQ ID No . 1387) TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT TGCCTCTTTT CTCTGTGCTT CAATTAATAA
A (SEQ ID No. 1388) CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT TGCCTCTTTT CTCTGTGCTT CAATTAATAA A (SEQ ID No. 1389)
AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC
(SEQ ID No. 1390) or the corresponding RNA sequence, or a nucleic acid sequence which is at least 40%, preferably at least about 50%, preferably at least about 60%, preferably at least about 70%, more preferably at least about 80%, more preferably at least about 90%, even more preferably at least about 95%, even more preferably at least about 99% identical to said nucleic acid sequences or the corresponding RNA sequence. Thus, the at least one 3'UTR element of the artificial nucleic acid molecule according to the present invention may comprise or consist of a nucleic acid fragment as described above. Obviously, the thymidine nucleotides comprised in the fragments according to SEQ ID Nos. 1378-1390 may be replaced by uridine nucleotides.
Preferably, said variants, fragments or variant fragments are functional variants, functional fragments, or functional variant fragments as described above, exhibiting at least one function of the nucleic acid sequence according to SEQ ID Nos. 1369-1377, 1391 , 1392, or 1393 such as stabilization of the artificial nucleic acid molecule according to the invention, stabilizing and/or prolonging protein expression from the artificial nucleic acid molecule according to the invention, and/or increasing protein production, preferably with an efficiency of at least 40%, more preferably of at least 50%, more preferably of at least 60%, even more preferably of at least 70%, even more preferably of at least 80%, most preferably of at least 90% of the stabilizing efficiency and/or protein production increasing efficiency exhibited by the nucleic acid sequence according to SEQ ID Nos. 1369-1377, 1391 , 1392, or 1393. Preferably, variants, fragments or variant fragments are functional variants, functional fragments, or functional variant fragments exhibit the function of acting synergistically with the 5'UTR element to increase protein production from the artificial nucleic acid molecule. Preferably, the at least one 3'UTR element of the artificial nucleic acid molecule according to the present invention exhibits a length of at least about 40 nucleotides, preferably of at least about 50 nucleotides, preferably of at least about 75 nucleotides, more preferably of at least about 100 nucleotides, even more preferably of at least about 125 nucleotides, most preferably of at least about 150 nucleotides. For example, the 3'UTR may exhibit a length of about 50 to about 300 nucleotides, preferably of about 100 to about 250 nucleotides, more preferably of about 150 to about 200 nucleotides. Furthermore, the artificial nucleic acid molecule according to the present invention may comprise more than one 3'UTR elements as described above. For example, the artificial nucleic acid molecule according to the present invention may comprise one, two, three, four or more 3'UTR elements, wherein the individual 3'UTR elements may be the same or they may be different. For example, the artificial nucleic acid molecule according to the present invention may comprise two essentially identical 3'UTR elements as described above, e.g. two 3'UTR elements comprising or consisting of a nucleic acid sequence which is derived from the 3'UTR of an albumin gene or from a variant of the 3'UTR of an albumin gene, such as a nucleic acid sequence according to SEQ ID No. 1369 or 1 376, functional variants thereof, functional fragments thereof, or functional variant fragments thereof as described above.
Surprisingly, the inventors found that an artificial nucleic acid molecule comprising a 5'UTR element comprising or consisting of a nucleic acid sequence derived from a TOP gene as described above may represent or may provide an mRNA molecule exhibiting strongly enhanced protein production from said artificial nucleic acid molecule.
The artificial nucleic acid molecule according to the present invention may be RNA, such as mRNA, DNA, such as a DNA vector, or may be a modified RNA or DNA molecule. It may be provided as a double-stranded molecule having a sense strand and an anti-sense strand, for example, as a DNA molecule having a sense strand and an anti-sense strand.
The artificial nucleic acid molecule according to the present invention may further comprise a 5'-cap. The optional 5'-cap is preferably attached to the 5'-side of the 5'UTR element. In a preferred embodiment, the artificial nucleic acid sequence comprises a 5'UTR element which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a TOP gene encoding a ribosomal protein as described above, for example, encoding a ribosomal Large protein, or from a variant thereof, and a 3'UTR element which comprises or consists of a nucleic acid sequence which is derived from the 3'UTR of an albumin gene or a variant thereof as described above.
In a particularly preferred embodiment, the artificial nucleic acid sequence comprises a 5'UTR element which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a ribosomal protein Large 32 gene (RPL32), a ribosomal protein Large 35 gene (RPL35), a ribosomal protein Large 21 gene (RPL21 ), an ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 , cardiac muscle (ATP5A1 ) gene, an hydroxysteroid (1 7-beta) dehydrogenase 4 gene (HSD1 7B4), an androgen-induced 1 gene (AIG1 ), cytochrome c oxidase subunit Vic gene (COX6C), or a N-acylsphingosine amidohydrolase (acid ceramidase) 1 gene (ASAH1 ) or from a variant thereof, preferably from a vertebrate ribosomal protein Large 32 gene (RPL32), a vertebrate ribosomal protein Large 35 gene (RPL35), a vertebrate ribosomal protein Large 21 gene (RPL21 ), a vertebrate ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 , cardiac muscle (ATP5A1 ) gene, a vertebrate hydroxysteroid (1 7-beta) dehydrogenase 4 gene (HSD1 7B4), a vertebrate androgen-induced 1 gene (AIG1 ), a vertebrate cytochrome c oxidase subunit Vic gene (COX6C), or a vertebrate N-acylsphingosine amidohydrolase (acid ceramidase) 1 gene (ASAH1 ) or from a variant thereof, more preferably from a mammalian ribosomal protein Large 32 gene (RPL32), a ribosomal protein Large 35 gene (RPL35), a ribosomal protein Large 21 gene (RPL21 ), a mammalian ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 , cardiac muscle (ATP5A1 ) gene, a mammalian hydroxysteroid (1 7-beta) dehydrogenase 4 gene (HSD1 7B4), a mammalian androgen-induced 1 gene (AIG1 ), a mammalian cytochrome c oxidase subunit Vic gene (COX6C), or a mammalian N- acylsphingosine amidohydrolase (acid ceramidase) 1 gene (ASAH1 ) or from a variant thereof, most preferably from a human ribosomal protein Large 32 gene (RPL32), a human ribosomal protein Large 35 gene (RPL35), a human ribosomal protein Large 21 gene (RPL21 ), a human ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 , cardiac muscle (ATP5A1 ) gene, a human hydroxysteroid (1 7-beta) dehydrogenase 4 gene (HSD1 7B4), a human androgen-induced 1 gene (AIG1 ), a human cytochrome c oxidase subunit Vic gene (COX6C), or a human N-acylsphingosine amidohydrolase (acid ceramidase) 1 gene (ASAH1 ) or from a variant thereof, wherein preferably the 5'UT element does not comprise the 5'TOP of said gene, and a 3'UTR element which comprises or consists of a nucleic acid sequence which is derived from an albumin gene as described above.
In a particularly preferred embodiment, the artificial nucleic acid molecule according to the present invention comprises a 5'UTR element which comprises or consists of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to the nucleic acid sequence according to SEQ ID No. 1368 or SEQ ID NOs 1412-1420, or a corresponding RNA sequence, and a 3'UTR element which comprises or consist of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99%, most preferably of 100% to the nucleic acid sequence according to SEQ ID No. 1369, 1376, 1377, 1391 , or 1392, e.g., a 5'UTR element which comprises or consists of a nucleic acid sequence which has an identity of at least about 90% to the nucleic acid sequence according to SEQ ID No. 1368 or a corresponding RNA sequence and a 3'UTR element which comprises or consist of a nucleic acid sequence which has an identity of at least about 90% to the nucleic acid sequence according to SEQ ID No. 1369, 1376, 1377, 1391 , or 1392.
Preferably, the artificial nucleic acid molecule according to the present invention further comprises a poly(A) sequence and/or a polyadenylation signal. Preferably, the optional poly(A) sequence is located 3' to the ORF or the at least one 3'UTR element, preferably is connected to the 3'-end of the ORF or the 3'UTR element. The connection may be direct or indirect, for example, via a stretch of 2, 4, 6, 8, 10, 20 etc. nucleotides, such as via a linker of 1 -50, preferably of 1 -20 nucleotides, e.g. comprising or consisting of one or more restriction sites. In one embodiment, the optional polyadenylation signal is located within the 3'UTR element. Preferably, the polyadenylation signal comprises the consensus sequence NN(U/T)ANA, with N = A or U, preferably AA(U/T)AAA or A(U/T)(U/OAAA. Such consensus sequence may be recognised by most animal and bacterial cell-systems, for example by the polyadenylation-factors, such as cleavage/polyadenylation specificity factor (CPSF) cooperating with CstF, PAP, PAB2, CFI and/or CFII. Preferably, the polyadenylation signal, preferably the consensus sequence NNUANA, is located less than about 50 nucleotides, more preferably less than about 30 nucleotides, most preferably less than about 25 nucleotides, for example 21 nucleotides, upstream of the 3'-end of the 3'UTR element.
Using an appropriate transcription system will then lead to attachment of a poly(A) sequence to the premature-RNA. For example, the inventive artificial nucleic acid molecule may be a DNA molecule comprising a 3'UTR element as described above and a polyadenylation signal, which may result in polyadenylation of an RNA upon transcription of this DNA molecule. Accordingly, a resulting RNA may comprise a combination of the 3'UTR element followed by a poly(A) sequence.
Potential transcription systems are in vitro transcription systems or cellular transcription systems etc. Accordingly, transcription of an artificial nucleic acid molecule according to the invention, e.g. transcription of an artificial nucleic acid molecule comprising a 5'UTR element, an open reading frame, a 3'UTR element and a polyadenylation-signal, may result in an mRNA molecule comprising a 5'UTR element, an open reading frame, a 3'UTR element and a poly(A) sequence.
The invention also provides an artificial nucleic acid molecule which is an mRNA molecule comprising a, 5'UTR element, an open reading frame, an optional 3'UTR element as described above and a poly(A) sequence. In one embodiment, the invention provides an artificial nucleic acid molecule which is an artificial DNA molecule comprising a 5'UTR element as described above, an open reading frame and optionally a nucleic acid sequence according to any one of SEQ ID Nos. 1369- 1377, 1391 , and 1392 or a sequence having an identity of at least about 40% or more to a nucleic acid sequence according to any one of SEQ ID Nos. 1369-1377, 1391 , and 1392 or a fragment thereof. Furthermore, the invention provides an artificial nucleic acid molecule which is an artificial RNA molecule comprising a 5'UTR element as described above, an open reading frame and optionally an RNA sequence corresponding to a sequence according to any one of SEQ ID Nos. 1369-1377, 1391 , and 1392 or a sequence having an identity of at least about 40 % or more to any one of SEQ ID Nos. 1369-1377, 1391 , and 1392, or a fragment thereof.
Accordingly, the invention provides an artificial nucleic acid molecule which may be a template for an RNA molecule, preferably for an mRNA molecule, which is stabilised and optimized with respect to translation efficiency. In other words, the artificial nucleic acid molecule may be a DNA or RNA which may be used for production of an mRNA. The obtainable mRNA, may, in turn, be translated for production of a desired peptide or protein encoded by the open reading frame. If the artificial nucleic acid molecule is a DNA, it may, for example, be used as a double-stranded storage form for continued and repetitive in vitro or in vivo production of mRNA.
In one embodiment, the artificial nucleic acid molecule according to the present invention further comprises a poly(A) sequence. The length of the poly(A) sequence may vary. For example, the poly(A) sequence may have a length of about 20 adenine nucleotides up to about 300 adenine nucleotides, preferably of about 40 to about 200 adenine nucleotides, more preferably from about 50 to about 100 adenine nucleotides, such as about 60, 70, 80, 90 or 100 adenine nucleotides.
For example, the artificial nucleic acid molecule according to the present invention may comprise a nucleic acid sequence corresponding to the DNA sequence
CATCACATTT AAAAGCATCT CAGCCTACCA TGAGAATAAG AGAAAGAAAA TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT TGCCTCTTTT CTCTGTGCTT CAATTAATAA AAAATGGAAA GAATCTAGAT CTAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAA (SEQ ID No. 1377). Transcription of such a sequence may result in an artificial nucleic acid molecule comprising a corresponding RNA sequence.
Such artificial RNA molecule may also be obtainable in vitro by common methods of chemical synthesis without being necessarily transcribed from a DNA progenitor.
In a particularly preferred embodiment, the artificial nucleic acid molecule according to the present invention is an RNA molecule, preferably an mRNA molecule comprising in 5'-to- 3'-direction a 5'UTR element as described above, an open reading frame, a 3'UTR element as described above and a poly(A) sequence.
In a preferred embodiment, the open reading frame does not code for human albumin, provided that the 3'UTR element is identical to the 3'UTR of human albumin. In some further embodiments, it is preferred that the open reading frame does not code for human albumin according to GenBank Accession number NM_000477.5 provided that the 3'UTR element is identical to the 3'UTR of human albumin. In some further embodiments, it is preferred that the open reading frame does not code for human albumin or variants thereof provided that the 3'UTR element is a sequence which is identical to SEQ ID No. 1369. Furthermore, in some embodiments, it is preferred that the open reading frame does not code for a reporter protein, e.g., selected from the group consisting of globin proteins, luciferase proteins, GFP proteins or variants thereof, for example, variants exhibiting at least 70% sequence identity to a globin protein, a luciferase protein, or a GFP protein.
In some embodiments, it is preferred that the 3'UTR element does not consist of a histone stem-loop, preferably does not comprise a histone stem-loop. In one embodiment, the artificial nucleic acid molecule according to the present invention does not comprise a histone stem-loop. However, in some embodiments, the 3'UTR element of the artificial nucleic acid molecule or the artificial nucleic acid molecule according to the present invention may comprise a histone stem-loop in addition to the nucleic acid sequence derived form the 3'UTR of an albumin gene. Such artificial nucleic acid molecule according to the present invention, for example, may comprise in 5'-to-3'-direction a 5'UTR element, an ORF, a 3'UTR element, preferably comprising a polyadenylation signal, an optional histone stem-loop and an optional poly(A) sequence. It may also comprise in 5'-to-3'- direction a 5'UTR element as described above, an ORF, a 3'UTR element, e.g. comprising a polyadenylation signal, a poly(A) sequence and an optional histone stem-loop.
In the context of the present invention, such a histone stem-loop is typically derived from a histone gene and comprises an intramolecular base pairing of two neighbored entirely or partially reverse complementary sequences, thereby forming a stem-loop. A stem-loop can occur in single-stranded DNA or, more commonly, in RNA. The structure is also known as a hairpin or hairpin loop and usually consists of a stem and a (terminal) loop within a consecutive sequence, wherein the stem is formed by two neighbored entirely or partially reverse complementary sequences separated by a short sequence as sort of spacer, which builds the loop of the stem-loop structure. The two neighbored entirely or partially reverse complementary sequences may be defined as e.g. stem-loop elements steml and stem2. The stem loop is formed when these two neighbored entirely or partially reverse complementary sequences, e.g. stem-loop elements steml and stem2, form base-pairs with each other, leading to a double stranded nucleic acid sequence comprising an unpaired loop at its terminal ending formed by the short sequence located between stem-loop elements steml and stem2 on the consecutive sequence. The unpaired loop thereby typically represents a region of the nucleic acid which is not capable of base pairing with either of these stem-loop elements. The resulting lollipop-shaped structure is a key building block of many RNA secondary structures. The formation of a stem-loop structure is thus dependent on the stability of the resulting stem and loop regions, wherein the first prerequisite is typically the presence of a sequence that can fold back on itself to form a paired double strand. The stability of paired stem-loop elements is determined by the length, the number of mismatches or bulges it contains (a small number of mismatches is typically tolerable, especially in a long double strand), and the base composition of the paired region. In the context of the present invention, optimal loop length is 3-10 bases, more preferably 3 to 8, 3 to 7, 3 to 6 or even more preferably 4 to 5 bases, and most preferably 4 bases. An example for a histone stem-loop sequence is the sequence according to SEQ ID NO: 1394 (CAAAGGCTCT I I I CAGAGCCACCA) or the corresponding RNA sequence. Thus, in some embodiments, the artificial nucleic acid molecule according to the present invention comprises (a.) at least one 5'UTR element as described herein, (b.) at least one open reading frame, and at least one histone-stem loop which may, for example, comprise or consist of a sequence having a sequence identity of at least about 75%, preferably of at least about 80%, preferably at least about 85%, more preferably at least about 90%, even more preferably at least about 95% to the sequence according to SEQ ID NO. 1394 or the corresponding RNA sequence, wherein preferably positions 6, 13 and 20 of the sequence having a sequence identity of at least about 75%, preferably of at least about 80%, preferably at least about 85%, more preferably at least about 90%, even more preferably at least about 95% to the sequence according to SEQ ID NO. 1394 or the corresponding RNA sequence are conserved, i.e. are identical to the nucleotides at positions 6, 13 and 20 of SEQ ID NO. 1394.
In some embodiments, the artificial nucleic acid molecule comprises further elements such as a 5'-cap, a poly(C) sequence and/or an IRES-motif. A 5'-cap may be added post- transcriptionally to the 5'end of an RNA. Further, the inventive artificial nucleic acid molecule, particularly if the nucleic acid is in the form of an mRNA or codes for an mRNA, may be modified by a sequence of at least 10 cytidines, preferably at least 20 cytidines, more preferably at least 30 cytidines (so-called "poly(C) sequence"). Particularly, the inventive nucleic acid molecule may contain, especially if the nucleic acid is in the form of an (m)RNA or codes for an mRNA, a poly(C) sequence of typically about 10 to 200 cytidine nucleotides, preferably about 10 to 100 cytidine nucleotides, more preferably about 10 to 70 cytidine nucleotides or even more preferably about 20 to 50 or even 20 to 30 cytidine nucleotides.
An internal ribosome entry side (IRES) sequence or IRES-motif may separate several open reading frames, for example if the artificial nucleic acid molecule encodes for two or more peptides or proteins. An IRES-sequence may be particularly helpful if the mRNA is a bi- or multicistronic RNA.
Furthermore, the artificial nucleic acid molecule may comprise additional 5'-elements such as a promoter containing-sequence. The promoter may drive and or regulate transcription of the artificial nucleic acid molecule according to the present invention, for example of an artificial DNA-molecule according to the present invention.
In preferred embodiments, the invention provides artificial nucleic acid molecules, prefer- ably m NA molecules, comprising in 5'-to-3'-direction at least one of the following structures
5'-cap - 5'UTR element - ORF - 3'UTR element - histone stem-loop - poly(A) sequence
5'-cap - 5'UTR element - ORF - 3'UTR element - poly(A) sequence - histone stem-loop 5'-cap - 5'UTR element - ORF - IRES - ORF - 3'UTR element - histone stem-loop - poly(A) sequence
5'-cap - 5'UTR element - ORF - IRES - ORF - 3'UTR element - poly(A) sequence - histone stem-loop
5'-cap - 5'UTR element - ORF - 3'UTR element - poly(A) sequence - poly(C) sequence 5'-cap - 5'UTR element - ORF - 3'UTR element - poly(A) sequence - poly(C) sequence - histone stem-loop
5'-cap - 5'UTR element - ORF - IRES - ORF - 3'UTR element - histone stem-loop - poly(A) sequence - poly(C) sequence Preferably, the artificial nucleic acid molecule, preferably the open reading frame, is at least partially G/C modified. Thus, the inventive artificial nucleic acid molecule may be thermodynamically stabilized by modifying the G (guanosine)/C (cytidine) content of the molecule. The G/C content of the open reading frame of an artificial nucleic acid molecule according to the present invention may be increased compared to the G/C content of the open reading frame of a corresponding wild type sequence, preferably by using the degeneration of the genetic code. Thus, the encoded amino acid sequence of the nucleic acid molecule is preferably not modified by the G/C modification compared to the coded amino acid sequence of the particular wild type sequence. The codons of a coding sequence or a whole nucleic acid molecule, e.g. an mRNA, may therefore be varied compared to the wild type coding sequence, such that they include an increased amount of G/C nucleotides while the translated amino acid sequence is maintained. In respect to the fact that several codons code for one and the same amino acid (so-called degeneration of the genetic code), the most favourable codons for the stability can be determined (so-called alternative codon usage).
Depending on the amino acid to be encoded by the coding region of the inventive nucleic acid molecule as defined herein, there are various possibilities for modification of the nucleic acid sequence, e.g. the open reading frame, compared to its wild type coding region. In the case of amino acids which are encoded by codons which contain exclusively G or C nucleotides, no modification of the codon is necessary. Thus, the codons for Pro (CCC or CCG), Arg (CGC or CGG), Ala (GCC or GCG) and Gly (GGC or GGG) require no modifica- tion, since no A or U/T is present.
In contrast, codons which contain A and/or U T nucleotides may be modified by substitution of other codons which code for the same amino acids but contain no A and/or U/T. For example the codons for Pro can be modified from CC(U/T) or CCA to CCC or CCG;
the codons for Arg can be modified from CG(U/T) or CGA or AGA or AGG to CGC or CGG; the codons for Ala can be modified from GC(U/T) or GCA to GCC or GCG;
the codons for Gly can be modified from GG(U/T) or GGA to GGC or GGG.
In other cases, although A or (U/T) nucleotides cannot be eliminated from the codons, it is however possible to decrease the A and (U/T) content by using codons which contain a lower content of A and/or (U/T) nucleotides. Examples of these are: The codons for Phe can be modified from (U T)(U T)(U/T) to (U T) (UAT)C;
the codons for Leu can be modified from (U/T) (U/T) A, (U/T) (U T)G, C(U T) (U/T) or C(U T)A to C(UJT)C or C(UJT)G;
the codons for Ser can be modified from (U/T)C(U/T) or (U T)CA or AG(U/T) to (UAT)CC, (U DCG or AGC;
the codon for Tyr can be modified from (U T)A(U T) to (UAT)AC;
the codon for Cys can be modified from (U/T)G(U/T) to (U/T)GC;
the codon for His can be modified from CA(U/T) to CAC;
the codon for Gin can be modified from CAA to CAG; the codons for lie can be modified from A(UAT)(U T) or A(U T)A to A(U T)C; the codons for Thr can be modified from AC(U/T) or ACA to ACC or ACG;
the codon for Asn can be modified from AA(U/T) to AAC;
the codon for Lys can be modified from AAA to AAG;
the codons for Val can be modified from G(U/T)(U/T) or G(U/T)A to G(U T)C or G(U/T)G; the codon for Asp can be modified from GA(U/T) to GAC;
the codon for Glu can be modified from GAA to GAG;
the stop codon (U T)AA can be modified to (U T)AG or (U T)GA. In the case of the codons for Met (A(U/T)G) and Trp ((U/T)GG), on the other hand, there is no possibility of sequence modification without altering the encoded amino acid sequence.
The substitutions listed above can be used either individually or in all possible combinations to increase the G/C content of the open reading frame of the inventive nucleic acid sequence as defined herein, compared to its particular wild type open reading frame (i.e. the original sequence). Thus, for example, all codons for Thr occurring in the wild type sequence can be modified to ACC (or ACG).
Preferably, the G/C content of the open reading frame of the inventive artificial nucleic acid molecule as defined herein is increased by at least 7%, more preferably by at least 1 5%, particularly preferably by at least 20%, compared to the G/C content of the wild type coding region. According to a specific embodiment at least 5%, 10%, 20%, 30%, 40%, 50%, 60%, more preferably at least 70 %, even more preferably at least 80% and most preferably at least 90%, 95% or even 100% of the substitutable codons in the open reading frame of the inventive artificial nucleic acid molecule or a fragment, variant or derivative thereof are substituted, thereby increasing the G/C content of said open reading frame.
In this context, it is particularly preferable to increase the G/C content of the open reading frame of the inventive nucleic acid sequence as defined herein, to the maximum (i.e. 100% of the substitutable codons), compared to the wild type open reading frame.
Furthermore, the open reading frame is preferably at least partially codon-optimized. Codon-optimization is based on the finding that the translation efficiency may be determined by a different frequency in the occurrence of transfer RNAs (tRNAs) in cells. Thus, if so-called "rare codons" are present in the coding region of the inventive artificial nucleic acid molecule as defined herein, to an increased extent, the translation of the corresponding modified nucleic acid sequence is less efficient than in the case where codons coding for relatively "frequent" tRNAs are present. Thus, the open reading frame of the inventive nucleic acid sequence is preferably modified compared to the corresponding wild type coding region such that at least one codon of the wild type sequence which codes for a tRNA which is relatively rare in the cell is exchanged for a codon which codes for a tRNA which is comparably frequent in the cell and carries the same amino acid as the relatively rare tRNA. By this modification, the open reading frame of the inventive artificial nucleic acid molecule as defined herein, is modified such that codons for which frequently occurring tRNAs are available may replace codons which correspond to rare tRNAs. In other words, according to the invention, by such a modification all codons of the wild type open reading frame which code for a rare tRNA may be exchanged for a codon which codes for a tRNA which is more frequent in the cell and which carries the same amino acid as the rare tRNA. Which tRNAs occur relatively frequently in the cell and which, in contrast, occur relatively rarely is known to a person skilled in the art; cf. e.g. Akashi, Curr. Opin. Genet. Dev. 2001 , 1 1 (6): 660-666. Accordingly, preferably, the open reading frame is codon-optimized, preferably with respect to the system in which the nucleic acid molecule according to the present invention is to be ex- pressed, preferably with respect to the system in which the nucleic acid molecule according to the present invention is to be translated. Preferably, the codon usage of the open reading frame is codon-optimized according to mammalian codon usage, more preferably according to human codon usage. Preferably, the open reading frame is codon-optimized and G/C-content modified. For further improving degradation resistance, e.g. resistance to in vivo degradation by an exo- or endonuclease, and/or for further improving protein production from the artificial nucleic acid molecule according to the present invention, the artificial nucleic acid molecule may further comprise modifications, such as backbone modifications, sugar modifications and/or base modifications, e.g., lipid-modifications or the like. Preferably, the tran- scription and/or the translation of the artificial nucleic acid molecule according to the present invention is not significantly impaired by said modifications. Nucleotide analogues/modifications that may be used in the context of the present invention may be selected, for example, from 2-amino-6-chloropurineriboside-5'-triphosphate, 2- aminoadenosine-5'-triphosphate, 2-thiocytidine-5'-triphosphate, 2-thiouridine-5'- triphosphate, 4-thiouridine-5'-triphosphate, 5-aminoallylcytidine-5'-triphosphate, 5- aminoallyluridine-5'-triphosphate, 5-bromocytidine-5'-triphosphate, 5-bromouridine-5'- triphosphate, 5-iodocytidine-5'-triphosphate, 5-iodouridine-5'-triphosphate, 5- methylcytidine-5 '-triphosphate, 5-methyluridine-5 '-triphosphate, 6-azacytidine-5'- triphosphate, 6-azauridine-5'-triphosphate, 6-chloropurineriboside-5'-triphosphate, 7- deazaadenosine-5 '-triphosphate, 7-deazaguanosine-5 '-triphosphate, 8-azaadenosine-5'- triphosphate, 8-azidoadenosine-5'-triphosphate, benzimidazole-riboside-5'-triphosphate, N1 -methyladenosine-5'-triphosphate, N1 -methylguanosine-5'-triphosphate, N6- methyladenosine-5 '-triphosphate, 06-methylguanosine-5 '-triphosphate, pseudouridine-5'- triphosphate, or puromycin-5'-triphosphate, xanthosine-5'-triphosphate. Particular preference is given to nucleotides for base modifications selected from the group of base-modified nucleotides consisting of 5-methylcytidine-5'-triphosphate, 7-deazaguanosine-5'- triphosphate, 5 -bromocytidine-5' -triphosphate, and pseudouridine-5'-triphosphate.
Further, lipid-modified artificial nucleic acid molecules may typically comprise at least one linker which is covalently linked with the artificial nucleic acid molecule, and at least one lipid which is covalently linked with this linker. Alternatively, a lipid-modified artificial nu- cleic acid molecule may comprise at least one artificial nucleic acid molecule as defined herein and at least one, preferably bifunctional lipid which is covalently linked, preferably without a linker, with that artificial nucleic acid molecule. According to a third alternative, a lipid-modified artificial nucleic acid molecule may comprise an artificial nucleic acid molecule as defined herein, at least one linker which is covalently linked with that artificial nucleic acid molecule, at least one lipid which is covalently linked with this linker, and additionally at least one, preferably bifunctional lipid which is covalently linked, preferably without a linker, with the artificial nucleic acid molecule.
In a further aspect, the present invention provides a vector comprising
a. at least one 5'-untranslated region element (5'UT element) which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a TOP gene or which is derived from a variant of the 5'UTR of a TOP gene; b. at least one open reading frame (ORF) and/or a cloning site; and c. optionally, at least one 3'UTR element which comprises or consists of a nucleic acid sequence derived from the 3'UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene, or from a variant of the 3'UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene.
The at least one 5'UTR element, the optional at least one 3'UTR element and the at least one ORF are as described herein for the artificial nucleic acid molecule according to the present invention. The cloning site may be any sequence that is suitable for introducing an open reading frame or a sequence comprising an open reading frame, such as one or more restriction sites. The vector comprising a cloning site is preferably suitable for inserting an open reading frame into the vector 3' to the 5'UTR element, preferably directly 3' to the 5'UTR element. Thus, the vector comprising a cloning site is preferably suitable for inserting an open reading frame into the vector, preferably for inserting an open reading frame between the 5'UTR element and the optional 3'UTR element, preferably 5' to the optional 3'UTR element and 3' to the 5'UTR element. Preferably, the cloning site or the ORF is located 5' to the 3'UTR element, preferably in close proximity to the 5'-end of the 3'UTR element. For example, the cloning site or the ORF may be directly connected to the 5'-end of the 3'UTR element or they may be connected via a stretch of nucleotides, such as by a stretch of 2, 4, 6, 8, 10, 20 etc. nucleotides as described above for the artificial nucleic acid molecule according to the present invention. Preferably the cloning site or the ORF is located 3' to the 5'UTR element, preferably in close proximity to the 3'-end of the 5'UTR element. For example, the cloning site or the ORF may be directly connected to the 3'-end of the 5'UTR element or they may be connected via a stretch of nucleotides, such as by a stretch of 2, 4, 6, 8, 10, 20 etc. nucleotides as described above for the artificial nucleic acid molecule according to the present invention.
Preferably the vector according to the present invention is suitable for producing the artificial nucleic acid molecule according to the present invention, preferably for producing an artificial mRNA according to the present invention, for example, by optionally inserting an open reading frame or a sequence comprising an open reading frame into the vector and transcribing the vector. Thus, preferably, the vector comprises elements needed for transcription, such as a promoter, e.g. an RNA polymerase promoter. Preferably, the vector is suitable for transcription using eukaryotic, prokaryotic, viral or phage transcription systems, such as eukaryotic cells, prokaryotic cells, or eukaryotic, prokaryotic, viral or phage in vitro transcription systems. Thus, for example, the vector may comprise a promoter sequence, which is recognized by a polymerase, such as by an RNA polymerase, e.g. by a eukaryotic, prokaryotic, viral, or phage RNA polymerase. In a preferred embodiment, the vector comprises a phage RNA polymerase promoter such as an SP6 or T7, preferably a T7 promoter. Preferably, the vector is suitable for in vitro transcription using a phage based in vitro transcription system, such as a T7 RNA polymerase based in vitro transcription system.
The vector may further comprise a poly(A) sequence and/or a polyadenylation signal as described above for the artificial nucleic acid molecule according to the present invention. The vector may be an RNA vector or a DNA vector. Preferably, the vector is a DNA vector. The vector may be any vector known to the skilled person, such as a viral vector or a plasmid vector. Preferably, the vector is a plasmid vector, preferably a DNA plasmid vector.
In a preferred embodiment, the vector according to the present invention comprises the artificial nucleic acid molecule according to the present invention.
Preferably, a vector according to the present invention comprises a sequence according to SEQ ID NOs. 1 -1363, 1395, 1421 , 1422, 1368, or 1412-1420, or a sequence having an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%; even more preferably of at least about 99%; even more preferably of 100% sequence identity to a sequence according to any one of SEQ ID NOs. 1 -1363, 1395, 1421 , 1422, 1368, or 1412- 1420, or a fragment thereof, preferably a functional fragment thereof, or a corresponding RNA sequence.
Preferably, a vector, such as a DNA vector, according to the present invention comprises a sequence according to SEQ ID NOs. 1368-1392 or 1412-1420, or a sequence having an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%; even more preferably of at least about 99%; even more preferably of 100% sequence identity to a sequence according to any one of SEQ ID NOs. 1368-1392 or 1412-1420 or a fragment thereof, preferably a functional fragment thereof, or a corresponding RNA sequence.
Preferably, the vector is a circular molecule. Preferably, the vector is a double-stranded molecule, such as a double stranded DNA molecule. Such circular, preferably double stranded DNA molecule may be used conveniently as a storage form for the inventive artificial nucleic acid molecule. Furthermore, it may be used for transfection of cells, for example, cultured cells. Also it may be used for in vitro transcription for obtaining an artificial RNA molecule according to the invention. Preferably, the vector, preferably the circular vector, is linearizable, for example, by restriction enzyme digestion. In a preferred embodiment, the vector comprises a cleavage site, such as a restriction site, preferably a unique cleavage site, located immediately 3' to the ORF, or - if present - immediately 3' to the 3'UTR element, or - if present - immediately 3' to the poly(A) sequence or polyadenylation signal, or - if present - located 3' to the poly(C) sequence, or - if present - located 3' to the histone stem-loop". Thus, preferably, the product obtained by linearizing the vector terminates at the 3'end with the stop codon, or - if present - the 3'-end of the 3'UTR element, or - if present - with the 3'-end of the poly(A) sequence or with the 3'-end of the polyadenylation signal, or - if present - with the 3'-end of the poly(C) sequence, or - if present - with the 3'-end of the histone stem-loop, plus optionally some nucleotides remaining from the restriction site after cleavage.
In a further aspect, the present invention relates to a cell comprising the artificial nucleic acid molecule according to the present invention or the vector according to present invention. The cell may be any cell, such as a bacterial cell, insect cell, plant cell, vertebrate cell, e.g. a mammalian cell. Such cell may be, e.g., used for replication of the vector of the present invention, for example, in a bacterial cell. Furthermore, the cell may be used for transcribing the artificial nucleic acid molecule or the vector according to the present invention and/or translating the open reading frame of the artificial nucleic acid molecule or the vector according to the present invention. For example, the cell may be used for recombinant protein production.
The cells according to the present invention are, for example, obtainable by standard nucleic acid transfer methods, such as standard transfection methods. For example, the artificial nucleic acid molecule or the vector according to the present invention may be transferred into the cell by electroporation, lipofection, e.g. based on cationic lipids and/or liposomes, calcium phosphate precipitation, nanoparticle based transfection, virus based transfection, or based on cationic polymers, such as DEAE-dextran or polyethylenimine etc.
Preferably, the cell is a mammalian cell, such as a cell of human subject, a domestic animal, a laboratory animal, such as a mouse or rat cell. Preferably the cell is a human cell. The cell may be a cell of an established cell line, such as a CHO, BHK, 293T, COS-7, HELA, HEK etc. cell, or the cell may be a primary cell, e.g. a HDF cell, preferably a cell isolated from an organism. In a preferred embodiment, the cell is an isolated cell of a mammalian subject, preferably of a human subject. For example, the cell may be an immune cell, such as a dendritic cell, a cancer or tumor cell, or any somatic cell etc., preferably of a mammalian subject, preferably of a human subject. In a further aspect, the present invention provides a pharmaceutical composition comprising the artificial nucleic acid molecule according to the present invention, the vector according the present invention, or the cell according to the present invention. The pharmaceutical composition according to the invention may be used, e.g., as a vaccine, for example, for genetic vaccination. Thus, the O F may, e.g., encode an antigen to be administered to a patient for vaccination. Thus, in a preferred embodiment, the pharmaceutical composition according to the present invention is a vaccine. Furthermore, the pharmaceutical composition according to the present invention may be used, e.g., for gene therapy.
Preferably, the pharmaceutical composition further comprises one or more pharmaceuti- cally acceptable excipients, vehicles, fillers and/or diluents. In the context of the present invention, a pharmaceutically acceptable vehicle typically includes a liquid or non-liquid basis for the inventive pharmaceutical composition. In one embodiment, the pharmaceutical composition is provided in liquid form. In this context, preferably, the vehicle is based on water, such as pyrogen-free water, isotonic saline or buffered (aqueous) solutions, e.g. phosphate, citrate etc. buffered solutions. The buffer may be hypertonic, isotonic or hypotonic with reference to the specific reference medium, i.e. the buffer may have a higher, identical or lower salt content with reference to the specific reference medium, wherein preferably such concentrations of the afore mentioned salts may be used, which do not lead to damage of mammalian cells due to osmosis or other concentration effects. Reference media are e.g. liquids occurring in "in vivd' methods, such as blood, lymph, cytosolic liquids, or other body liquids, or e.g. liquids, which may be used as reference media in "in vitrd' methods, such as common buffers or liquids. Such common buffers or liquids are known to a skilled person. Ringer-Lactate solution is particularly preferred as a liquid basis.
One or more compatible solid or liquid fillers or diluents or encapsulating compounds suitable for administration to a patient may be used as well for the inventive pharmaceutical composition. The term "compatible" as used herein preferably means that these components of the inventive pharmaceutical composition are capable of being mixed with the inventive nucleic acid, vector or cells as defined herein in such a manner that no interaction occurs which would substantially reduce the pharmaceutical effectiveness of the inventive pharmaceutical composition under typical use conditions. The pharmaceutical composition according to the present invention may optionally further comprise one or more additional pharmaceutically active components. A pharmaceutically active component in this context is a compound that exhibits a therapeutic effect to heal, ameliorate or prevent a particular indication or disease. Such compounds include, without implying any limitation, peptides or proteins, nucleic acids, (therapeutically active) low molecular weight organic or inorganic compounds (molecular weight less than 5000, preferably less than 1000), sugars, antigens or antibodies, therapeutic agents already known in the prior art, antigenic cells, antigenic cellular fragments, cellular fractions, cell wall components (e.g. polysaccharides), modified, attenuated or de-activated (e.g. chemically or by irradiation) pathogens (virus, bacteria etc.). Furthermore, the inventive pharmaceutical composition may comprise a carrier for the artificial nucleic acid molecule or the vector. Such a carrier may be suitable for mediating dissolution in physiological acceptable liquids, transport and cellular uptake of the pharmaceutical active artificial nucleic acid molecule or the vector. Accordingly, such a carrier may be a component which may be suitable for depot and delivery of an artificial nucleic acid molecule or vector according to the invention. Such components may be, for example, cationic or polycationic carriers or compounds which may serve as transfection or com- plexation agent.
Particularly preferred transfection or complexation agents in this context are cationic or polycationic compounds, including protamine, nucleoline, spermine or spermidine, or other cationic peptides or proteins, such as poly-L-lysine (PLL), poly-arginine, basic polypeptides, cell penetrating peptides (CPPs), including HIV-binding peptides, HIV-1 Tat (HIV), Tat-derived peptides, Penetratin, VP22 derived or analog peptides, HSV VP22 (Herpes sim- plex), MAP, KALA or protein transduction domains (PTDs), PpT620, prolin-rich peptides, arginine-rich peptides, lysine-rich peptides, MPG-peptide(s), Pep-1 , L-oligomers, Calcitonin peptide(s), Antennapedia-derived peptides (particularly from Drosophila antennapedia), pAntp, plsl, FGF, Lactoferrin, Transportan, Buforin-2, Bac715-24, SynB, SynB(1 ), pVEC, hCT-derived peptides, SAP, or histones.
Furthermore, such cationic or polycationic compounds or carriers may be cationic or polycationic peptides or proteins, which preferably comprise or are additionally modified to comprise at least one -SH moiety. Preferably, a cationic or polycationic carrier is selected from cationic peptides having the following sum formula (I):
{(Arg),;(Lys)m;(His)n;(Orn)0;(Xaa)x}; formula (I) wherein l + m + n + o + x = 3-100, and I, m, n or o independently of each other is any number selected from 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 1 6, 1 7, 18, 1 9, 20, 21 -30, 31 -40, 41 -50, 51 -60, 61 -70, 71 -80, 81 -90 and 91 -100 provided that the overall content of Arg (Arginine), Lys (Lysine), His (Histidine) and Orn (Ornithine) represents at least 10% of all amino acids of the oligopeptide; and Xaa is any amino acid selected from native (= naturally occurring) or non-native amino acids except of Arg, Lys, His or Orn; and x is any number selected from 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 1 6, 1 7, 18, 19, 20, 21 -30, 31 -40, 41 -50, 51 -60, 61 -70, 71 -80, 81 -90, provided, that the overall content of Xaa does not exceed 90 % of all amino acids of the oligopeptide. Any of amino acids Arg, Lys, His, Orn and Xaa may be positioned at any place of the peptide. In this context cati- onic peptides or proteins in the range of 7-30 amino acids are particular preferred.
Further, the cationic or polycationic peptide or protein, when defined according to formula {(Arg)i;(Lys)m;(His)n;(Orn)0;(Xaa)x} (formula (I)) as shown above and which comprise or are additionally modified to comprise at least one -SH moeity, may be, without being restricted thereto, selected from subformula (la):
{(Arg),;(Lys)m;(His)n;(Orn)0;(Xaa')x (Cys)y} subformula (la) wherein (Arg)[,-(Lys)m;(His)n;(Orn)0; and x are as defined herein, Xaa' is any amino acid selected from native (= naturally occurring) or non-native amino acids except of Arg, Lys, His, Orn or Cys and y is any number selected from 0, 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 1 7, 18, 19, 20, 21 -30, 31 -40, 41 -50, 51 -60, 61 -70, 71 -80 and 81-90, provided that the overall content of Arg (Arginine), Lys (Lysine), His (Histidine) and Orn (Ornithine) represents at least 10% of all amino acids of the oligopeptide. Further, the cationic or polycationic peptide may be selected from subformula (lb):
Cys, {(Arg),;(Lys)m;(His)n;(Orn)0;(Xaa)x} Cys2 subformula (lb) wherein empirical formula {(Arg),;(Lys)m;(His)n;(Orn)0;(Xaa)x} (formula (III)) is as defined herein and forms a core of an amino acid sequence according to (semiempirical) formula (III) and wherein Cys, and Cys2 are Cysteines proximal to, or terminal to (Arg)i;(Lys)m;(His)n;(Orn)0;(Xaa)x.
Further preferred cationic or polycationic compounds, which can be used as transfection or complexation agent may include cationic polysaccharides, for example chitosan, poly- brene, cationic polymers, e.g. polyethyleneimine (PEI), cationic lipids, e.g. DOTMA: [1 - (2,3-sioleyloxy)propyl)]-N,N,N-trimethylammonium chloride, DMRIE, di-C14-amidine, DOTIM, SAINT, DC-Choi, BGTC, CTAP, DOPC, DODAP, DOPE: Dioleyl phosphati- dylethanol-amine, DOSPA, DODAB, DOIC, DMEPC, DOGS: Dioctadecylamidoglicylspermin, DIMRI: Dimyristo-oxypropyl dimethyl hydroxyethyl ammonium bromide, DOTAP: dioleoyloxy-3-(trimethylammonio)propane, DC-6-14: O,O- ditetradecanoyl-N^a rimethylammonioacetyl)diethanolamine chloride, CLIP1 : rac-[(2,3- dioctadecyloxypropyl)(2-hydroxyethyl)]-dimethylammonium chloride, CLIP6: rac-[2(2,3- dihexadecyloxypropyl-oxymethyloxy)ethyl]trirnethylammonium, CLIP9: rac-[2(2,3- dihexadecyloxypropyl-oxysuccinyloxy)ethyl]-trimethylammonium, oligofectamine, or cati- onic or polycationic polymers, e.g. modified polyaminoacids, such as β-aminoacid- polymers or reversed polyamides, etc., modified polyethylenes, such as PVP (poly(N-ethyl- 4-vinylpyridinium bromide)), etc., modified acrylates, such as pDMAEMA (poly(dimethylaminoethyl methylacrylate)), etc., modified Amidoamines such as pAMAM (poly(amidoamine)), etc., modified polybetaaminoester (PBAE), such as diamine end modi- fied 1 ,4 butanediol diacrylate-co-5-amino-l -pentanol polymers, etc., dendrimers, such as polypropylamine dendrimers or pAMAM based dendrimers, etc., polyimine(s), such as PEI: poly(ethyleneimine), poly(propyleneimine), etc., polyallylamine, sugar backbone based polymers, such as cyclodextrin based polymers, dextran based polymers, chitosan, etc., si Ian backbone based polymers, such as PMOXA-PDMS copolymers, etc., blockpolymers consisting of a combination of one or more cationic blocks (e.g. selected from a cationic polymer as mentioned above) and of one or more hydrophilic or hydrophobic blocks (e.g polyethyleneglycole); etc.
In this context, it is particularly preferred that the inventive artificial nucleic acid molecule or the inventive vector is complexed at least partially with a cationic or polycationic compound, preferably cationic proteins or peptides. Partially means that only a part of the inventive artificial nucleic acid molecule or the inventive vector is complexed with a cationic or polycationic compound and that the rest of the inventive artificial nucleic acid molecule or the inventive vector is in uncomplexed form ("free"). Preferably the ratio of complexed nucleic acid to: free nucleic acid is selected from a range, of about 5:1 (w/w) to about 1 :10 (w/w), more preferably from a range of about 4:1 (w/w) to about 1 :8 (w/w), even more preferably from a range of about 3:1 (w/w) to about 1 :5 (w/w) or 1 :3 (w/w), and most preferably the ratio of complexed nucleic acid to free nucleic acid is selected from a ratio of about 1 :1 (w/w).
The pharmaceutical composition according to the present invention may optionally further comprise one or more adjuvants, for example, adjuvants for stimulating the innate immune system or for enhancing cellular uptake of the artificial nucleic acid molecule or vector. In this context, an adjuvant may be understood as any compound, which is suitable to initiate or increase an immune response of the innate immune system, i.e. a non-specific immune response. In other words, when administered, the inventive pharmaceutical composition preferably elicits an innate immune response due to the adjuvant, optionally contained therein. Preferably, such an adjuvant may be an adjuvant supporting the induction of an innate immune response in a mammal. Such an adjuvant may be, for example, an immunostimulatory nucleic acid, i.e. a nucleic acid that may bind to a Toll-like-receptor or the like, preferably an immunostimulatory RNA. Such adjuvants, preferably such immunostimulatory nucleic acids, may induce an innate, i.e. unspecific, immune response which may support a specific, i.e. adaptive, immune response to the peptide or protein, i.e. the antigen, encoded by the artificial nucleic acid molecule of the pharmaceutical composition, preferably the vaccine. The inventive pharmaceutical composition may also additionally comprise any further compound, which is known to be immunostimulating due to its binding affinity (as ligands) to human Toll-like receptors TLR1 , TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, or due to its binding affinity (as ligands) to murine Toll-like receptors TLR1 , TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR1 1 , TLR12 or TLR13.
Further additives which may be included in the inventive pharmaceutical composition are, e.g., emulsifiers, such as, for example, Tween®; wetting agents, such as, for example, sodium lauryl sulfate; colouring agents; taste-imparting agents, pharmaceutical carriers; tablet- forming agents; stabilizers; antioxidants; preservatives etc.
The pharmaceutical composition according to the present invention preferably comprises a "safe and effective amount" of the components of the pharmaceutical composition, particularly of the inventive nucleic acid sequence, the vector and/or the cells as defined herein. As used herein, a "safe and effective amount" means an amount sufficient to significantly induce a positive modification of a disease or disorder as defined herein. At the same time, however, a "safe and effective amount" preferably avoids serious side-effects and permits a sensible relationship between advantage and risk. The determination of these limits typically lies within the scope of sensible medical judgment. In a further aspect, the present invention provides the artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention for use as a medicament, for example, as vaccine (in genetic vaccination) or in gene therapy.
The artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention are particularly suitable for any medical application which makes use of the therapeutic action or effect of peptides, polypeptides or proteins, or where supplementation of a particular peptide or protein is needed. Thus, the present invention provides the artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention for use in the treatment or prevention of diseases or disorders amenable to treatment by the therapeutic action or effect of peptides, polypeptides or proteins or amenable to treatment by supplementation of a particular peptide, polypeptide or protein. For example, the artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention may be used for the treatment or prevention of genetic diseases, autoimmune diseases, cancerous or tumour-related diseases, infectious diseases, chronic diseases or the like, e.g., by genetic vaccination or gene therapy. In particular, such therapeutic treatments which benefit from a stable, prolonged and/or increased presence of therapeutic peptides, polypeptides or proteins in a subject to be treated are especially suitable as medical application in the context of the present invention, since the 5'UTR element optionally in combination with the 3'UTR element provides for increased protein expression from the ORF and the 3'UTR element provides for a stable and prolonged expression of the ORF of the inventive nucleic acid molecule. Thus, a particularly suitable medical application for the artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention is vaccination, for example against infections or tumours. Thus, the present invention provides the artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention for vaccination of a subject, preferably a mammalian subject, more preferably a human subject. Preferred vaccination treatments are vaccination against infectious diseases, such as bacterial, protozoal or viral infections, and anti-tumour-vaccination. Such vaccination treatments may be prophylactic or therapeutic. Depending on the disease to be treated or prevented, the ORF may be selected. For example, the open reading frame may code for a protein that has to be supplied to a patient suffering from total lack or at least partial loss of function of a protein, such as a patient suffering from a genetic disease. Additionally, the open reading frame may be chosen from an ORF coding for a peptide or protein which beneficially influences a disease or the condition of a subject. Furthermore, the open reading frame may code for a peptide or protein which effects down-regulation of a pathological overproduction of a natural peptide or protein or elimination of cells expressing pathologically a protein or peptide. Such lack, loss of function or overproduction may, e.g., occur in the context of tumour and neoplasia, autoimmune diseases, allergies, infections, chronic diseases or the like. Furthermore, the open reading frame may code for an antigen or immunogen, e.g. for an epitope of a pathogen or for a tumour antigen. Thus, in preferred embodiments, the artificial nucleic acid molecule or the vector according to the present invention comprises an ORF encoding an amino acid sequence comprising or consisting of an antigen or immunogen, e.g. an epitope of a pathogen or a tumour-associated antigen, a 5'UTR element as described above, and optional further components, such as a 3'UTR element and/or a poly(A) sequence etc. as described above.
In the context of medical application, in particular, in the context of vaccination, it is preferred that the artificial nucleic acid molecule according to the present invention is RNA, preferably mRNA, since DNA harbours the risk of eliciting an anti-DNA immune response and tends to insert into genomic DNA. However, in some embodiments, for example, if a viral delivery vehicle, such as an adenoviral delivery vehicle is used for delivery of the artificial nucleic acid molecule or the vector according to the present invention, e.g., in the context of gene therapeutic treatments, it may be desirable that the artificial nucleic acid molecule or the vector is a DNA molecule.
The artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, intracra- nial, transdermal, intradermal, intrapulmonal, intraperitoneal, intracardial, intraarterial, and sublingual injection or infusion techniques.
Preferably, the artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the phar- maceutical composition according to the present invention is administered parenterally, e.g. by parenteral injection, more preferably by subcutaneous, intravenous, intramuscular, intraarticular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, intracranial, transdermal, intradermal, intrapulmonal, intraperitoneal, intracardial, intraarterial, sublingual injection or via infusion techniques. Particularly preferred is intradermal and intramus- cular injection. Sterile injectable forms of the inventive pharmaceutical composition may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention may also be administered orally in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
The artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention may also be administered topically, espe- dally when the target of treatment includes areas or organs readily accessible by topical application, e.g. including diseases of the skin or of any other accessible epithelial tissue. Suitable topical formulations are readily prepared for each of these areas or organs. For topical applications, the artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention may be formulated in a suitable ointment suspended or dissolved in one or more carriers.
In one embodiment, the use as a medicament comprises the step of transfection of mammalian cells, preferably in vitro transfection of mammalian cells, more preferably in vitro transfection of isolated cells of a subject to be treated by the medicament. If the use comprises the in vitro transfection of isolated cells, the use as a medicament may further comprise the (re)administration of the transfected cells to the patient. The use of the inventive artificial nucleic acid molecules or the vector as a medicament may further comprise the step of selection of successfully transfected isolated cells. Thus, it may be beneficial if the vector further comprises a selection marker. Also, the use as a medicament may comprise in vitro transfection of isolated cells and purification of an expression- product, i.e. the encoded peptide or protein from these cells. This purified peptide or protein may subsequently be administered to a subject in need thereof.
The present invention also provides a method for treating or preventing a disease or disorder as described above comprising administering the artificial nucleic acid molecule according to the present invention, the vector according to the present invention, the cell according to the present invention, or the pharmaceutical composition according to the present invention to a subject in need thereof.
Furthermore, the present invention provides a method for treating or preventing a disease or disorder comprising transfection of a cell with an artificial nucleic acid molecule according to the present invention or with the vector according to the present invention. Said transfection may be performed in vitro or in vivo. In a preferred embodiment, transfection of a cell is performed in vitro and the transfected cell is administered to a subject in need thereof, preferably to a human patient. Preferably, the cell which is to be transfected in vitro is an isolated cell of the subject, preferably of the human patient. Thus, the present invention provides a method of treatment comprising the steps of isolating a cell from a subject, preferably from a human patient, transfecting the isolated cell with the artificial nucleic acid molecule according to the present invention or the vector according to the present invention, and administering the transfected cell to the subject, preferably the human patient.
The method of treating or preventing a disorder according to the present invention is preferably a vaccination method and/or a gene therapy method as described above. As described above, the 5'UTR element and the optional 3'UTR element are capable of increasing protein production from an artificial nucleic acid molecule, such as an mRNA or vector, comprising the 5'UTR element and an ORF. Thus, in a further aspect, the present invention relates to a method for increasing protein production from an artificial nucleic acid molecule comprising the step of associating the artificial nucleic acid molecule, preferably the ORF contained within the artificial nucleic acid molecule, with (i) at least one 5'-untranslated region element (5'UTR element) which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a TOP gene or which is derived from a variant of the 5'UTR of a TOP gene as described above and (ii) optionally at least one 3'UTR element which comprises or consists of a nucleic acid sequence derived from the 3'UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene, or from a variant of the 3'UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene as described above. The term "associating the artificial nucleic acid molecule or the vector with a 5 'UTR element and an optional 3'UTR element" in the context of the present invention preferably means functionally associating or functionally combining the artificial nucleic acid molecule, such as the mRNA or the vector, with the 5'UTR element and the optional 3'UTR element. This means that the artificial nucleic acid molecule, preferably the ORF contained within the artificial nucleic acid molecule, the 5'UTR element and the optional 3'UTR element as described above are associated or coupled such that the function of the 5'UTR element and the optional 3'UTR element, e.g., protein production increasing function, is exerted. Typically, this means that the 5'UTR element and the optional 3'UTR element are integrated into the artificial nucleic acid molecule, preferably into the m NA molecule or the vector, such that the open reading frame is positioned 3' to the 5'UTR element, preferably between the 5'UTR element and the optional 3'UTR element. In a further aspect, the present invention provides the use of at least one 5 '-untranslated region element (5'UTR element) which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a TOP gene or which is derived from a variant of the 5'UTR of a TOP gene as described above and optionally at least one 3'UTR element which comprises or consists of a nucleic acid sequence derived from the 3'UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene, or from a variant of the 3'UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene as described above for increasing protein production from an artificial nucleic acid molecule, such as an mRNA or a vector.
The use according to the present invention preferably comprises associating the artificial nucleic acid molecule with the 5'UTR element and the optional 3'UTR element as described above. The method for increasing protein production from an artificial nucleic acid molecule and the above use may also comprise associating the artificial nucleic acid molecules with one or more further elements, such as a polyadenylation signal, a poly(A) sequence, a poly(C) sequence and/or a histone stem loop as described above. The compounds and ingredients of the inventive pharmaceutical composition may also be manufactured and traded separately of each other. Thus, the invention relates further to a kit or kit of parts comprising an artificial nucleic acid molecule according to the invention, a vector according the invention, a cell according to the invention, and/or a pharmaceutical composition according to the invention. Preferably, such kit or kit of parts may, additionally, comprise instructions for use, cells for transfection, an adjuvant, a means for administration of the pharmaceutical composition, a pharmaceutically acceptable carrier and/or an pharmaceutically acceptable solution for dissolution or dilution of the artificial nucleic acid molecule, the vector, the cells or the pharmaceutical composition. The following Figures, Sequences and Examples are intended to illustrate the invention further. They are not intended to limit the subject-matter of the invention thereto.
Fig. 1 shows the nucleotide sequence of a Photinus pyralis luciferase encoding nucleic acid molecule PpLuc(GC) - A64N64. This artificial construct does not comprise a 5'UTR element or a 3'UTR element in the sense of the present invention. The coding region for PpLuc(GC) is depicted in italics.
Fig. 2 shows the nucleotide sequence of PpLuc(GC) - albumin7 - A64N64. The 3'UTR of human albumin, with a T7 termination signal as well as a Hindlll and Xbal restriction site removed by three single point mutations, was inserted between the ORF and poly(A) of the construct shown in Figure 1 . The coding region for PpLuc(GC) is depicted in italics. The albumin 3'UTR is underlined.
Fig. 3 shows the nucleotide sequence of RPL32 - PpLuc(GC) - A64N64. The 5'UTR of human ribosomal protein Large 32 gene lacking the 5' terminal oligopyrimidine tract (RPL32) according to SEQ ID NO. 1368 was inserted 5' of the ORF in the construct shown in Figure 1 . The coding region for PpLuc(GC) is depicted in italics. The RPL32 5'UTR is underlined.
Fig. 4 shows the nucleotide sequence of RPL32 - PpLuc(GC) - albumin7 - A64N64.
The 5'UTR of human ribosomal protein Large 32 gene lacking the 5' terminal oligopyrimidine tract (RPL32) according to SEQ ID NO. 1368 and the albumin7 3'UTR element according to SEQ ID NO. 1376 were inserted 5' and 3' of the ORF in the construct shown in Figure 1 , respectively.
Fig. 5 is a graphical representation of the effect of the TOP 5'UTR element which is derived from the 5'UTR of the TOP gene RPL23 according to SEQ ID NO. 1368, the albumin 3' UTR element according to SEQ ID NO. 1376 and the combination of the TOP 5'UTR element and the albumin 3'UTR element on luciferase expression from mRNA. A variety of mRNAs were transfected into human dermal fibroblasts (HDF) by lipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection. The albumin 3'UTR element extends luciferase expression, while the TOP 5'UTR element increases luciferase levels compared to mRNA lacking 5'- and 3'UTR elements. Strikingly, the combination of TOP 5'UTR element and albumin 3'UTR element further strongly increases the luciferase level, much above the level observed with either of the individual elements, thus acting synergistically. Data are graphed as mean RLU ± SD (relative light units ± standard deviation) for triplicate transfections. RLU are summarized in Example 5.1 . shows the nucleotide sequence of RPL35 - PpLuc(GC) - albumin7 - A64N64. The 5'UTR of human ribosomal protein Large 35 gene lacking the 5' terminal oligopyrimidine tract (RPL35) according to SEQ ID NO. 1412 and the albumin7 3'UTR element according to SEQ ID NO. 1376 were inserted 5' and 3' of the ORF in the construct shown in Figure 1 , respectively. shows the nucleotide sequence of RPL21 - PpLuc(GC) - albumin7 - A64N64. The 5'UTR of human ribosomal protein Large 21 gene lacking the 5' terminal oligopyrimidine tract (RPL21 ) according to SEQ ID NO. 141 3 and the albumin7 3'UTR element according to SEQ ID NO. 1376 were inserted 5' and 3' of the ORF in the construct shown in Figure 1 , respectively. shows the nucleotide sequence of atp5a1 - PpLuc(GC) - albumin7 - A64N64. The 5'UTR of human ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 gene lacking the 5' terminal oligopyrimidine tract (atp5a1 ) according to SEQ ID NO. 1414 and the albumin7 3'UTR element according to SEQ ID NO. 1376 were inserted 5' and 3' of the ORF in the construct shown in Figure 1 , respectively. shows the nucleotide sequence of HSD1 7B4 - PpLuc(GC) - albumin7 - A64N64. The 5'UTR of human hydroxysteroid (17-beta) dehydrogenase 4 gene lacking the 5' terminal oligopyrimidine tract (HSD1 7B4) according to SEQ ID NO. 1415 and the albumin7 3'UTR element according to SEQ ID NO. 1376 were inserted 5' and 3' of the ORF in the construct shown in Figure 1 , respectively. shows the nucleotide sequence of A1G1 - PpLuc(GC) - albumin7 - A64N64. The 5'UTR of human androgen-induced 1 gene lacking the 5' terminal oligopyrimidine tract (AIG1 ) according to SEQ ID NO. 141 6 and the albumin7 3'UTR element according to SEQ ID NO. 1376 were inserted 5' and 3' of the ORF in the construct shown in Figure 1 , respectively.
Fig. 1 1 shows the nucleotide sequence of COX6C - PpLuc(GC) - albumin7 - A64N64. The 5'UTR of human cytochrome c oxidase subunit Vic gene lacking the 5' terminal oligopyrimidine tract (COX6C) according to SEQ ID NO. 141 7 and the albumin7 3'UTR element according to SEQ ID NO. 1376 were inserted 5' and 3' of the ORF in the construct shown in Figure 1 , respectively.
Fig. 12 shows the nucleotide sequence of ASAH1 - PpLuc(GC) - albumin7 - A64N64. The 5'UTR of human N-acylsphingosine amidohydrolase (acid cera- midase) 1 lacking the 5' terminal oligopyrimidine tract (ASAH1 ) according to SEQ ID NO. 1418 and the albumin7 3'UTR according to SEQ ID NO. 1376 were inserted 5' and 3' of the ORF in the construct shown in Figure 1 , respectively.
Fig. 13 shows the nucleotide sequence of mRPL21 - PpLuc(GC) - albumin7 - A64N64. The 5'UTR of murine ribosomal protein Large 21 gene lacking the 5' terminal oligopyrimidine tract (mRPL21 ) according to SEQ ID NO. 1419 and the albumin7 3'UTR element according to SEQ ID NO. 1376 were inserted 5' and 3' of the ORF in the construct shown in Figure 1 , respectively.
Fig. 14 shows the nucleotide sequence of mRPL35A - PpLuc(GC) - albumin7 - A64N64. The 5'UTR of murine ribosomal protein Large 35a gene lacking the 5' terminal oligopyrimidine tract (mRPL35A) according to SEQ ID NO. 1420 and the albumin7 3'UTR element according to SEQ ID NO. 1376 were inserted 5' and 3' of the ORF in the construct shown in Figure 1 , respectively.
Fig. 15 shows the nucleotide sequence of RPL35 - PpLuc(GC) - A64N64. The
5'UTR of human ribosomal protein Large 35 gene lacking the 5' terminal oligopyrimidine tract (RPL35) according to SEQ ID NO. 1412 was inserted 5' of the ORF in the construct shown in Figure 1 .
Fig. 16 shows the nucleotide sequence of RPL21 - PpLuc(GC) - A64N64. The
5'UTR of human ribosomal protein Large 21 gene lacking the 5' terminal oli- gopyrimidine tract (RPL21 ) according to SEQ ID NO. 1413 was inserted 5' of the ORF in the construct shown in Figure 1 . shows the nucleotide sequence of atp5a1 - PpLuc(GC) - A64N64. The 5'UTR of human ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 gene lacking the 5' terminal oligopyrimidine tract (atp5a1 ) according to SEQ ID NO. 1414 was inserted 5' of the ORF in the construct shown in Figure 1 . shows the nucleotide sequence of HSD1 7B4 - PpLuc(GC) - A64N64. The 5'UTR of human hydroxysteroid (1 7-beta) dehydrogenase 4 gene lacking the 5' terminal oligopyrimidine tract (HSD1 7B4) according to SEQ ID NO. 1415 was inserted 5' of the ORF in the construct shown in Figure 1 . shows the nucleotide sequence of AIG1 - PpLuc(GC) - A64N64. The 5'UTR of human androgen-induced 1 gene lacking the 5' terminal oligopyrimidine tract (AIG1 ) according to SEQ ID NO. 1416 was inserted 5' of the ORF in the construct shown in Figure 1 . shows the nucleotide sequence of COX6C - PpLuc(GC) - A64N64. The 5'UTR of human cytochrome c oxidase subunit Vic gene lacking the 5' terminal oligopyrimidine tract (COX6C) according to SEQ ID NO. 141 7 was inserted 5' of the ORF in the construct shown in Figure 1 . shows the nucleotide sequence of ASAH1 - PpLuc(GC) - A64N64. The 5'UTR of human N-acylsphingosine amidohydrolase (acid ceramidase) 1 gene lacking the 5' terminal oligopyrimidine tract (ASAH1 ) according to SEQ ID NO. 1418 was inserted 5' of the ORF in the construct shown in Figure 1 . is a graphical representation of the effect of different TOP 5'UTR elements on luciferase expression from mRNA. A variety of mRNAs were transfected into human dermal fibroblasts (HDF) by lipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection. TOP 5'UTR elements strongly increase luciferase levels compared to mRNA lacking a 5'UTR element. mRNAs comprising 5'UTR elements derived from the 5'UTRs of the TOP genes ASAH1 , COX6C, AIG1 , HSD17B4, atp5a1 , RPL21 , RPL35 and RPL32 were transfected into human dermal fibroblasts (HDF) by Iipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection. The TOP 5'UTR elements increases luciferase levels compared to mRNA lacki ng a 5'UTR element. Data are graphed as mean RLU + SEM (relative light units + standard error) for triplicate transfections. RLU are summarized in Example 5.2.
Fig. 23 is a graphical representation of the effect of the RPL35 TOP 5'UTR element, the albumin 3'UTR element and the combi nation of RPL35 TOP 5' UTR element and al bum i n 3 'UTR element on luciferase expression from mRNA. A variety of mRNAs were transfected into human dermal fibroblasts (HDF) by Iipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection. The albumin 3'UTR element extends luciferase expression, while the RPL35 TOP 5'UTR element increases luciferase levels compared to mRNA lacking 5'- and 3 'UTR elements. Stri kingly, the combination of RPL35 TOP 5'UTR element and albumin 3'UTR element further strongly increases the luciferase level, much above the level observed with either of the individual elements, thus acting synergistically. Data are graphed as mean RLU ± SEM (relative light units ± standard error) for triplicate transfections. Synergy is summarized in Example 5.3.
Fig. 24 is a graphical representation of the effect of the RPL21 TOP 5'UTR element, the albumin 3'UTR element and the combination of RPL21 TOP 5'UTR element and albumin 3'UTR element on luciferase expression from mRNA. A variety of mRNAs were transfected into human dermal fibroblasts (HDF) by Iipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection. The albumin 3'UTR element extends luciferase expression, while the RPL21 TOP 5'UTR element increases luciferase levels compared to mRNA lacking 5'- and 3'UTR elements. Strikingly, the combination of RPL21 TOP 5'UTR element and albumin 3'UTR element further strongly increases the luciferase level, much above the level observed with either of the individual elements, thus acting synergistically. Data are graphed as mean RLU ± SEM (relative light units ± standard error) for triplicate transfections. Synergy is summarized in Example Fig. 25 is a graphical representation of the effect of the atp5a1 TOP 5'UTR element, the albumin 3'UTR element and the combi nation of atp5a1 TOP 5 ' UTR element and album i n 3 ' UTR element on luciferase expression from mRNA. A variety of mRNAs were transfected into human dermal fibroblasts (HDF) by lipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection. The albumin 3'UTR element extends luciferase expression, while the atp5a1 TOP 5'UTR element increases luciferase levels compared to mRNA lacking 5'- and 3'UTR elements. Stri kingly, the combination of atp5a1 TOP 5'UTR element and albumin 3'UTR element further strongly increases the luciferase level, much above the level observed with either of the individual elements, thus acting synergistically. Data are graphed as mean RLU ± SEM (relative light units ± standard error) for triplicate transfections. Synergy is summarized in Example 5.3.
Fig. 26 is a graphical representation of the effect of the HSD17B4 TOP 5'UTR element, the albumin 3'UTR element and the combi nation of HSD 1 7B4 TOP 5' UTR element and a lbu m i n 3 'UTR element on luciferase expression from mRNA. A variety of mRNAs were transfected into human dermal fibroblasts (HDF) by lipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection. The albumin 3'UTR element extends luciferase expression, while the HSD1 7B4 TOP 5'UTR element increases luciferase levels compared to mRNA lacking 5'- and 3'UTR elements. Striki ngly, the combination of HSD1 7B4 TOP 5'UTR element and albumin 3'UTR element further strongly increases the luciferase level, much above the level observed with either of the individual elements, thus acting synergistically. Data are graphed as mean RLU ± SEM (relative light units + standard error) for triplicate transfections. Synergy is summarized in Example 5.3.
Fig. 27 is a graphical representation of the effect of the AIG1 TOP 5'UTR element, the albumin 3'UTR element and the combi nation of AIG 1 TOP 5 'UTR element and albumi n 3 ' UTR element on luciferase expression from mRNA. A variety of mRNAs were transfected into human dermal fibroblasts (HDF) by lipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection. The albumin 3'UTR element extends luciferase expression, while the AIG1 TOP 5'UTR element increases luciferase levels compared to mRNA lacki ng 5'- and 3'UTR elements. Stri ki ngly, the combi nation of AIG 1 TOP 5'UTR element and albumin 3'UTR element further strongly increases the luciferase level, much above the level observed with either of the individual elements, thus acting synergistically. Data are graphed as mean RLU ± SEM (relative light units + standard error) for triplicate transfections. Synergy is summarized in Example 5.3.
Fig. 28 is a graphical representation of the effect of the COX6C TOP 5'UTR element, the albumin 3'UTR element and the combi nation of COX6C TOP 5 ' UTR element and album i n 3 ' UTR element on luciferase expression from mRNA. A variety of mRNAs were transfected into human dermal fibroblasts (HDF) by lipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection. The albumin 3'UTR element extends luciferase expression, while the COX6C TOP 5'UTR element increases luciferase levels compared to mRNA lacking 5'- and 3'UTR elements. Stri kingly, the combination of COX6C TOP 5'UTR element and albumin 3'UTR element further strongly increases the luciferase level, much above the level observed with either of the individual elements, thus acting synergistically. Data are graphed as mean RLU ± SEM (relative light units ± standard error) for triplicate transfections. Synergy is summarized in Example 5.3.
Fig. 29 is a graphical representation of the effect of the ASAH1 TOP 5'UTR element, the albumin 3'UTR element and the combi nation of ASAH 1 TOP 5 ' UTR element and album i n 3 ' UTR element on luciferase expression from mRNA. A variety of mRNAs were transfected into human dermal fibroblasts (HDF) by lipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection. The albumin 3'UTR element extends luciferase expression, while the ASAH1 TOP 5'UTR element increases luciferase levels compared to mRNA lacking 5'- and 3'UTR elements. Strikingly, the combination of ASAH1 TOP 5'UTR element and albumin 3'UTR element further strongly increases the luciferase level, much above the level observed with either of the individual elements, thus acting synergistically. Data are graphed as mean RLU ± SEM (relative light units + standard error) for triplicate transfections. Synergy is summarized in Example 5.3.
Fig. 30 is a graphical representation of the effect of the TOP 5'UTR element from mouse genes on luciferase expression from mRNA. mRNAs containing either a mouse or a human TOP 5'UTR element were transfected into human dermal fibroblasts (HDF) by lipofection. Luciferase levels were measured at 24, 48, and 72 hours after transfection. Mouse TOP 5'UTR elements strongly increase luciferase levels compared to mRNA lacking a 5'-element, similarly as the human TOP 5'UTR element. Data are graphed as mean RLU + SEM (relative light units ± standard error) for triplicate transfections. RLU are summarized in
Example 5.4.
SEQ ID No. 1 -1363, 1395, 1421 , and 1422 Sequences comprising 5'UTRs of TOP gene
SEQ ID No. 1364 PpLuc(GC) - A64N64
SEQ ID No. 1365 PpLuc(GC) - albumin7 - A64N64
SEQ ID No. 1366 RPL32 - PpLuc(GC) - A64N64
SEQ ID No. 1367 RPL32 - PpLuc(GC) - albumin7 - A64N64
SEQ ID No. 1368 5'UTR of human ribosomal protein Large 32 lacking the 5' termin oligopyrimidine tract
SEQ ID No. 1369 Human albumin 3'UTR
SEQ ID No. 1370 3'UTR of Homo sapiens hemoglobin, alpha 1 (HBA1 )
SEQ ID No. 1371 3'UTR of Homo sapiens hemoglobin, alpha 2 (HBA2)
SEQ ID No. 1372 3'UTR of Homo sapiens hemoglobin, beta (HBB)
SEQ ID No. 1373 3'UTR of Homo sapiens tyrosine hydroxylase (TH)
SEQ ID No. 1374 3'UTR of Homo sapiens arachidonate 15-lipoxygenase (ALOX1 5)
SEQ ID No. 1375 3'UTR of Homo sapiens collagen, type I, alpha 1 (COL1 A1 )
SEQ ID No. 1376 albumin7 3'UTR
SEQ ID No. 1377 Human albumin 3'UTR + poly(A) sequence
SEQ ID No. 1378 Human albumin 3'UTR fragment 1
SEQ ID No. 1379 Human albumin 3'UTR fragment 2
SEQ ID No. 1380 Human albumin 3'UTR fragment 3
SEQ ID No. 1381 Human albumin 3'UTR fragment 4 SEQ ID No. 1382 Human albumin 3'UTR fragment 5
SEQ ID No. 1383 Human albumin 3'UTR fragment 6
SEQ ID No. 1384 Human albumin 3'UTR fragment 7
SEQ ID No. 1385 Human albumin 3'UTR fragment 8
SEQ ID No. 1386 Human albumin 3'UTR fragment 9
SEQ ID No. 1387 Human albumin 3'UTR fragment 10
SEQ ID No. 1388 Human albumin 3'UTR fragment 1 1
SEQ ID No. 1389 Human albumin 3'UTR fragment 12
SEQ ID No. 1390 Human albumin 3'UTR fragment 13
SEQ ID No. 1391 Albumin7 3'UTR - poly(A) sequence - poly(C) sequence - HL
SEQ ID No. 1392 Albumin7 3'UTR - poly(A) sequence - poly(C) sequence
SEQ ID No. 1393 Center, α-complex-binding portion of the 3'UTR of ana-globin gene
SEQ ID No. 1394 Histone stem-loop
SEQ ID NO. 1396 RPL35 - PpLuc(GC) - albumin7 - A64N64
SEQ ID NO. 1397 RPL21 - PpLuc(GC) - albumin7 - A64N64
SEQ ID NO. 1398 ATP5A1 - PpLuc(GC) - albumin7 - A64N64
SEQ ID NO. 1399 HSD1 7B4 - PpLuc(GC) - albumin7 - A64N64
SEQ ID NO. 1400 AIG1 - PpLuc(GC) - albumin7 - A64N64
SEQ ID NO. 1401 COX6C - PpLuc(GC) - albumin7 - A64N64
SEQ ID NO. 1402 ASAH1 - PpLuc(GC) - albumin7 - A64N64
SEQ ID NO. 1403 mRPL21 - PpLuc(GC) - albumin7 - A64N64
SEQ ID NO. 1404 mRPL35A - PpLuc(GC) - albumin7 - A64N64
SEQ ID NO. 1405 RPL35 - PpLuc(GC) - A64N64
SEQ I D NO. 1406 RPL21 - PpLuc(GC) - A64N64
SEQ ID NO. 1407 ATP5A1 - PpLuc(GC) - A64N64
SEQ ID NO. 1408 HSD1 7B4 - PpLuc(GC) - A64N64
SEQ ID NO. 1409 AIG1 - PpLuc(GC) - A64N64
SEQ ID NO. 1410 COX6C - PpLuc(GC) - A64N64
SEQ ID NO. 141 1 ASAH1 - PpLuc(GC) - A64N64
SEQ ID NO. 1412 5'UTR of human ribosomal protein Large 35 (RPL35) lacking the 5' terminal oligopyrimidine tract
SEQ ID NO. 1413 5'UTR of human ribosomal protein Large 21 (RPL21 ) lacking the 5' terminal oligopyrimidine tract SEQ ID NO. 1414 5'UTR of human ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 , cardiac muscle (ATP5A1 ) lacking the 5' terminal oligopyrimidine tract
SEQ ID NO. 1415 5'UTR of human hydroxysteroid (1 7-beta) dehydrogenase 4
(HSD1 7B4) lacking the 5' terminal oligopyrimidine tract
SEQ ID NO. 1416 5'UTR of human androgen-induced 1 (AIG1 ) lacking the 5' terminal oligopyrimidine tract
SEQ ID NO. 141 7 5'UTR of human cytochrome c oxidase subunit Vic (COX6C) lacking the 5' terminal oligopyrimidine tract
SEQ ID NO. 1418 5'UTR of human N-acylsphingosine amidohydrolase (acid cerami- dase) 1 (ASAH1 ) lacking the 5' terminal oligopyrimidine tract SEQ ID NO. 1419 5'UTR of mouse ribosomal protein Large 21 (mRPL21 ) lacking the 5' terminal oligopyrimidine tract
SEQ ID NO. 1420 5'UTR of mouse ribosomal protein large 35A (mRPL35A) lacking the
5' terminal oligopyrimidine tract
Examples
1. Preparation of DNA-templates
A vector for in vitro transcription was constructed containing a T7 promoter followed by a GC-enriched sequence coding for Photinus pyralis luciferase (PpLuc(GQ) and an A64 poly(A) sequence. The poly(A) sequence was followed by a restriction site used for linearization of the vector before in vitro transcription. mRNA obtained from this vector accordingly by in vitro transcription is designated as„PpLuc(GC) - A64N64". This vector was modified to include untranslated sequences 5' or 3' of the open reading frame (5'UTR or 3'UTR, respectively). In summary, vectors comprising the following mRNA encoding sequences have been generated (the mRNA coding sequences are depicted in Figures 1 to 4 and 6 to 21 ):
SEQ ID No. 1364 (Fig. 1 ) PpLuc(GC) - A64N64
SEQ ID No. 1365 (Fig. 2) PpLuc(GC) - albumin7 - A64N64
SEQ ID No. 1366 (Fig. 3) RPL32 - PpLuc(GC) - A64N64 SEQ ID No. 1367 (Fig. 4): RPL32 - PpLuc(GC) - albumin7 - A64N64
SEQ ID NO. 1396 (Fig . 6): RPL35 - PpLuc(GC) - albumin7 - A64N64
SEQ ID NO. 1397 (Fig . 7): RPL21 - PpLuc(GC) - albumin7 - A64N64
SEQ ID NO. 1398 (Fig . 8): ATP5A1 - PpLuc(GC) - albumin7 - A64N64
SEQ ID NO. 1399 (Fig . 9): HSD1 7B4 - PpLuc(GC) - albumin7 - A64N64
SEQ ID NO. 1400 (Fig . 10) AIG1 - PpLuc(GC) - albumin7 - A64N64
SEQ ID NO. 1401 (Fig . 1 1 ) COX6C - PpLuc(GC) - albumin7 - A64N64
SEQ ID NO. 1402 (Fig • 12) ASAH1 - PpLuc(GC) - albumin7 - A64N64
SEQ ID NO. 1403 (Fig . 13) mRPL21 - PpLuc(GC) - albumin7 - A64N64
SEQ ID NO. 1404 (Fig • 14) mRPL35A - PpLuc(GC) - albumin7 - A64N64
SEQ ID NO. 1405 (Fig . 15) RPL35 - PpLuc(GC) - A64N64
SEQ ID NO. 1406 (Fig . 16) RPL21 - PpLuc(GC) - A64N64
SEQ ID NO. 1407 (Fig • 1 7) ATP5A1 - PpLuc(GC) - A64N64
SEQ ID NO. 1408 (Fig . 18) HSD1 7B4 - PpLuc(GC) - A64N64
SEQ ID NO. 1409 (Fig . 19) AIG1 - PpLuc(GC) - A64N64
SEQ ID NO. 1410 (Fig . 20) COX6C - PpLuc(GC) - A64N64
SEQ ID NO. 141 1 (Fig . 21 ) ASAH1 - PpLuc(GC) - A64N64
2. In vitro transcription
The DNA-tempIate according to Example 1 was linearized and transcribed in vitro using T7- Polymerase. The DNA-template was then digested by DNase-treatment. mRNA transcripts contained a 5'-CAP structure obtained by adding an excess of N7-Methyl-Guanosine-5'- Triphosphate-5'-Guanosine to the transcription reaction. mRNA thus obtained was purified and resuspended in water.
3. Luciferase expression by mRNA lipofection
Human dermal fibroblasts (HDF) were seeded in 24 well plates at a density of 5x104 cells per well. The following day, cells were washed in opti-MEM and then transfected with 50 ng per well of Lipofectamine2000-complexed PpLuc-encoding mRNA in opti-MEM. As a control, mRNA not coding for PpLuc was lipofected separately. mRNA coding for Renilla reniformis luciferase (RrLuc) was transfected together with PpLuc mRNA to control for trans- fection efficiency (20 ng of RrLuc mRNA per well). 90 minutes after start of transfection, opti-MEM was exchanged for medium. 24, 48, 72 hours after transfection, medium was aspirated and cells were lysed in 200 μΙ of lysis buffer (25 mM Tris, pH 7.5 (HCI), 2 mM EDTA, 10% glycerol, 1 % Triton X-100, 2 mM DTT, 1 mM PMSF). Lysates were stored at -20°C until luciferase activity was measured.
Alternatively, HDF were seeded in 96 well plates three days before transfection at a density of 104 cells per well. Immediately before lipofection, cells were washed in opti-MEM. Cells were lipofected with 25 ng of PpLuc-encoding mRNA per well com- plexed with Lipofectamine2000. mRNA coding for Renilla reniformis luciferase (RrLuc) was transfected together with PpLuc mRNA to control for transfection efficiency (2.5 ng of RrLuc mRNA per well). 90 minutes after start of transfection, opti- MEM was exchanged for medium. 24, 48, 72 hours after transfection, medium was aspirated and cells were lysed in 100 μΐ of lysis buffer (Passive Lysis Buffer, Promega). Lysates were stored at -80°C until luciferase activity was measured.
4. Luciferase measurement
Luciferase activity was measured as relative light units (RLU) in a BioTek SynergyHT plate reader. PpLuc activity was measured at 15 seconds measuring time using 50 μΙ of lysate and 200 μΙ of luciferin buffer (75 μΜ luciferin, 25 mM Glycylglycin, pH 7.8 (NaOH), 15 mM MgS04, 2 mM ATP). RrLuc activity was measured at 15 seconds measuring time using 50 μΙ of lysate and 200 μΙ of coelenterazin buffer (40 μΜ coelenterazin in phosphate buffered saline adjusted to 500 mM NaCl).
Alternatively, luciferase activity was measured as relative light units (RLU) in a Hidex Cha- meleon plate reader. PpLuc activity was measured at 2 seconds measuring time using 20 μΙ of lysate and 50 μΙ of luciferin buffer (Beetle-Juice, PJK GmbH). RrLuc activity was measured at 2 seconds measuring time using 20 μΙ of lysate and 50 μΙ of coelenterazin buffer (Renilla-Juice, PJK GmbH).
Results 5.1 The combination of TOP 5'UTR element and albumin 3'UTR element increases protein expression from mRNA in a synergistic manner.
To investigate the effect of the combination of a TOP 5'UTR element and an albumin 3'UTR element on protein expression from mRNA, mRNAs with different UTRs were synthesized: mRNAs either lacked both TOP 5'UTR element and albumin 3'UTR element, or contained either a TOP 5'UTR element (RPL32) or an albumin 3'UTR element (albumin7), or both TOP 5'UTR element and albumin 3'UTR element. Luciferase encoding mRNAs or control mRNA were transfected into human dermal fibroblasts (HDF). Luciferase levels were measured at 24, 48, and 72 hours after transfection. The PpLuc signal was corrected for transfection efficiency by the signal of cotransfected RrLuc (see following Table 1 and Figure 5).
Table 1 :
Figure imgf000098_0001
Luciferase was clearly expressed from mRNA having neither TOP 5'UTR nor albumin 3'UTR (PpLuc(GC)-A64N64). The albumin 3'UTR element extended luciferase expression, while the TOP 5'UTR element increased luciferase levels compared to mRNA lacking 5'- and 3'UTR elements. Strikingly however, the combination of TOP 5'UTR element and albumin 3'UTR element further strongly increased the luciferase level, much above the level observed with either of the individual elements. The magnitude of the rise in luciferase level due to combining TOP 5'UTR element and albumin 3'UTR element in the same mRNA demonstrates that they are acting synergistically. The synergy between TOP 5'UTR element and albumin 3'UTR element was quantified by dividing the signal from mRNA combining both elements by the sum of the signal from mRNA lacking both elements plus the rise in signal effected by the TOP 5'UTR element plus the rise in signal effected by the albumin 3'UTR element. This calculation was performed for the three time points individually and for total protein expressed from 0 to 72 hours calculated from the area under the curve (AUC) (see following Table 2).
Table 2:
24 h
RPL32 albumin RLU Δ RLU RLU predicted (additive) synergy
— — 1 15147
— + 120234 5088
+ — 671815 556668
+ + 913310 676903 1 ,35
48 h
RPL32 albumin RLU Δ RLU RLU predicted (additive) synergy
— — 28973
— + 48546 19573
+ — 168741 139768
+ + 381288 188313 2,02
72 h
RPL32 albumin RLU Δ RLU RLU predicted (additive) synergy
— — 8371
— + 38138 29767
+ — 21 709 13338
+ + 100890 51476 1 ,96
AUC 0 - 72 hours
RPL32 albumin RLU Δ RLU RLU predicted (additive) synergy
— — 3559000
— + 4508000 949000
+ — 20430000 16871000 + + 32280000 21379000 1 ,51
The synergy thus calculated specifies how much higher the luciferase level from mRNA combining TOP 5'UTR element and albumin 3'UTR element is than would be expected if the effects of TOP 5'UTR element and albumin 3'UTR element were purely additive. The luciferase level from mRNA combining TOP 5'UTR element and albumin 3'UTR element was up to two times higher than if their effects were purely additive. This result confirms that the combination of TOP 5'UTR element and albumin 3'UTR element effects a markedly synergistic increase in protein expression.
5.2 TOP 5'UTR elements increase protein expression from mRNA.
To investigate the effect of TOP 5'UTR elements on protein expression from mRNA, mRNAs comprising different TOP 5'UTR elements were synthesized. In addition, mRNAs contained the albumin7 3'UTR element. Luciferase encoding mRNAs were transfected into human dermal fibroblasts (HDF). Luciferase levels were measured at 24, 48, and 72 hours after transfection (see following Table 3 and Figure 22).
Table 3:
5'UTR RLU at 24 hours RLU at 48 hours RLU at 72 hours none 1 14277 121852 68235
RPL32 332236 286792 1 14148
RPL35 49591 7 234070 96993
RPL21 563314 352241 156605 atp5a1 1000253 538287 187159
HSD1 7B4 1 1 79847 636877 299337
AIG1 620315 446621 167846 COX6C 592190 806065 1 73743
ASAH1 820413 529901 198429
Luciferase was clearly expressed from mRNA lacking a 5'UTR element. Strikingly however, all TOP 5'UTR elements strongly increased the luciferase level.
5.3 The combination of TOP 5'UTR elements and albumin 3'UTR element increases protein expression from mRNA in a synergistic manner.
To investigate the effect of the combination of TOP 5'UTR elements and an albumin 3'UTR element on protein expression from mRNA, mRNAs comprising different UTR elements were synthesized: mRNAs either lacked both TOP 5'UTR element and albumin 3'UTR element, or contained an albumin 3'UTR element, or contained one of different TOP 5'UTR elements, or contained both one of different TOP 5'UTR elements and an albumin 3'UTR element. Luciferase encoding mRNAs were transfected into human dermal fibroblasts (HDF). Luciferase levels were measured at 24, 48, and 72 hours after transfection (see Figures 23 to 30). Luciferase was clearly expressed from mRNA having neither a TOP 5'UTR element nor an albumin 3'UTR element. The albumin 3'UTR element extended luciferase expression, while TOP 5'UTR elements increased luciferase levels compared to mRNA lacking 5' and 3'UTRs. Strikingly however, the combinations of TOP 5'UTR elements and albumin 3'UTR element further strongly increased the luciferase level, much above the level observed with either of the individual elements. The magnitude of the rise in luciferase level due to combining TOP 5'UTR element and albumin 3'UTR element in the same mRNA demonstrates that they are acting synergisti- cally.
The synergy between TOP 5'UTR element and albumin 3'UTR element was quantified by dividing the signal from mRNA combining both elements by the sum of the signal from mRNA lacking both elements plus the rise in signal effected by the TOP 5'UTR element plus the rise in signal effected by the albumin 3'UTR element. This calculation was performed for total protein expressed from 0 to 72 hours calculated from the area under the curve (AUC) (see following Table 4). Table 4:
Figure imgf000102_0001
The synergy thus calculated specifies how much higher the luciferase level from mRNA combining TOP 5'UTR elements and albumin 3'UTR element is than would be expected if the effects of TOP 5'UTR element and albumin 3'UTR element were purely additive. The luciferase level from mRNA combining TOP 5'UTR element and albumin 3'UTR element was up to three times higher than if their effects were purely additive. This result confirms that the combination of TOP 5'UTR element and albumin 3'UTR element effects a markedly synergistic increase in protein expression.
5.4 TOP 5'UTR elements from mouse genes increase protein expression from mRNA.
To investigate the effect of TOP 5'UTR elements from mouse genes on protein expression from mRNA, mRNAs with two different mouse TOP 5'UTR elements were synthesized. In addition, mRNAs contained the albumin7 3'UTR element. Luciferase encoding mRNAs were transfected into human dermal fibroblasts (HDF). For comparison, mRNA containing the human RPL32 TOP 5'UTR element was transfected. Luciferase levels were measured at 24, 48, and 72 hours after transfection (see following Table 5 and Figure 30). Table 5:
Figure imgf000103_0001
Luciferase was clearly expressed from mRNA lacking a 5'UTR element. Both mouse TOP 5'UTR elements strongly increased the luciferase level, similarly as the human TOP 5'UTR element.
SEQUENCES:
Homo sapiens alpha-2-macroglobulin (A2M) : gctccttctttctgcaacatg (Seq ID No: 1)
Homo sapiens acyl-CoA dehydrogenase, C-4 to C-12 straight chain (ACADM) :
ggctctctttccgcgctgcggtcagcctcggcgtcccacagagagggccagaggtggaaacgcaga aaaccaaaccaggactatcagagattgcccggagaggggatg (Seq ID No: 2)
Homo sapiens arylsulfatase E (chondrodysplasia punctata 1) (ARSE) : cttcctcttcttgatcggggattcaggaaggagcccaggagcagaggaagtagagagagagacaac atg (Seq ID No: 3 )
Homo sapiens Bruton agammaglobulinemia tyrosine kinase (BTK) :
tgtccttcctctctggactgtaagaatatgtctccagggccagtgtctgctgcgatcgagtcccac cttccaagtcctggcatctcaatgcatctgggaagctacctgcattaagtcaggactgagcacaca ggtgaactccagaaagaagaagctatg (Seq ID No: 4)
Homo sapiens complement component 2 (C2) :
tgaccttttccctcccgcggctctctacctctcgccgcccctagggaggacaccatg
(Seq ID No: 5)
Homo sapiens cyclin-dependent kinase 4 (CDK4) :
gggcctctctagcttgcggcctgtgtctatggtcgggccctctgcgtccagctgctccggaccgag ctcgggtgtatggggccgtaggaaccggctccggggccccgataacgggccgcccccacagcaccc cgggctggcgtgagggtctcccttgatctgagaatg (Seq ID No: 6)
Homo sapiens cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1) : agctcttctactccactgctgtctatcttgcctgccggcacccagccaccatg (Seq ID No: 7)
Homo sapiens endoglin (ENG) :
cttcctctacccggttggcaggcggcctggcccagccccttctctaaggaagcgcatttcctgcct ccctgggccggccgggctggatg (Seq ID No: 8)
Homo sapiens excision repair cross-complementing rodent repair def iciency, complementation group 3 (ERCC3) :
tcttctctctgctgctgtagctgccatg (Seq ID No: 9)
Homo sapiens excision repair cross-complementing rodent repair def iciency, complementation group 5 (ERCC5) :
ctgtctttcttccgggaggcggtgacagctgctgagacgtgttgcagccagagtctctccgcttta atgcgctcccattagtgccgtcccccactggaaaaccgtggcttctgtattatttgccatctttgt tgtgtaggagcagggagggcttcctcccggggtcctaggcggcggtgcagtccgtcgtagaagaat tagagtagaagttgtcggggtccgctcttaggacgcagccgcctcatg (Seq ID No: 10)
Homo sapiens ferritin, light polypeptide (FTL) :
cgtcccctcgcagttcggcggtcccgcgggtctgtctcttgcttcaacagtgtttggacggaacag atccggggactctcttccagcctccgaccgccctccgatttcctctccgcttgcaacctccgggac catcttctcggccatctcctgcttctgggacctgccagcaccgtttttgtggttagctccttcttg ccaaccaaccatg (Seq ID No: 11)
Homo sapiens galactosylceramidase (GALC) :
ccgcctccctgggcgccggagtcatgtgacccacacaatg (Seq ID No: 12)
Homo sapiens gap junction protein, alpha 1, 43kDa (GJAl) :
ttttctttcattagggggaaggcgtgaggaaagtaccaaacagcagcggagttttaaactttaaat agacaggtctgagtgcctgaacttgccttttcattttacttcatcctccaaggagttcaatcactt ggcgtgacttcactacttttaagcaaaagagtggtgcccaggcaacatg (Seq ID No: 13)
Homo sapiens gap junction protein, beta 1, 32kDa (GJB1) :
cattctctgggaaagggcagcagcagccaggtgtggcagtgacagggaggtgtgaatgaggcagga tg (Seq ID No: 14)
Homo sapiens glucose-6-phosphate isomerase (GPI) :
cgctccttcctcctcggctcgcgtctcactcagtgtaccttctagtcccgccatg
(Seq ID No: 15)
Homo sapiens hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase /enoyl-CoA hydratase (trifunctional protein) , alpha subunit
(HADHA) : ctgtcctcttcagctcaagatg (Seq ID No: 16)
Homo sapiens hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase /enoyl-CoA hydratase (trifunctional protein) , beta subunit
(HADHB) :
gggccctttctgggcaggacccgccccttggtcccgcagagccttggtacttggacctgaaccttg ctccgagagggagtcctcgcggacgtcagccaagattccagaatg (Seq ID No: 17) Homo sapiens complement factor H (CFH) :
cttccttttgcagcaagttctttcctgcactaatcacaattcttggaagaggagaactggacgttg tgaacagagttagctggtaaatgtcctcttaaaagatccaaaaaatg (Seq ID No: 18)
Homo sapiens sarcoglycan, gamma
(35kDa dystrophin-associated glycoprotein) (SGCG) :
agccctttctccagggacagttgctgaagcttcatcctttgctctcattctgtaagtcatagaaaa gtttgaaacattctgtctgtggtagagctcgggccagctgtagttcattcgccagtgtgcttttct taatatctaagatg (Seq ID No: 19)
Homo sapiens lipase A, lysosomal acid, cholesterol esterase
(LIPA) :
ggtcccctatccgcaccccggcccctgagagctggcactgcgactcgagacagcggcccggcagga cagctccagaatg (Seq ID No: 20)
Homo sapiens lipoprotein lipase (LPL) :
ccccctcttcctcctcctcaagggaaagctgcccacttctagctgccctgccatcccctttaaagg gcgacttgctcagcgccaaaccgcggctccagccctctccagcctccggctcagccggctcatcag tcggtccgcgccttgcagctcctccagagggacgcgccccgagatg (Seq ID No: 21)
Homo sapiens mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1) : ggctcttctggcgccaaaatg (Seq ID No: 22)
Homo sapiens Niemann-Pick disease, type CI (NPC1) :
cttccttcctgaccggcgcgcgcagcctgctgccgcggtcagcgcctgctcctgctcctccgctcc tcctgcgcggggtgctgaaacagcccggggaagtagagccgcctccggggagcccaaccagccgaa cgccgccggcgtcagcagccttgcgcggccacagcatg (Seq ID No: 23)
Homo sapiens peroxisomal biogenesis factor 12 (PEX12) :
gcgcctctcttccgccaggcatcccagaggtcctggtggttteatttccgggtgcggcttctgtea taaagcggagacctcccttcaaacgtggcgtcgtgggttgtttgcgcctcgcctggggtcagcgag caaggacgggcgcgggcggggatactcaaagccaacagctggagtcagcccttgtgtcccgggctc acagtggcacgactgaatcctcagagtcggctggcttttgagctctcacgattggggaggaggggg cgtttctggttcgcagctccagaggattgcgttccttcccccatacctgtcccccacagtcacgct ctgccctgacgtgcagcatttgacaagttaccccctcgccacatactacttccacccacgtccgag ttaactttgttcttaaccttcttgagactaccctcggcctccaggtctttttttcccagttcattt ttgcccataagattgagtttcgagtttcagatatcatgcagaaagtttacctttaagactgagcac ccatctgatactcttcctcccgaaaaagttcatgctcacgagagagtttgtgggaaaagtgaaagc cagtacacgcaggaaactatg (Seq ID No: 24)
Homo sapiens peroxisomal biogenesis factor 6 (PEX6) :
cgctccttcaccctcctcgttggtgtcctgtcaccatg (Seq ID No: 25)
Homo sapiens phosphofructokinase, muscle (PFKM) :
gagccttcttgtcagcatctgttagtggaggttgggaagcctctcctccttccccctccctctttg cctccacctggctcctccccatgttcgtccatcacccctcccccctttcccaaggacaatctgcaa gaaagcagcggcggaggagagctaagactaaaagagtggatcatg (Seq ID No: 26) Homo sapiens serpin peptidase inhibitor, clade A (al- pha-1 antiproteinase, antitrypsin) , member 1 (SERPINA1) :
ctgtctcctcagcttcaggcaccaccactgacctgggacagtgaatcgacaatg
(Seq ID No: 27) Homo sapiens phosphatase and tensin homolog (PTEN) :
agttctctcctctcggaagctgcagccatgatggaagtttgagagttgagccgctgtgaggcgagg ccgggctcaggcgagggagatgagagacggcggcggccgcggcccggagcccctctcagcgcctgt gagcagccgcgggggcagcgccctcggggagccggccggcctgcggcggcggcagcggcggcgttt ctcgcctcctcttcgtcttttctaaccgtgcagcctcttcctcggcttctcctgaaagggaaggtg gaagccgtgggctcgggcgggagccggctgaggcgcggcggcggcggcggcacctcccgctcctgg agcgggggggagaagcggcggcggcggcggccgcggcggctgcagctccagggagggggtctgagt cgcctgtcaecatttccagggctgggaacgccggagagttggtctctccccttctactgcctccaa cacggcggcggcggcggcggcacatccagggacccgggccggttttaaacctcccgtccgccgccg ccgcaccccccgtggcccgggctccggaggccgccggcggaggcagccgttcggaggattattcgt cttctccccattccgctgccgccgctgccaggcctctggctgctgaggagaagcaggcccagtcgc tgcaaccatccagcagccgccgcagcagccattacccggctgcggtccagagccaagcggcggcag agcgaggggcatcagctaccgccaagtccagagccatttccatcctgcagaagaagccccgccacc agcagcttctgccatctctctcctcctttttcttcagccacaggctcccagacatg
(Seq ID No: 28)
Homo sapiens solute carrier family 3
(cystine, dibasic and neutral amino acid transporters, activator o f cystine, dibasic and neutral amino acid transport) , member 1 (SLC3A1) : cctcccttactgcaggaaggcactccgaagacataagtcggtgagacatg (Seq ID No: 29)
Homo sapiens aldehyde dehydrogenase 3 family, member A2 (ALDH3A2) : ccgcctcccactccccagcgcccccggaccgtgcagttctctgcaggaccaggccatg
(Seq ID No: 30)
Homo sapiens bleomycin hydrolase (BLMH) :
gtttctcccagcctcagcctccccgccgccgccgccgccgccgccgccgagccggtttcctttttc cggcgctccgggtgcgagagacaggtcgggccccctaggcagcgagccgcagcgcaatcccggcgc tcgcccaaggaccctggaagctaccgttaccccgccgggcagcgtgggcgccatg
(Seq ID No: 31)
Homo sapiens cathepsin K (CTSK) :
cctcctcctcttacccaaattttccagccgatcactggagctgacttccgcaatcccgatggaata aatctagcacccctgatggtgtgcccacactttgctgccgaaacgaagccagacaacagatttcca tcagcaggatg (Seq ID No: 32)
Homo sapiens GM2 ganglioside activator (GM2A) :
gcttctttgcgtaaccaatactggaaggcatttaaaggcacctctgccgccacagaccttgcagtt aactccgccctgacccacccttcccgatg (Seq ID No: 33)
Homo sapiens hydroxysteroid (17-beta) dehydrogenase 4 (HSD17B4) : ccgcctcctcctgtcccgcagtcggcgtccagcggctctgcttgttcgtgtgtgtgtcgttgcagg ccttattcatg (Seq ID No: 34)
Homo sapiens neutrophil cytosolic factor 2 (NCF2) :
ctctctctgcttctttccttttctctctcatggtagggttatgagtcagttgccaaaaggtgggga catttcctgatgcatttgcaacactgagaagttatcttaagggaggctgggccccattctactcat ctggcccagaaagtgaacaccttgggggccactaaggcagccctgctaggggagacgctccaacct gtcttctctctgtctcctggcagctctcttggcctcctagtttctacctaatcatg
(Seq ID No: 35)
Homo sapiens 3-oxoacid CoA transferase 1 (OXCT1)
cagcctcctcctgcctcaccgcccgaagatg (Seq ID No: 36) Homo sapiens sulfite oxidase (SUOX) :
ccgccccttctcgagaactcgcagagctgggctggtaaaattgcagtgctgaagacactggacccg caaaaggctgtccctcccaaacctgggattctgggctcactgagttcacctgcgagtcagccctac ctgcactgctctggtctagtacaaacaggctgctggcattgagggacggagtctccaactcctggc ctctagcagtcctcctgtgtaggtctcccaaagtgctagtgtgtccggaattggtgggttcttggt ctcactgacttcaagaatgaagccgcggaccctcgcagtctgctacaatg (Seq ID No: 37)
Homo sapiens albumin (ALB) : ttttctcttctgtcaaccccacacgcctttggca- caatg (Seq ID No: 38)
Homo sapiens arylsulfatase A (ARSA) :
ctccctctagcgccttccccccggcccgactccgctggtcagcgccaagtgacttacgcccccgac cctgagcccggaccgctaggcgaggaggatcagatctccgctcgagaatctgaaggtgccctggtc ctggaggagttccgtcccagcccgcggtctcccggtactgtcgggccccggccctctggagcttca ggaggcggccgtcagggtcggggagtatttgggtccggggtctcagggaagggcggcgcctgggtc tgcggtatcggaaagagcctgctggagccaagtagccctccctctcttgggacagacccctcggtc ccatg (Seq ID No: 39)
Homo sapiens elastin (ELN) :
ctccctccctctttccctcacagccgacgaggcaacaattaggctttggggataaaacgaggtgcg gagagcgggctggggcatttctccccgagatg (Seq ID No: 40)
Homo sapiens hemoglobin, alpha 2 (HBA2) : cactcttctggtccccaca- gactcagagagaacccaccatg (Seq ID No: 41)
Homo sapiens hexosaminidase B (beta polypeptide) (HEXB) :
cttcctctgatccgggccgggcgggaagtcgggtcccgaggctccggctcggcagaccgggcggaa agcagccgagcggccatg (Seq ID No: 42)
Homo sapiens mannosidase, alpha, class 2B, member 1 (MAN2B1) :
cggcctttccagggccggggaaccccaggaggaagctgctgagccatg (Seq ID No: 43)
Homo sapiens recombination activating gene 2 (RAG2) :
cactctctttacagtcagccttctgcttgccacagtcatagtgggcagtcagtgaatcttccccaa gtgctgacaattaatacctggtttagcggcaaagattcagagaggcgtgagcagcccctctggcct tcagacaaaaatctacgtaccatcagaaactatg (Seq ID No: 44)
Homo sapiens CD53 molecule (CD53) :
tctccttttacacaaatagccccggatatctgtgttaccagccttgtctcggccacctcaaggata atcactaaattctgccgaaaggactgaggaacggtgcctggaaaagggcaagaatatcacggcatg (Seq ID No: 45)
Homo sapiens Fc fragment of IgG, low affinity Ilia, receptor (CD16a) (FCGR3A) : tggtccctttagggctccggatatctttggtgacttgtccactccag- tgtggcatcatg (Seq ID No: 46)
Homo sapiens interleukin 1, beta (IL1B) :
aaacctcttcgaggcacaaggcacaacaggctgctctgggattctcttcagccaatcttcattgct caagtgtctgaagcagccatg (Seq ID No: 47)
Homo sapiens CD4 molecule (CD4) :
ctgtctctcttcatttaagcacgactctgcagaaggaacaaagcaccctccccactgggctcctgg ttgcagagctccaagtcctcacacagatacgcctgtttgagaagcagcgggcaagaaagacgcaag cccagaggccctgccatttctgtgggctcaggtccctactggctcaggcccctgcctccctcggca aggccacaatg (Seq ID No: 48)
Homo sapiens serpin peptidase inhibitor, clade A (al- pha-1 antiproteinase, antitrypsin) , member 5 (SERPINA5) :
agccctctgccctttctgagcccgagggactgccacctccactgtgtgcacactcagctacgggac acatttcaggtatccaaggcagcagaggtgagtgggtcccccgagctctgtgaccttatgctccac actaactctggcagagcctccgtttcctcatagaacaaagaacagccaccatg
(Seq ID No: 49)
Homo sapiens vitronectin (VTN) :
tgccctccttccctgtctctgcctctccctcccttcctcaggcatcagagcggagacttcagggag accagagcccagcttgccaggcactgagctagaagccctgccatg (Seq ID No: 50)
Homo sapiens aldehyde dehydrogenase 9 family, member Al (ALDH9A1) : ccgcccctcccgcggccccgcccctcccgcggcccgtcagcctctgccgcggagctgcgtccgcca ctcatg (Seq ID No: 51)
Homo sapiens annexin Al (ANXAl) :
cttcctttaaaatcctataaaatcagaagcccaagtctccactgccagtgtgaaatcttcagagaa gaatttctctttagttctttgcaagaaggtagagataaagacactttttcaaaaatg
(Seq ID No: 52)
Homo sapiens ATPase, Na+/K+ transporting, alpha 1 polypeptide (ATP1A1) : ttttctctctgattctccagcgacaggacccggcgccgggcactgagcaccgc- caccatg (Seq ID No: 53)
Homo sapiens ATPase, Na+/K+ transporting, alpha 2 polypeptide (ATP1A2) :
ctttctctgtctgccagggtctccgactgtcccagacgggctggtgtgggcttgggatcctcctgg tgacctctcccgctaaggtccctcagccactctgccccaagatg (Seq ID No: 54)
Homo sapiens calcium channel, voltage-dependent, beta 3 subunit (CACNB3) :
ccctccttcgcgctctctcgctccctgccgccgcccgcagggctgcggggctcggtggcatctccc gggcgcggcccgcagtccttgcccctgcctccgggccgctcccgcccccggcgccgctcgctcccc cgacccggactcccccatg (Seq ID No: 55)
Homo sapiens cholinergic receptor, nicotinic, alpha 7 (neuronal) (CHRNA7) :
gtgcctctgtggccgcaggcgcaggcccgggcgacagccgagacgtggagcgcgccggctcgctgc agctccgggactcaacatg (Seq ID No: 56)
Homo sapiens cytochrome P450, family 51, subfamily A, polypeptide 1 (CYP51A1) :
gcttctctcgttccgtcgattgggaggagcggtggcgacctcggccttcagtgtttccgacggagt gaatg (Seq ID No: 57)
Homo sapiens glutamate decarboxylase 1 (brain, 67kDa) (GADl) :
atctctctcttctcctggcgctcgcgtgcgagagggaactagcgagaacgaggaagcagctggagg tgacgccgggcagattacgcctgtcagggccgagccgagcggatcgctgggcgctgtgcagaggaa aggcgggagtgcccggctcgctgtcgcagagccgagcctgtttctgcgccggaccagtcgaggact ctggacagtagaggccccgggacgaccgagctgatg (Seq ID No: 58) Homo sapiens gamma-glutamyl carboxylase (GGCX) :
aattctcctggcggcctccgttcagacgcggcagctgtgacccacctgcctcctccgcagagcaat g (Seq ID No: 59)
Homo sapiens glutamate receptor, metabotropic 3 (GR 3) :
tcccctctttccccaacctcctccctctcttctactccacccctccgttttcccactccccactga ctcggatgcctggatgttctgccaccgggcagtggtccagcgtgcagccgggagggggcaggggca gggggcactgtgacaggaagctgcgcgcacaagttggccatttcgagggcaaaataagttctccct tggatttggaaaggacaaagccagtaagctacctcttttgtgtcggatgaggaggaccaaccatga gccagagcccgggtgcaggctcaccgccgccgctgccaccgcggtcagctccagttcctgccagga gttgtcggtgcgaggaattttgtgacaggctctgttagtctgttcctcccttatttgaaggacagg ccaaagatccagtttggaaatgagagaggactagcatgacacattggctccaccattgatatctcc cagaggtacagaaacaggattcatgaagatg (Seq ID No: 60)
Homo sapiens guanylate cyclase 1, soluble, alpha 3 (GUCY1A3) :
ggttcctttggggtgatcaaagagggagacacagacacagagagacaaaggcaaggaggactgtct gggagccacgcgggcgatacagtttccgaggcacgccgcgtcccgcctagcctgttgaacaggtag acatgagcgacccaagctgcggatttgcgaggcgcgccctggagctgctagagatccggaagcaca gccccgaggtgtgcgaagccaccaagtcaagttcctaacgagtcttcagaggaggcagcaggaagc tcagagagctgcaaagcaaccgtgcccatctgtcaagacattcctgagaagaacatacaagaaagt cttcctcaaagaaaaaccagtcggagccgagtctatcttcacactttggcagagagtatttgcaaa ctgattttcccagagtttgaacggctgaatgttgcacttcagagaacattggcaaagcacaaaata aaagaaagcaggaaatctttggaaagagaagactttgaaaaaacaattgcagagcaagcagttgca gcaggagttccagtggaggttatcaaagaatctcttggtgaagaggtttttaaaatatgttacgag gaagatgaaaacatccttggggtggttggaggcacccttaaagattttttaaacagcttcagtacc cttctgaaacagagcagccattgccaagaagcaggaaaaaggggcaggcttgaggacgcctccatt ctatgcctggataaggaggatgattttctacatgtttactacttcttccctaagagaaccacctcc ctgattcttcccggcatcataaaggcagctgctcacgtattatatgaaacggaagtggaagtgtcg ttaatg (Seq ID No: 61)
Homo sapiens 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) : ggctccttccgctccgcgactgcgttaactggagccaggctgagcgtcggcgccggggttcggtgg cctctagtgagatctggaggatccaaggattctgtagctacaatg (Seq ID No: 62)
Homo sapiens IMP (inosine 5 ' -monophosphate) dehydrogenase 2
( IMPDH2 ) : aggtctctgcggcgcggtcctcggagacacgcggcggtgtcctgtgttggccatg
(Seq ID No: 63)
Homo sapiens leukotriene A4 hydrolase (LTA4H) :
acttcctttcccggcgtgcaccgcgaatccctcctcctcttctttacctctctccctcctcctcag gttctctatcgacgagtctggtagctgagcgttgggctgtaggtcgctgtgctgtgtgatccccca gagccatg (Seq ID No: 64)
Homo sapiens neuropeptide Y receptor Yl (NPY1R) :
ccttctttaataagcaggagcgaaaaagacaaattccaaagaggattgttcagttcaagggaatga agaattcagaataattttggtaaatggattccaatatggggaataagaataagctgaacagttgac ctgctttgaagaaacatactgtccatttgtctaaaataatctataacaaccaaaccaatcaaaatg (Seq ID No: 65)
Homo sapiens pyruvate dehydrogenase (lipoamide) beta (PDHB) :
cggcccctctgttgtcgtttggcagcggatagaggacacgaccaagatg (Seq ID No: 66) Homo sapiens ribosomal protein L36a-like (RPL36AL) :
cttccctttcctgttaggcgagagctgcgaaaggcgagagctgcgaagggccaggtgtcgggcgct gtttctcgttttcatcatatagacaaaacagccctgctgcaaagatg (Seq ID No: 67)
Homo sapiens ATPase, Ca++ transporting, type 2C, member 1
(ATP2C1) :
gcttcttctcacgccgggagcaggctcccgcctcgcaccgctgccccgcgagcagctcctcttctc ccgaggcgcgcggggcgcccccgcgagccccgcggctgagaccccgcagcctggaggagggctgtc cggggctttggatgctgctgctaggggtggtgggagcagccgtgggacgcgtggccgggagcgggg gtgacagcctgggattccgggggcttctcttccttgtcctcctcctctcctctctattcccagtgt ggccgtggctgacactaaagactttgtagccatcaacccgagtgcagtttcgatggaaaatg (Seq ID No: 68)
Homo sapiens UDP-glucose pyrophosphorylase 2 (UGP2) :
ccgcctctttcattgaagaaatttaagttcgtgtggttttaccttttccgggagtctccagctggc cctcatttgtgtccggagctcaggagttcccaaaccgactcagtcgcaccaagtttccgtcttttg gaattggggaaggagtttctttctttcttttcttttttcttgagccagttttaatcgctttgaata aatactcccttaagtagttaaatataggaggagaaagaatacatcggttgttaaagcaggagagga agagagacctgccctgtagcgtgactcctctagaaaaaaaaaaaaaaagccggagtattttactaa gcccctaaaatg (Seq ID No: 69)
Homo sapiens ATPase, Na+/ + transporting, beta 1 polypeptide (ATP1B1) :
cctcctcctgctcctgccttggctcctccgccgcgcgtctcgcactccgagagccgcagcggcagc ggcgcgtcctgcctgcagagagccaggccggagaagccgagcggcgcagaggacgccagggcgcgc gccgcagccacccaccctccggaccgcggcagctgctgacccgccatcgccatg
(Seq ID No: 70)
Homo sapiens glycoprotein M6B (GP 6B) :
ctgtctttatggaccagtaggcagagcgaaattgacgctgacaagacttttgcatcttggaaggga ctgtaatctactgtagtgaagaacagagcctctcaatcagacgggtgtaaataagagacggagggg agtccaaaagaaaaggaagaggaggaaaaacaagtgtgtgttggggggaacagggggaaaagcatt tttggtggatggtatg (Seq ID No: 71)
Homo sapiens wntless homolog (Drosophila) (WLS) :
gctcctttaagcgtccacaggcggcggagcggccacaatcacagctccgggcattgggggaacccg agccggctgcgccgggggaatccgtgcgggcgccttccgtcccggtcccatcctcgccgcgctcca gcacctctgaagttttgcagcgcccagaaaggaggcgaggaaggagggagtgtgtgagaggaggga gcaaaaagctcaccctaaaacatttatttcaaggagaaaagaaaaagggggggcgcaaaaatg (Seq ID No: 72)
Homo sapiens flavin containing monooxygenase 3 (FM03) :
ttttctctttcaaactgcccagacggttggacaggacgtagacacacagaagaaaagaagacaaag aacgggtaggaaaattaaaaaggttaccatg (Seq ID No: 73)
Homo sapiens multiple C2 domains, transmembrane 1 (MCTP1) :
cagcctcttttgccggtattcagtgaagaaagcaagtctaaatatgcagttctctcactggagtga aagatgttttgttcatttctaatcaactatg (Seq ID No: 74)
Homo sapiens structural maintenance of chromosomes 4 (SMC4) :
ccgcctctcggcgagcccgccctcttctgaagaggcgtttctggaccactgagccccgcctcccac tgtgagcggaaccctaccgtttttaaaaaaatctttttcaaaacttgccaggttgtctttccaaat atttttaataatagtgctgctgctgtagaccacagagaaaagaatccctcgctcttccttttcact tagtagaaacttctaccgcgtaggtcccgccaggagttcgcgcatgcgcaggagcgacaataagat ggcggtgataatcgccgcactttttttcaaattagtggatcccagaaatcattgcgcgcatttgta acgaatttccgttcgagtttgtattttaggcgccattttcgagtgaaggacccggagccgaaacac cggtaggagcggggaggtgggtactacacaaccgtctccagccttggtctgagtggactgtcctgc agcgaccatg (Seq ID No: 75)
Homo sapiens GLEl RNA export mediator homolog (yeast) (GLE1) :
tggccttcccggcggctgattcgagggcttgtttggtcagaaggggggcgtcagagaagctgcccc ttagccaaccatg (Seq ID No: 76)
Homo sapiens tripartite motif containing 6 (TRIM6) :
gagtctttcggcctgggtggaggacgcggctgcttcaagtccttggctctgatccaggccacagat tccaggattctacaggcaggaaacatcttagaaatcagggttgggcaggcaggagccaggagagta gctacaatg (Seq ID No: 77)
Homo sapiens ecotropic viral integration site 2A (EVI2A) :
tatccttttttactgcagatttactttaaggctcatattctccaagtctattctgctttaaaaaga agacaagaaaagaagtggtttatcaaaatcacgttataatcagattttgaccaagcattttgtaag tatacaaatgtcagccaatgacatataacaaccatttcttataaaaccttgatgttcaaaagcctg actagcagtggcatccatg (Seq ID No: 78)
Homo sapiens heterogeneous nuclear ribonucleoprotein L (HNRNPL) : tgctcttttcgatccgggacggccggtcaggctcgccgccgagctggagaactacgatgacccgca caaaacccctgcctccccagttgtccacatcaggggcctgattgacggtgtggtggaagcagacct tgtggaggccttgcaggagtttggacccatcagctatgtggtggtaatg (Seq ID No: 79)
Homo sapiens mitochondrial translational initiation factor 2 (MTIF2) :
cattcttccgggtccagaaggtgatctccgcccgtgctcagaatccaggggcccggggctgtagat tccttgacaaggatatcctagcggcgaaacaacaccgtactgggagtcagaacgtctgggttctag tcttgactgccattaactagcggtatgacattggagaagcttttttgacccttctggatttccgtt tccttttctgtaaaatgaggagcttggaagatccggaaaatgaggcccataggaaacaagtgactt gctgagtccagataacactgactgtcagagagaaacatg (Seq ID No: 80)
Homo sapiens nuclear factor of kappa light polypeptide gene enhanc er in B-cells inhibitor, zeta (NFKBIZ) :
tggcctcctcttgccacgaggtcagacggcgagttcttagagaaaaaggctgcttagctgctgctt atcatgtaacctcaaaaggaaactgatcgtctttctcatgctgtcacgtacttgggttattatcgc tgattacagctggaaacaattgatttgctcttacgtatttgtgtgacttgactcttcaaacacaaa ggttaacaggaagatctcgagggccctggctgaacttcaccttttggctttcttggcctgatgctg aactctcgaggttgagccccatatg (Seq ID No: 81)
Homo sapiens v-erb-b2 erythroblastic leukemia viral oncogene homol og 3 (avian) (ERBB3) :
atccctccccggactccggctccggctccgattgcaatttgcaacctccgctgccgtcgccgcagc agccaccaattcgccagcggttcaggtggctcttgcctcgatgtcctagcctaggggcccccgggc cggacttggctgggctcccttcaccctctgcggagtcatg (Seq ID No: 82)
Homo sapiens podoplanin (PDPN) : ccgcctcctcgggagagataaatg
(Seq ID No: 83)
Homo sapiens ribonucleotide reductase Ml (RRMl) :
gcgcccctttgtgcgtcacgggtggcgggcgcgggaaggggatttggattgttgcgcctctgctct gaagaaagtgctgtctggctccaactccagttctttcccctgagcagcgcctggaacctaaccctt cccactctgtcaccttctcgatcccgccggcgctttagagccgcagtccagtcttggatccttcag agcctcagccactagctgcgatg (Seq ID No: 84)
Homo sapiens solute carrier family 2 (facilitated glucose transporter) , member 4 (SLC2A4) :
gcgtcttttcccccagccccgctccaccagatccgcgggagccccactgctctccgggtccttggc ttgtggctgtgggtcccatcgggcccgccctcgcacgtcactccgggacccccgcggcctccgcag gttctgcgctccaggccggagtcagagactccaggatcggttctttcatcttcgccgcccctgcgc gtccagctcttctaagacgagatg (Seq ID No: 85)
Homo sapiens steroid-5-alpha-reductase, alpha polypeptide 1
(3-oxo-5 alpha-steroid delta 4-dehydrogenase alpha 1) (SRD5A1) : aaccctttctgcagagtcccggcagtgcgggactccggtagccgcccctccggtagccgcccctcc tgcccccgcgccgccgccctatatgttgcccgccgcggcctctggggcatggagcacgctgcccag ccctggcgatg (Seq ID No: 86)
Homo sapiens thromboxane A synthase 1 (platelet) (TBXAS1) :
gttcccttttctacctgcagagcacggttcccataagggcggcgagatcagcctcctgtctcatct ggaagaccaccactctggggtctcagaggaatg (Seq ID No: 87)
Homo sapiens transketolase (TKT) :
ctatctctgtgtgtccgcgtgtgcgcccggtccccgcctgccgcaccatg (Seq ID No: 88)
Homo sapiens tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A) :
cctcctcctccagctcttcctgtcccgctgttgcaacactgcctcactcttcccctcccaccttct ctcccctcctctctgctttaattttctcagaattctctggactgaggctccagttctggcctttgg ggttcaagatcactgggaccaggccgtgatctctatgcccgagtctcaaccctcaactgtcacccc aaggcacttgggacgtcctggacagaccgagtcccgggaagccccagcactgccgctgccacactg ccctgagcccaaatgggggagtgagaggccatagctgtctggcatg (Seq ID No: 89)
Homo sapiens tubulin, beta 2A class Ila (TUBB2A) :
aggtctctgcgcagcccagcccgccggtccacgccgcgcaccgctccgagggccagcgccacccgc tccgcagccggcaccatg (Seq ID No: 90)
Homo sapiens actin, beta (ACTB) : tcgcctttgccgatccgccgcccgtcca- cacccgccgccagctcaccatg (Seq ID No: 91)
Homo sapiens adenylosuccinate synthase (ADSS) :
ggctccttcttcctctgcatgtggctggcggccgcagagcagttcagttcgctcactcctcgccgg ccgcctctccttcgggctctcctcgcgtcactggagccatg (Seq ID No: 92)
Homo sapiens alanyl (membrane) aminopeptidase (ANPEP) :
cgttctctgcctggcctgaggctccctgagccgcctccccaccatcaccatg
(Seq ID No: 93)
Homo sapiens beaded filament structural protein 1, filensin
(BFSP1) :
gcctcctttctttctcagcccagacctggccctctggagagggttttggagtcctgggtaggcagg gtacctcaggcagcaggcagcacaccttggatgtgagctgaatggattttcaaatttcacagaagg agcctccatgctggagaaagtatgtatg (Seq ID No: 94)
Homo sapiens basic transcription factor 3 (BTF3) :
cggcctccctttagctgccatcttgcgtccccgcgtgtgtgcgcctaatctcaggtggtccacccg agaccccttgagcaccaaccctagtcccccgcgcggccccttattcgctccgacaagatg (Seq ID No: 95)
Homo sapiens complement component 1, q subcomponent binding protei n (C1QBP) : ttgtcctttgcatctgcacgtgttcgcagtcgtttccgcgatg
(Seq ID No: 96)
Homo sapiens calsequestrin 1 (fast-twitch, skeletal muscle)
(CASQ1) :
tttcctttcttaatatggcgatgagctcttaggccagtgtggggaccggggctgaggtgccctgga cactggaggagggggagggaaggagcccctgggagcctggggtagaagtgtaggaggtgggaggat tccggcccgcatggagctgtcctggcctcagaaggttatccgtctctcctgccaaccatggagaca tatttagacaggaccaggtggggactgaggggtgccaatttcagggggcagctccggttccctccc cgccccctgctcctattcctccacctgaccctttttcccttggctctgtcggcagtttctccagga cccagcagtgccctctgtccactgctctgggccattccccaatcccccctcccacttgagccccta actcagaatctgggacccaggggcccctccctaccccagctaacctcttctggaccaggagagcca acccagatcccactacctccatg (Seq ID No: 97)
Homo sapiens caveolin 3 (CAV3) :
gtctctctgcccctctctgccccaagtattttcagccccagccggccacacagctcggatctcctc ctgtggatccccccagctctgcgatg (Seq ID No: 98)
Homo sapiens serpin peptidase inhibitor, clade H
(heat shock protein 47), member 1, (collagen binding protein 1) (SERPINH1) :
aggtctttggctttttttggcggagctggggcgccctccggaagcgtttccaactttccagaagtt tctcgggacgggcaggagggggtggggactgccatatatagatcccgggagcaggggagcgggcta agagtagaatcgtgtcgcggctcgagagcgagagtcacgtcccggcgctagcccagcccgacccag gcccaccgtggtgcacgcaaaccacttcctggccatg (Seq ID No: 99)
Homo sapiens CD68 molecule (CD68):
tttcctcctttccaagagagggctgagggagcagggttgagcaactggtgcagacagcctagctgg actttgggtgaggcggttcagccatg (Seq ID No: 100)
Homo sapiens cell division cycle 20 homolog (S. cerevisiae)
(CDC20) :
gggtccctttctgtcccctgagcaccgtcgcctcctttcctccagggctccgtaggcaccaactgc aaggacccctccccctgcgggcgctcccatg (Seq ID No: 101)
Homo sapiens cadherin 13, H-cadherin (heart) (CDH13) :
gagcctctcctcaaagcctggctcccacggaaaatatgctcagtgcagccgcgtgcatgaatgaaa acgccgccgggcgcttctagtcggacaaaatg (Seq ID No: 102)
Homo sapiens regulator of chromosome condensation (RCC1) and BTB (POZ) domain containing protein 2 (RCBTB2) :
cgctcccttcgtttccgtctcggccgggcacccgagcgcatcccgccgaggccgggccgtttcagg gggaggcgccaactcatcgcggcgccgggcccctgaccgtgcagtaaccgctacccaggaggcgga gcggacaaggctccggcctgcgaggagtcacattaactttgctctagaagacaactttacaaggat ctaaaaggaacaggattaaagatgactgaatactgggttccagaaatttaaaacaatcagcttagc aaatcatatattcttctgtggagctgagaattgatgtccgctcttccccgtgatttggaactttcc aatcccagagaaaagttgacaaagggactgcccaggactgagtccatatg
(Seq ID No: 103) Homo sapiens cold inducible RNA binding protein (CIRBP) :
ccccccctcactcgcgcgttaggaggctcgggtcgttgtggtgcgctgtcttcccgcttgcgtcag ggacctgcccgactcagtggccgccatg (Seq ID No: 104)
Homo sapiens LIM domain binding 2 (LDB2) :
cctcctctcctctccctctcctctcctgctatagagggctccgacagcagttcccagccagcgtgt tcagcctgcctgcctgcctgcctctgtgtgtgtgtgagcgtgtgtgcgtgcgtctactttgtactg ggaagaacacagcccatgtgctctgcatggacgttactgatactctgtttagcttgattttcgaaa agcaggcaagatg (Seq ID No: 105)
Homo sapiens chloride channel, nucleotide-sensitive, 1A (CLNS1A) : ctgcctcttccagggcgggcggtgtggtgcacgcattgctgtgctccaactccctcagggcctgtg ttgccgcactctgctgctatg (Seq ID No: 106)
Homo sapiens collapsin response mediator protein 1 (CRMP1) :
cctcctccttctcccgccctcctcgccgatccgggcggtgctggcagccggagcggcggcgggcgg gccgagcagccggggcagccgcgcgtgggcatccacgggcgccgagcctccgtccgtgtctctatc cctcccgggcctttgtcagcgcgcccgctgggagcggggccgagagcgccggttccagtcagacag ccccgcaggtcagcggccgggccgagggcgccagagggggccatg (Seq ID No: 107)
Homo sapiens catenin (cadherin-associated protein) , delta 1
(CTNND1) :
ttgcctttggctgggtgcaacttccattttaggtgttggatctgagggggaaaaaaaagagagagg gagagagagagaaagaagagcaggaaagatcccgaaaggaggaagaggtggcgaaaaatcaactgc cctgctggatttgtctttctcagcaccttggcgaagccttgggtttctttcttaaaggactgattt ttagaactccacatttgaggtgtgtggcttttgaagaaaatgtatgtactgacgggaaaaggagga taagcaagtcgaatttttgtcttacgctctctccttcctgcttcctccttgctgtggtggctggga tgcttcttccatgattttttgaatctagactgggctgttctctgtgttaaaccaatcagttgcgac cttctcttaacagtgtgaagtgagggggtctctctccctccttctccttcctctgtgattcacctt cctttttaccctgccctgcggcggctccgccccttaccttcatg (Seq ID No: 108)
Homo sapiens diacylglycerol kinase, alpha 80kDa (DGKA) :
ccgtcccctccagcccagctcgggctccagctccagcgccggcgcttcagctgcgaccgcgagccc tctcaagcaagatataacttccccaagtcacacagtggtatcagagctaagaatgggacccagata tgactgatctagttctgttccaaaaccgtgctgtattatattaacgcctaccctctgaagaggtcc aagcaacggaagtactactacgaagctgcctttctggccatccttgagaaaaatagacagatgagt tcctgccagtgagtccctaggcctccatctctctcccttgctgtaccaccttcaccaccatccatg cgaccccaagagccttaatgactctagaagagactccaggcaggggaagctgaaaggacctttcac tccctacttttggccagggccttctgtgccacctgccaagaccagcaggcctaccctctgaagagg tccaagcaacggaagtactactacgaagctgcctttctggccatccttgagaaaaatagacagatg (Seq ID No: 109)
Homo sapiens aspartyl-tRNA synthetase (DARS) :
cgatctttctggagccgcacctccacgcggagtccgagcgcgtgtgctgagaccccagggtcggga gggcggagactgggagggagggagaagcccctttggcctgccttacggaagcctgcgagggagggt ggtgtccactgcccagttccgtgtcccgatg (Seq ID No: 110)
Homo sapiens dynein, cytoplasmic 1, intermediate chain 2
(DYNC1I2) :
agttcttctcgatcgtgtcagtttgtaaggcgagggcggaagttggattcctggcctgagaatatt aggcgtagttttccagtttttggcaaagcggaaatacttaaggcccctgggttgactgggttcttt gttttatctaccggcttctgctttacgacaggtcacaaacatg (Seq ID No: 111) Homo sapiens dedicator of cytokinesis 1 (DOCKl) :
tttcctccccatcctgtcgcggctcgaaaggaatggaaaatggcggcctagacgcggagtttcctg cccgacccgcggcggctccggcggcgccatg (Seq ID No: 112)
Homo sapiens dihydropyrimidinase-like 2 (DPYSL2) :
ctctctcttttttttccgccctagctggggctgtgttggaggagaggaagaaagagagacagagga ttgcattcatccgttacgttcttgaaatttcctaatagcaagaccagcgaagcggttgcacccttt tcaatcttgcaaaggaaaaaaacaaaacaaaacaaaaaaaacccaagtccccttcccggcagtttt tgccttaaagctgccctcttgaaattaattttttcccaggagagagatg (Seq ID No: 113)
Homo sapiens developmentally regulated GTP binding protein 2 (DRG2) :
tgttctctttggcttccgggcgcacgctactctgtcgccgccgtcagaccggaattgccggtgccg ccgccaccgctgtctgtgcgcccacctctgctgctaccatg (Seq ID No: 114)
Homo sapiens eukaryotic translation elongation factor 1 alpha 1 (EEF1A1) :
cgttctttttcgcaacgggtttgccgccagaacacaggtgtcgtgaaaactacccctaaaagccaa aatg (Seq ID No: 115)
Homo sapiens eukaryotic translation elongation factor 1 gamma (EEF1G) :
tctcctctttccccctcccttctctcccgggcggcttactttgcggcagcgccgagaaccccaccc cctttctttgcggaatcaccatg (Seq ID No: 116)
Homo sapiens eukaryotic translation initiation factor 2, subunit 3 gamma, 52kDa (EIF2S3) : atttccttcctcttttggcaacatggcgggc
(Seq ID No: 117)
Homo sapiens eukaryotic translation initiation factor 4B (EIF4B) : gggtcttttgcgttctctttccctctcccaacatg (Seq ID No: 118)
Homo sapiens eukaryotic translation initiation factor 4 gamma, 2 (EIF4G2) : tattcttttgaagattcttcgttgtcaagccgccaaagtg
(Seq ID No: 119)
Homo sapiens epithelial membrane protein 1 (EMP1) :
cttcccctcagtgcggtcacatacttccagaagagcggaccagggctgctgccagcacctgccact cagagcgcctctgtcgctgggacccttcagaactctctttgctcacaagttaccaaaaaaaaaaga gccaacatg (Seq ID No: 120)
Homo sapiens fibrillarin (FBL) :
cgctcttttccacgtgcgaaagccccggactcgtggagttgtgaacgccgcggactccggagccgc acaaaccagggctcgccatg (Seq ID No: 121)
Homo sapiens exostoses (multiple) -like 2 (EXTL2) :
ctgtcccttgctccaggcgctcactttgcgggcggcactttttccaggttgttaatccagctaatg gagaaggatagatgcacgctacttggtttagaaaaaaaaacaaaaatgagcaaacgagacgcccct tccgttttatgataactaagctgcagggaaataaatcggctggccctactgcaatctactgcactc gagaaacatcacagaaaattctttgatttatcttaatagtgacaagtgagcctgcttctgtcaatt actgaagctataaggagattttttaaaaattaaacttcaacacaatg (Seq ID No: 122)
Homo sapiens solute carrier family 37 (glucoses-phosphate transporter) , member 4 (SLC37A4) : ccgcctctgttcaggacactgggtccccttggagcctccccaggcttaatgattgtccagaaggcg gctataaagggagcctgggaggctgggtggaggagggagcagaaaaaacccaactcagcagatctg ggaactgtgagagcggcaagcaggaactgtggtcagaggctgtgcgtcttggctggtagggcctgc tcttttctaccatg (Seq ID No: 123)
Homo sapiens GDP dissociation inhibitor 2 (GDI2) :
agccctcccctcctcgctccctcccctcctctccccgcccagttcttctcttcccgtctgaggtgg cggtcggtctcgccttgtcgccagctccattttcctctctttctcttcccctttccttcgcgccca agagcgcctcccagcctcgtagggtggtcacggagcccctgcgccttttccttgctcgggtcctgc gtccgcgcctgccccgccatg (Seq ID No: 124)
Homo sapiens UDP-Gal : betaGlcNAc beta 1,4- galactosyltransferase, p olypeptide 1 (B4GALT1) : cacccttcttaaagcggcggcgggaagatg
(Seq ID No: 125)
Homo sapiens GDP-mannose 4, 6-dehydratase (GMDS) :
ggccctccctgcacggcctcccgtgcgcccctgtcagactgtggcggccggtcgcgcggtgcgctc tccctccctgcccgcagcctggagaggcgcttcgtgctgcacacccccgcgttcctgccggcaccg cgcctgccctctgccgcgctccgccctgccgccgaccgcacgcccgccgcgggacatg
(Seq ID No: 126)
Homo sapiens histone deacetylase 2 (HDAC2) :
ggccccctcctcgcgagttggtgccgctgccacctccgattccgagctttcggcacctctgccggg tggtaccgagccttcccggcgccccctcctctcctcccaccggcctgcccttccccgcgggactat cgcccccacgtttccctcagcccttttctctcccggccgagccgcggcggcagcagcagcagcagc agcagcaggaggaggagcccggtggcggcggtggccggggagcccatg (Seq ID No: 127)
Homo sapiens protein arginine methyltransferase 2 (PRMT2) :
gggccttcccggctgacggcctgcgtgcactgcgcttgcgcgggttgagggcggtggctcaggctc ctggaaaggaccgtccacccctccgcgctggcggtgtggacgcggaactcagcggagaaacgcgat tgagagcagtgtgtggattacactatcactggaaaaatacgaattgagaagaaggaaaagactgga agatgcagaccttggttcctgttagtggaaacactgtaaggtcccagaaatggaaaagaaaatgaa ataaatcagcagttatgaggcagagcctaagagaactatg (Seq ID No: 128)
Homo sapiens immunoglobulin (CD79A) binding protein 1 (IGBP1) : gttcctctctccccaagatg (Seq ID No: 129)
Homo sapiens eukaryotic translation initiation factor 3, subunit E (EIF3E) : actcccttttctttggcaagatg (Seq ID No: 130)
Homo sapiens activated leukocyte cell adhesion molecule (ALCAM) : gtccctctactcagagcagcccggagaccgctgccgccgctgccgctgctaccaccgctgccacct gaggagacccgccgcccccccgtcgccgcctcctgcgagtccttcttagcacctggcgtttcatgc acattgccactgccattattattatcattccaatacaaggaaaataaaagaagataccagcgaaaa gaaccgcttacacctttccgaattactcaagtgtctcctggaaacagagggtcgttgtccccggag gagcagccgaagggcccgtgggctggtgttgaccgggagggaggaggagttgggggcattgcgtgg tggaaagttgcgtgcggcagagaaccgaaggtgcagcgccacagcccaggggacggtgtgtctggg agaagacgctgcccctgcgtcgggacccgccagcgcgcgggcaccgcggggcccgggacgacgccc cctcctgcggcgtggactccgtcagtggcccaccaagaaggaggaggaatatg
(Seq ID No: 131)
Homo sapiens acyloxyacyl hydrolase (neutrophil) (AOAH) :
ttttctttatcctgcagtctttacctcagcagaaccgcacaccacagactccctccagctctttgt gtgtggctctctcagggtccaacaagagcaagctgtgggtctgtgagtgtttatgtgtgcttttat tcacttcacacttattgaaaagtgtgtatgtgagagggtggggtgtgtgtgtcaaagagagtgagg aagagaaggagagagagatcaattgattctgcagcctcagctccagcatccctcagttgggagctt ccaaagccgggtgatcacttggggtgcatagctcggagatg (Seq ID No: 132)
Homo sapiens ADP-ribosylation factor 1 (ARF1) :
ccgccccttacccggcgtgccccgcgcccggaggcgctgacgtggccgccgtcagagccgccatct tgtgggagcaaaaccaacgcctggctcggagcagcagcctctgaggtgtccctggccagtgtcctt ccacctgtccacaagcatg (Seq ID No: 133)
Homo sapiens ADP-ribosylation factor 6 (ARF6) :
gcgccttttccggcagcggcggcggcagaactgggaggaggagttggaggccggagggagcccgcg ctcggggcggcggctggaggcagcgcaccgagttcccgcgaggatccatgacctgacggggccccg gagccgcgctgcctctcgggtgtcctgggtcggtggggagcccagtgctcgcaggccggcgggcgg gccggagggctgcagtctccctcgcggtgagaggaaggcggaggagcgggaaccgcggcggcgctc gcgcggcgcctgcggggggaagggcagttccgggccgggccgcgcctcagcagggcggcggctccc agcgcagtctcagggcccgggtggcggcggcgactggagaaatcaagttgtgcggtcggtgatgcc cgagtgagcggggggcctgggcctctgcccttaggaggcaactcccacgcaggccgcaaaggcgct ctcgcggccgagaggcttcgtttcggtttcgcggcggcggcggcgttgttggctgaggggacccgg gacacctgaatgcccccggccccggctcctccgacgcgatg (Seq ID No: 134)
Homo sapiens ras homolog family member A (RHOA) :
cgccctcccgccgccgcccgccctcgctctctcgcgctaccctcccgccgcccgcggtcctccgtc ggttctctcgttagtccacggtctggtcttcagctacccgccttcgtctccgagtttgcgactcgc ggaccggcgtccccggcgcgaagaggctggactcggattcgttgcctgagcaatg
(Seq ID No: 135)
Homo sapiens ras homolog family member G (RHOG) :
cggcctcccgctctcacttccttctcgagcccggagccgctgccgccgcccccagctcccccgcct cggggagggcaccaggtcactgcagccagaggggtccagaagagagaggaggcactgcctccacta cagcaactgcacccacgatg (Seq ID No: 136)
Homo sapiens ATP synthase, H+ transporting, mitochondrial Fl compl ex, 0 subunit (ATP50) : ctctcttcccactcgggtttgacctacagccgcccgggagaa- gatg (Seq ID No: 137)
Homo sapiens B lymphoid tyrosine kinase (BLK) :
ccacctctgtctgctgccggcagaaagccacaagccatgaaaactgattgagatgagaagaattca tctgggactggcttttgctttaggatggtgttggaagttgctcgttgtcgctaggagcctgctcca ctgtaagggtgtcaggatctgaagagctatggtgaaacaccactgaagcattgccaaggatg (Seq ID No: 138)
Homo sapiens B-cell translocation gene 1, anti-proliferative (BTG1) :
gcatctcttcgcctctcggagctggaaatgcagctattgagatcttcgaatgctgcggagctggag gcggaggcagctggggaggtccgagcgatgtgaccaggccgccatcgctcgtctcttcctctctcc tgccgcctcctgtctcgaaaataacttttttagtctaaagaaagaaagacaaaagtagtcgtccgc ccctcacgccctctcttcctctcagccttccgcccggtgaggaagcccggggtggctgctccgccg tcggggccgcgccgccgagccccagccgccccgggccgcccccgcacgccgcccccatg
(Seq ID No: 139)
Homo sapiens calcium modulating ligand (CAMLG) :
cggcctctagtcatcgccctcgcagcggcggccaacatcaccgccactgccacccctcccagactg tggacgggaggatg (Seq ID No: 140) Homo sapiens calnexin (CANX) :
aggcctcttggttctgcggcacgtgacggtcgggccgcctccgcctctctctttactgcggcgcgg ggcaaggtgtgcgggcgggaaggggcacgggcacccccgcggtccccgggaggctagagatcatg (Seq ID No: 141)
Homo sapiens calpain 2, (m/II) large subunit (CAPN2) :
cgacctttctctgcgcagtacggccgccgggaccgcagcatg (Seq ID No: 142)
Homo sapiens caveolin 1, caveolae protein, 22kDa (CAV1) :
gcgcctttttttccccccatacaatacaagatcttccttcctcagttcccttaaagcacagcccag ggaaacctcctcacagttttcatccagccacgggccagcatg (Seq ID No: 143)
Homo sapiens CDld molecule (CD1D) :
cgacctctttgcagctcgcacagctaagggcgagggcgcccttcggcagaagcagcaaaccgccgg caagcccagcgaggagggctgccggggtctgggcttgggaattggctggcacccagcggaaaggga cgtgagctgagcggcgggggagaagagtgcgcaggtcagagggcggcgcgcagcggcgctccgcga ggtccccacgccgggcgatatg (Seq ID No: 144)
Homo sapiens CD22 molecule (CD22) :
tctccttttgctctcagatgctgccagggtccctgaagagggaagacacgcggaaacaggcttgca cccagacacgacaccatg (Seq ID No: 145)
Homo sapiens CD37 molecule (CD37) :
cttcctcttttggggttcttcctttctctctcagctctccgtctctctttctctctcagcctcttt ctttctccctgtctcccccactgtcagcacctcttctgtgtggtgagtggaccgcttaccccacta ggtgaagatg (Seq ID No: 146)
Homo sapiens CD38 molecule (CD38) :
gcctctctcttgctgcctagcctcctgccggcctcatcttcgcccagccaaccccgcctggagccc tatg (Seq ID No: 147)
Homo sapiens CD48 molecule (CD48) :
cggcctttttctagccaggctctcaactgtctcctgcgttgctgggaagttctggaaggaagcatg (Seq ID No: 148)
Homo sapiens chromogranin B (secretogranin 1) (CHGB) :
cttcctttccgcacaggggccgccgagcggggccatg (Seq ID No: 149)
Homo sapiens chloride channel, voltage-sensitive 3 (CLCN3) :
ttccccttccgtgggtcagggccggtccggtccggaacctgcagcccctttcccagtgttctagtt cgcccgtgacccggaataatgagcaaggagggtgtggtgggttgaaagccatcctactttactccc gagttagagcatggattcagttttagtcttaagggggaagtgagattggagatttttatttttaat tttgggcagaagcaggttgactctagggatctccagagcgagaggatttaacttcatgttgctccc gtgtttgaaggaggacaataaaagtcccaccgggcaaaattttcgtaacctctgcggtagaaaacg tcaggtatcttttaaatcgcgatagttttcgctgtgtcaggctttcttcggtggagctccgagggt agctaggttctaggtttgaaacagatgcagaatccaaaggcagcgcaaaaaacagccaccgatttt gctatgtctctgagctgcgagataatcagacagctaaatg (Seq ID No: 150)
Homo sapiens colipase, pancreatic (CLPS) :
ttccccttccgtgggtcagggccggtccggtccggaacctgcagcccctttcccagtgttctagtt cgcccgtgacccggaataatgagcaaggagggtgtggtgggttgaaagccatcctactttactccc gagttagagcatggattcagttttagtcttaagggggaagtgagattggagatttttatttttaat tttgggcagaagcaggttgactctagggatctccagagcgagaggatttaacttcatgttgctccc gtgtttgaaggaggacaataaaagtcccaccgggcaaaattttcgtaacctctgcggtagaaaacg tcaggtatcttttaaatcgcgatagttttcgctgtgtcaggctttcttcggtggagctccgagggt agctaggttctaggtttgaaacagatgcagaatccaaaggcagcgcaaaaaacagccaccgatttt gctatgtctctgagctgcgagataatcagacagctaaatg (Seq ID No: 151)
Homo sapiens cytochrome c oxidase subunit IV isoform 1 (COX4I1) : ctacccttttccgctccacggtgacctccgtgcggccgggtgcgggcggagtcttcctcgatcccg tggtgctccgcggcgcggccttgctctcttccggtcgcgggacaccgggtgtagagggcggtcgcg gcgggcagtggcggcagaatg (Seq ID No: 152)
Homo sapiens cytochrome c oxidase subunit VIIc (COX7C) :
ctttcttttcagtccttgcgcaccggggaacaaggtcgtgaaaaaaaaggtcttggtgaggtgccg ccatttcatctgtcctcattctctgcgcctttcgcagagcttccagcagcggtatg
(Seq ID No: 153)
Homo sapiens activating transcription factor 2 (ATF2) :
cagccttttcctccaggggtgctttgtaaacacggctgtgctcagggctcgcgggtgaccgaaagg atcatgaactagtgacctggaaagggtactagatggaaacttgagaaaggactgcttattgataac agctaaggtattcctggaagcagagtaaataaagctcatggcccaccagctagaaagtattcttgc catgagaaaaagaatgtgataagttattcaacttatg (Seq ID No: 154)
Homo sapiens casein kinase 1, alpha 1 (CSNK1A1) :
agatccctttcccagagtgctctgcgccgtgaagaagcggctcccggggactgggggcattttgtg ttggctggagctggagtaacaagatggcgtcgtccgcggagtgacaggggtccctctgggccggag ccggcggcagtggtggcagcggtatcgccgccctagctcaccgcgccccttttccagcccgcgacg tcgccgcgcaagcgaggcagcggcggccgccgagaaacaagtggcccagcctggtaaccgccgaga agcccttcacaaactgcggcctggcaaaaagaaacctgactgagcggcggtgatcaggttcccctc tgctgattctgggccccgaaccccggtaaaggcctccgtgttccgtttcctgccgccctcctccgt agccttgcctagtgtaggagccccgaggcctccgtcctcttcccagaggtgtcggggcttggcccc agcctccatcttcgtctctcaggatg (Seq ID No: 155)
Homo sapiens catenin (cadherin-associated protein) , beta 1, 88kDa (CTNNB1) :
aagcctctcggtctgtggcagcagcgttggcccggccccgggagcggagagcgaggggaggcggag acggaggaaggtctgaggagcagcttcagtccccgccgagccgccaccgcaggtcgaggacggtcg gactcccgcggcgggaggagcctgttcccctgagggtatttgaagtataccatacaactgttttga aaatccagcgtggacaatg (Seq ID No: 156)
Homo sapiens dCMP deaminase (DCTD) :
ccgcctcctcccccgacttccttccctgagcacggcggcggcggggacgagcaccggcctgcgcgc ggagccggcaccggatgacccaacatg (Seq ID No: 157)
Homo sapiens damage-specific DNA binding protein 1, 127kDa (DDB1) : ctgtcttttcgcttgtgtccctctttctagtgtcgcgctcgagtcccgacgggccgctccaagcct cgacatg (Seq ID No: 158)
Homo sapiens desmin (DES) :
ctgtctcccctcgccgcatccactctccggccggccgcctgcccgccgcctcctccgtgcgcccgc cagcctcgcccgcgccgtcaccatg (Seq ID No: 159)
Homo sapiens deoxyhypusine synthase (DHPS) :
cgttccctacttcctgtgctcttgcggagacgcgcgcgtcggggtttaacgcgtttctgggccgcc gtaagcccggcctaggggcagctttgactcgagagccggctataggcgcatg
(Seq ID No: 160) Homo sapiens dihydrolipoamide S-acetyltransferase (DLAT) :
caccctttcggatgcctcccctagaaccctaccactttccacccctttccgtctgttatttctccc aaacttgcgcccgcacaggcccctctggaacactcctgccccgtagtgcccctcgtccccgctccg tagagaaagagcgtgcgtgccgcgcatttctggcctggggagcgggtggagtaaacctgcgggaac cattttacgacaacgtgcggctgtgcggtgtggctgacggcaacgccgctgctcttggagaggtca ctccggagacggcgttggttttggggtgtggggggttggtggcactatg (Seq ID No: 161)
Homo sapiens down-regulator of transcription 1, TBP-binding (negative cofactor 2) (DR1) :
ccttccctggcatctggagggaccaccgttgccgcgtcttcggcttccacgatctgcgttcgggct acgcggccacggcggcagccactgcgactcccactgtgcctggctctgtccatattagttcccagg cggccgtcgccgttccagcagcggcagcggcagcggcagcggcggacatgttgtgaggcggcggcg cgggtgtctgaaggatggtttggccgaggcggcggcaacggctgctggcggcggcggcagcggcag cggggcctcgggctctatagagccgagcccgctgggtacccgcccggtaccgcggcgaggccagtg cccctggatcttgcctctgctccgacgccgttggggaccagttaggcgacagcgcccgcccctctg aggagacacgaaggtggttccccagccgctcaaatttccggaccaccgcgctttcccctcctcagc ctgggctgtgctctctctagaatcctcgggcccccactttcttcccaaactcatcctaaatctctc acacacgcgagtgttcccagccctcaagccagctgctcctccgttcattttctgcaccctcttcgc aaagcaccccccgggatcactctccgagggcgactttttgagaaatctcggtggagtagtggacca gagctggggagtttttaaaagccggggcgcgagaaacaggaaggtactatg
(Seq ID No: 162)
Homo sapiens endothelin receptor type A (EDNRA) :
ttttctttttcgtgcgagccctcgcgcgcgcgtacagtcatcccgctggtctgacgattgtggaga ggcggtggagaggcttcatccatcccacccggtcgtcgccggggattggggtcccagcgagacctc cccgggagaagcagtgcccaggaggttttctgaagccggggaagctgtgcagccgaagccgccgcc gcgccggagcccgggacaccggccaccctccgcgccacccaccctcgccggctccggcttcctctg gcccaggcgccgcgcggacccggcagctgtctgcgcacgccgagctccacggtgaaaaaaaagtga aggtgtaaaagcagcacaagtgcaataagagatatttcctcaaatttgcctcaagatg
(Seq ID No: 163)
Homo sapiens eukaryotic translation elongation factor 1 alpha 2 (EEF1A2):
cagtccctctggctgagacctcggctccggaatcactgcagcccccctcgccctgagccagagcac cccgggtcccgccagcccctcacactcccagcaaaatg (Seq ID No: 164)
Homo sapiens eukaryotic translation elongation factor 2 (EEF2) : cgttctcttccgccgtcgtcgccgccatcctcggcgcgactcgcttctttcggttctacctgggag aatccaccgccatccgccaccatg (Seq ID No: 165)
Homo sapiens eukaryotic translation initiation factor 4A2
(EIF4A2) : ctgtcttttcagtcgggcgctgagtggtttttcggatcatg
(Seq ID No: 166)
Homo sapiens egf-like module containing, mucin-like, hormone recep tor-like 1 (EMRl) : gtttcttttctttgaatgacagaactacagcataatg
(Seq ID No: 167)
Homo sapiens enolase 2 (gamma, neuronal) (EN02) :
gcgcctcctccgcccgccgcccgggagccgcagccgccgccgccactgccactcccgctctctcag cgccgccgtcgccaccgccaccgccaccgccactaccaccgtctgagtctgcagtcccgagatccc agccatcatg (Seq ID No: 168) Homo sapiens esterase D (ESD) :
ccgccttttacttcggcccgcttcttctggtcactccgccaccgtagaatcgcctaccatttggtg caagcaaaaagcaatcagcaattggacaggaaaagaatg (Seq ID No: 169)
Homo sapiens Finkel-Biskis-Reilly murine sarcoma virus
(FBR-MuSV) ubiquitously expressed (FAU) :
cttcctctttctcgactccatcttcgcggtagctgggaccgccgttcagtcgccaatatg (Seq ID No: 170)
Homo sapiens Friend leukemia virus integration 1 (FLI1) :
ctgtctctttcgctccgctacaacaacaaacgtgcacaggggagtgagggcagggcgctcgcaggg ggcacgcagggagggcccagggcgccagggaggccgcgccgggctaatccgaaggggctgcgaggt caggctgtaaccgggtcaatgtgtggaatattggggggctcggctgcagacttggccaaatg (Seq ID No: 171)
Homo sapiens fibromodulin (FMOD) :
gccccttttcacaatatttgattaggaatttggggcgggaccctggtctggcacaggcacgcacac tctcagtagactctttcactcctctctctcttcctctctcacacgttctccaacccaaggaggcca gacagagggacgtggtcactctctgaaaagttcaacttgagagacaaaatg
(Seq ID No: 172)
Homo sapiens ferritin, heavy polypeptide 1 (FTH1) :
cgttcttcgccgagagtcgtcggggtttcctgcttcaacagtgcttggacggaacccggcgctcgt tccccaccccggccggccgcccatagccagccctccgtcacctcttcaccgcaccctcggactgcc ccaaggcccccgccgccgctccagcgccgcgcagccaccgccgccgccgccgcctctccttagtcg ccgccatg (Seq ID No: 173)
Homo sapiens glyceraldehyde-3-phosphate dehydrogenase (GAPDH) : cgctctctgctcctcctgttcgacagtcagccgcatcttcttttgcgtcgccagccgagccacatc gctcagacaccatg (Seq ID No: 174)
Homo sapiens glycyl-tRNA synthetase (GARS) :
caccctctctggacagcccagggccgcaggctcatg (Seq ID No: 175)
Homo sapiens glutamic-oxaloacetic transaminase 2, mitochondrial (aspartate aminotransferase 2) (GOT2) :
ctgtccttaccttcagcaggagccggttccctgtgtgtgtgtccgctcgccctctgctccgtcctg cggctgcccactgccctcctacggtccaccatg (Seq ID No: 176)
Homo sapiens general transcription factor IIF, polypeptide 1, 74kD a (GTF2F1) :
gcgcctcttccggttaccttttcccagcgccagaggcgcctagggttggggtcctcgctcaggcac agagacccgacaccgagcggcggcttccccgggatcgagggacgcgcacgccagaggagacgaaag gaacccgggtcggaccagatcggaaccactgaccattgcccatg (Seq ID No: 177)
Homo sapiens glycogen synthase 1 (muscle) (GYS1) :
cggcctccttctgcctaggtcccaacgcttcggggcaggggtgcggtcttgcaataggaagccgag cgtcttgcaagcttcccgtcgggcaccagctactcggccccgcaccctacctggtgcattccctag acacctccggggtccctacctggagatccccggagccccccttcctgcgccagccatg
(Seq ID No: 178)
Homo sapiens major histocompatibility complex, class I, C (HLA-C) : cattctccccagaggccgagatg (Seq ID No: 179) Homo sapiens major histocompatibility complex, class II, DP beta 1 (HLA-DPB1) :
gctccctttagcgagtccttcttttcctgactgcagctcttttcattttgccatccttttccagct ccatg (Seq ID No: 180)
Homo sapiens 3-hydroxy-3-methylglutaryl-CoA synthase 1 (soluble) (H GCS1) :
ctgtcctttcgtggctcactccctttcctctgctgccgctcggtcacgcttgctctttcaccatg (Seq ID No: 181)
Homo sapiens hippocalcin (HPCA) :
ccgccttccctgcgcagtcggtgtctccgcgtcgctgggtgggacttggctcggcggccatg (Seq ID No: 182)
Homo sapiens hydroxysteroid (17-beta) dehydrogenase 2 (HSD17B2) : ctcccttcttgactctctgttcacagaactcaggctgcctccagccagcctttgcccgctagactc actggccctgagcacttgaaggtgcagcaagtcactgagaatg (Seq ID No: 183) Homo sapiens heat shock 60kDa protein 1 (chaperonin) (HSPD1) :
ctgtccctcactcgccgccgacgacctgtctcgccgagcgcacgccttgccgccgccccgcagaaa tg (Seq ID No: 184)
Homo sapiens intercellular adhesion molecule 3 (ICAM3):
ccgccttttcccctgcctgcccttcgggcacctcaggaaggcaccttcctctgtcagaatg (Seq ID No: 185)
Homo sapiens inositol polyphosphate-l-phosphatase (INPP1) :
cgtcctctggccgcgcctgcggccgcacgcccagcgcccctcgcctaacctcgcgcccgggccgcg cctcctcctcctcctgctccccgccgcttccgtttctcgagggaaaggctgctgcctcctgctctg tcctcatccccggcttagctgacggcccagagggtgggtgccaattccaccagcagctgcaactga aaagcaaggttcagaaatg (Seq ID No: 186)
Homo sapiens interferon regulatory factor 2 (IRF2) :
gtttcctctccttgttttgctttcgatctggactgttctcaggcaagccggggagtaacttttagt tttgctcctgcgattattcaactgacgggctttcatttccatttcacataccctagcaacacttat accttgcggaattgtattggtagcgtgaaaaaagcacactgagagggcaccatg
(Seq ID No: 187)
Homo sapiens inter-alpha-trypsin inhibitor heavy chain 2 (ITIH2) : ttttcttcttttttcttctttcttaaagcgaactgtactcctctgctgttcctttgaacttggttc agtaggaagaagtgatatcctccccagaccatctgctttggggagcttggcaaaactgtccagcaa aatg (Seq ID No: 188)
Homo sapiens karyopherin (importin) beta 1 (KPNBl) :
ccgccttcctccctccctcgctccctccctgcgcgccgcctctcactcacagcctcccttccttct ttctccctccgcctcccgagcaccagcgcgctctgagctgcccccagggtccctcccccgccgcca gcagcccatttggagggaggaagtaagggaagaggagaggaaggggagccggaccgactacccaga cagagccggtgaatgggtttgtggtgacccccgccccccaccccaccctcccttcccacccgaccc ccaacccccatccccagttcgagccgccgcccgaaaggccgggccgtcgtcttaggaggagtcgcc gccgccgccacctccgccatg (Seq ID No: 189)
Homo sapiens karyopherin alpha 3 (importin alpha 4) (KPNA3) :
ctctccccctcctccccctcccgctccaagattcgccgccgccgccgccgcagccgcaggagtagc cgccgccggagccgcgcgcagccatg (Seq ID No: 190) Homo sapiens keratin 19 (KRT19) :
gctcctcccgcgaatcgcagcttctgagaccagggttgctccgtccgtgctccgcctcgccatg (Seq ID No: 191)
Homo sapiens laminin, beta 1 (LAMB1) :
attcccttctttgggctcgggggctcccggagcagggcgagagctcgcgtcgccggaaaggaagac gggaagaaagggcaggcggctcggcgggcgtcttctccactcctctgccgcgtccccgtggctgca gggagccggcatg (Seq ID No: 192)
Homo sapiens ribosomal protein SA (RPSA) :
ctgtcttttccgtgctacctgcagaggggtccatacggcgttgttctggattcccgtcgtaactta aagggaaattttcacaatg (Seq ID No: 193)
Homo sapiens lymphocyte cytosolic protein 1 (L-plastin) (LCP1) : ttttctttcctggctgatgatttgtcattctagtcacttcctgccttgtgaccacacacccaggct tgacaaagctgttctgcagatcagaaagaaggggttcctggtcatacaccagtactaccaaggaca gcttttttcctgcaagatctgttacctaaagcaataaaaaatg (Seq ID No: 194) Homo sapiens lectin, galactoside-binding, soluble, 1 (LGALS1) : ccatctctctcgggtggagtcttctgacagctggtgcgcctgcccgggaacatcctcctggactca atcatg (Seq ID No: 195)
Homo sapiens SH2 domain containing 1A (SH2D1A) :
ttctctcttttttgcacatctggctgaactgggagtcaggtggttgacttgtgcctggctgcagta gcagcggcatctcccttgcacagttctcctcctcggcctgcccaagagtccaccaggccatg (Seq ID No: 196)
Homo sapiens mannosidase, alpha, class 2A, member 1 (MAN2A1) :
tgttcctttcccctccgcttctctgacctagctgcgcggccccggcccgggagctgccgaacccgc gcctcccctgggtgaggaggacacgcctgccctcgtcgagaaaacttttcctgccgactcagttgg ggcggcggtggcaggaagtgcgggcagcgacctctcctccgcctgccccgcgcgccctgccggagg tcggcgctgagcttgcgatcaagtttgtgggggccccccttcccagttgccggcgagtctcgcctc gagaggggcgcccgaccccggggagggcggcaggccagggcgaaggccaagggcgtgtggtggcgc cggagactaggtgcggagcaaggcggggactcgcacccgcatccgagagcgcggaggtcgcgcagc ccgggagaagggagcctccggcggctgcttcctagagtccacagtgcgctgtctcctttggctgag gagagtgtcctggccccgagtctatcgaggaaaatg (Seq ID No: 197)
Homo sapiens myelin basic protein (MBP) :
ccgcctcttttcccgagatgccccggggagggaggacaacaccttcaaagacaggccctctgagtc cgacgagctccagaccatccaagaagacagtgcagccacctccgagagcctggatgtgatg (Seq ID No: 198)
Homo sapiens melanocortin 1 receptor (alpha melanocyte stimulating hormone receptor) (MC1R) :
cattcttcccaggacctcagcgcagccctggcccaggaaggcaggagacagaggccaggacggtcc agaggtgtcgaaatgtcctggggacctgagcagcagccaccagggaagaggcagggagggagctga ggaccaggcttggttgtgagaatccctgagcccaggcggtagatgccaggaggtgtctggactggc tgggccatgcctgggctgacctgtccagccagggagagggtgtgagggcagatctgggggtgccca gatggaaggaggcaggcatgggggacacccaaggccccctggcagcaccatgaactaagcaggaca cctggaggggaagaactgtggggacctggaggcctccaacgactccttcctgcttcctggacagga ctatg (Seq ID No: 199)
Homo sapiens malic enzyme 1, NADP (+) -dependent, cytosolic (ME1) : gggcctttcccagtgcggccgccgccgccacagctgcagtcagcaccgtcaccccagcagcatccg ccgcctgcaccgcgcgtgcggcccgccccggcctgaccccgccgccgaacccggcgccagccatg (Seq ID No: 200)
Homo sapiens myocyte enhancer factor 2C (MEF2C) :
agctctctgctcgctctgctcgcagtcacagacacttgagcacacgcgtacacccagacatcttcg ggctgctattggattgactttgaaggttctgtgtgggtcgccgtggctgcatgtttgaatcaggtg gagaagcacttcaacgctggacgaagtaaagattattgttgttattttttttttctctctctctct ctcttaagaaaggaaaatatcccaaggactaatctgatcgggtcttccttcatcaggaacgaatgc aggaatttgggaactgagctgtgcaagtgctgaagaaggagatttgtttggaggaaacaggaaaga gaaagaaaaggaaggaaaaaatacataatttcagggacgagagagagaagaaaaacggggactatg (Seq ID No: 201)
Homo sapiens mannosyl (al- pha-1, 3-) -glycoprotein beta-1, 2-N-acetylglucosaminyltransferase ( GAT1) :
agcccttcttggggaagtcagctacccagcagcctgtagtcctcggctacccaccctcaccgcctg gggtcccatggtgagacagctgggtgggcatcaggcttctgcagagggccaggccggagggagctg ggcgagggagtggggctggctcctggcttgcaccggcctcgtggaatccaggcctcagacctgatc gctggcgaaactggctctgtgcgctggagcccctggtcttctgcgtctgtcctcctcccggccaga ctttactcctggctcagcgacaggtatttgctatggaagagctgtccctccctcccctcggtgggc ctgggtccacctccacctcctcttcaggtccgcaccttcctcccctttaaaacaccagccgggcgc agacccgttctaggcttttccatggtgcttccgccaaagcttgtgaccgagtccttcccgcctagg getggtgggcctcccctgctggtaggtctctcttcgctttctttactcagaactgaagctctcatt ccccacccaccaaggaaaaacaaaagggaagaagccacagctggccccggcttgctttggcacagg tgtttccccccggccccccgtcgggcaccctggttcctgttctgtccctgccccacgcgaccctgg ggctcccacccgggctcctcagcctcccctgggttggggtggggggactggctcccagcccttggc ctagggtttggtgaacgcctttcctggactgcgggcccacttcaggcgcggctccaggctgggcag ctgcgctggagggccgagggcaggggtggggtcgggcgtccaccctcagggttgcgccagggagcc ggaaagccgactcccgaagttggggtcctgggaaaacttgggtcctgggttgactgagaagcggcg gggaaaggaggcgggccaggaggagggggcctggcggacgccggccggggggcggggcgcggcggg gctgtcggtcacgcccctcagtccgccccgccccgccccgcctgccggggaagggccacgttgccc gcccggccgtccggccccggcgcgccgcagaaagggctggcgagtcgaaaggcgaggcggccgcgg cagcgcttgggacgcgcctgggcaccgggctcgctccctgcgccccggagcaggccaagttcgggg ccaggacgtcgggaggacctggtgcatggctgcctcctaatcccatagtccagaggaggcatccct aggactgcgggcaagggagccgggcaagcccagggcagccttgaaccgtcccctggcctgccctcc ccggtgggggccaggatg (Seq ID No: 202)
Homo sapiens mitogen-activated protein kinase kinase kinase 11 (MAP3K11) :
ctgcctcccgcccccggggccaaagtacaaagggaggaggaagaagggagcggggtcggagccgtc ggggccaaaggagacggggccaggaacaggcagtctcggcccaactgcggacgctccctccacccc ctgcgcaaaaagacccaaccggagttgaggcgctgcccctgaaggccccaccttacacttggcggg ggccggagccaggctcccaggactgctccagaaccgagggaagctcgggtccctccaagctagcca tggtgaggcgccggaggccccggggccccacccccccggcctgaccacactgccctgggtgccctc ctccagaagcccgagatgcggggggccgggagacaacactcctggctccccagagaggcgtgggtc tggggctgagggccagggcccggatgcccaggttccgggactagggccttggcagccagcgggggt ggggaccacgggcacccagagaaggtcctccacacatcccagcgccggctcccggccatg (Seq ID No: 203)
Homo sapiens membrane protein, palmitoylated 1, 55kDa (MPP1) :
ccgccttctccgcagccccgcaggccccgggccctgtcattcccagcgctgccctgtcttgcgttc cagtgttccagcttctgcgagatg (Seq ID No: 204) Homo sapiens v-myc myelocytomatosis viral oncogene homolog (avian) (MYC) :
ggccctttataatgcgagggtctggacggctgaggacccccgagctgtgctgctcgcggccgccac cgccgggccccggccgtccctggctcccctcctgcctcgagaagggcagggcttctcagaggcttg gcgggaaaaagaacggagggagggatcgcgctgagtataaaagccggttttcggggctttatctaa ctcgctgtagtaattccagcgagaggcagagggagcgagcgggcggccggctagggtggaagagcc gggcgagcagagctgcgctgcgggcgtcctgggaagggagatccggagcgaatagggggcttcgcc tctggcccagccctcccgctgatcccccagccagcggtccgcaacccttgccgcatccacgaaact ttgcccatagcagcgggcgggcactttgcactggaacttacaacacccgagcaaggacgcgactct cccgacgcggggaggctattctgcccatttggggacacttccccgccgctgccaggacccgcttct ctgaaaggctctccttgcagctgcttagacgctg (Seq ID No: 205)
Homo sapiens nuclear cap binding protein subunit 1, 80kDa (NCBPl) : tggcctctcggttccgcggcgcaccggagggcagcatg (Seq ID No: 206)
Homo sapiens necdin homolog (mouse) (NDN) :
cttcctctccaggaatccgcggagggagcgcaggctcgaagagctcctggacgcagaggccctgcc cttgccagacggcgcagacatg (Seq ID No: 207)
Homo sapiens NADH dehydrogenase
(ubiquinone) 1 beta subcomplex, 5, 16kDa (NDUFB5) :
ccttcttcctcctgcccgtagtagccatg (Seq ID No: 208)
Homo sapiens NADH dehydrogenase (ubiquinone) Fe-S protein 4, 18kDa (NADH-coenzyme Q reductase) (NDUFS4) :
ccgtcctttcatcctggcgtttgcctgcagcaagatg (Seq ID No: 209)
Homo sapiens nuclear factor of kappa light polypeptide gene enhanc er in B-cells 2 (p49/pl00) (NFKB2) :
tgccccttccccggccaagcccaactccggatctcgctctccaccggatctcacccgccacacccg gacaggcggctggaggaggcgggcgtctaaaattctgggaagcagaacctggccggagccactaga cagagccgggcctagcccagagacatg (Seq ID No: 210)
Homo sapiens non-metastatic cells 2, protein (NM23B) expressed in (NME2) :
gcccctcctccgccgccggctcccgggtgtggtggtcgcaccagctctctgctctcccagcgcagc gccgccgcccggcccctccagcttcccggaccatg (Seq ID No: 211)
Homo sapiens nucleophosmin (nucleolar phosphoprotein B23, numatrin) (NPMl) :
gcgtcctttccctggtgtgattccgtcctgcgcggttgttctctggagcagcgttcttttatctcc gtccgccttctctcctacctaagtgcgtgccgccacccgatg (Seq ID No: 212)
Homo sapiens 5 ' -nucleotidase, ecto (CD73) (NT5E) :
cattccttttgtagaaaaacccgtgcctcgaatgaggcgagactcagagaggacccaggcgcgggg cggacccctccaattccttcctcgcgcccccgaaagagcggcgcaccagcagccgaactgccggcg cccaggctccctggtccggccgggatgcggccggtacccgctccccgccgggaacaacctctccac tcttcctgcagggagctggtgccagccgacagccgcgccagggccgctccgggtaccagggtcgga tcgggtgacgtcgcgaacttgcgcctggccgccaagccggcctccaggctgaagaaggacccgccc cggccttgacccgggccccgcccctccagccggggcaccgagccccggccctagctgctcgcccct actcgccggcactcgcccggctcgcccgctttcgcacccagttcacgcgccacagctatg
(Seq ID No: 213) Homo sapiens phosphatidylethanolamine binding protein 1 (PEBP1) : gcgtcttcccgagccagtgtgctgagctctccgcgtcgcctctgtcgcccgcgcctggcctaccgc ggcactcccggctgcacgctctgcttggcctcgccatg (Seq ID No: 214)
Homo sapiens poly (A) binding protein, cytoplasmic 1 (PABPC1) :
gcttccccttctccccggcggttagtgctgagagtgcggagtgtgtgctccgggctcggaacacac atttattattaaaaaatccaaaaaaaatctaaaaaaatcttttaaaaaaccccaaaaaaatttaca aaaaatccgcgtctcccccgccggagacttttattttttttcttcctcttttataaaataacccgg tgaagcagccgagaccgacccgcccgcccgcggccccgcagcagctccaagaaggaaccaagagac cgaggccttcccgctgcccggacccgacaccgccaccctcgctccccgccggcagccggcagccag cggcagtggatcgaccccgttctgcggccgttgagtagttttcaattccggttgatttttgtccct ctgcgcttgctccccgctcccctccccccggctccggcccccagccccggcactcgctctcctcct ctcacggaaaggtcgcggcctgtggccctgcgggcagccgtgccgagatg
(Seq ID No: 215)
Homo sapiens proprotein convertase subtilisin/kexin type 2
(PCSK2) :
cgctctttctctccggtacacacagctccccacattcgcacccctgcccgcgcgccgggccgcctg actgcacggcttcccctccagccagatgctggagaacacacactgattcgctgctttccaagaccc tgttcagtctctttctctatacaaagatttttttaaaaactatatataagaattctttatttgcac cctccctccgagtcccctgctccgccagcctgcgcgcctcctagcaccacttttcactcccaaaga aggatg (Seq ID No: 216)
Homo sapiens phosphogluconate dehydrogenase (PGD) :
gggtctttccctcactcgtcctccgcgcgtcgccgctcttcggttctgctctgtccgccgccatg (Seq ID No: 217)
Homo sapiens phosphoglucomutase 1 (PGM1) :
cgctcccctttcccctcccgccggacctgccaggaggtgggctggcgcggagggagggccctgtcc cctgtccctttaaggaggagggccaaacgccggcctagagtgcggcgtagcccccacccgccgtgc cctcaccccagagcagctgcagcctcagccggccgcccctccgccagccaagtccgccgctctgac ccccggcagcaagtcgccaccatg (Seq ID No: 218)
Homo sapiens solute carrier family 25 (mitochon- drial carrier; phosphate carrier) , member 3 (SLC25A3) :
cggcctctgtgagccgcaacctttccaagggagtggttgtgtgatcgccatcttagggagtgagtg tggccgggccttctcctgtggcgggtgtggggagcggagcccagagctcctgtggggccgctgctt tggcggtgggcccagccgggagcagcctctttcgaaggccgccgtgacctcttcaagggcgtggag acgggaaggaaaaggccccggttggggttccagggcgccggtaacgttaaccggcgccttgcctgt cctctaaccgtcgctccctcctcccctagaaagatg (Seq ID No: 219)
Homo sapiens pim-1 oncogene (PIMl) :
cctcccctttactcctggctgcggggcgagccgggcgtctgctgcagcggccgcggtggctgagga ggcccgagaggagtcggtggcagcggcggcggcgggaccggcagcagcagcagcagcagcagcagc agcaaccactagcctcctgccccgcggcgctgccgcacgagccccacgagccgctcaccccgccgt tctcagcgctgcccgaccccgctggcgcgccctcccgccgccagtcccggcagcgccctcagttgt cctccgactcgccctcggccttccgcgccagccgcagccacagccgcaacgccacccgcagccaca gccacagccacagccccaggcatagccttcggcacagccccggctccggctcctgcggcagctcct ctgggcaccgtccctgcgccgacatcctggaggttgggatg (Seq ID No: 220)
Homo sapiens pyruvate kinase, muscle (PKM2) :
ggatctcttcgtctttgcagcgtagcccgagtcggtcagcgccggaggtgagcggtgcaggaggct acgccatcagtccccaccaagggccagtcgcccggctagtgcggaatcccggcgcgccggccggcc ccgggcacgcaggcagggcggcgcaggatccagggcgtctgggatgcagtggagctcagagagagg agaacggctcctcacgcctggggcctgctcttcagaagtccccagcgccgttccttccagatcagg acctcagcagccatg (Seq ID No: 221)
Homo sapiens pleiomorphic adenoma gene-like 1 (PLAGLl) :
cggcctcctcggcgcagccatcctcttggctgccgcgggcggcaaagcccacggcatctgccattt gtcattcagcccgtcggtaccgccccgagccttgatttagacacggctggggcgtgctctggcctc actctccgggcgggtgctggacggacggacggacggggcagccgtgctcacagctcagcagcgcgg ggccttggcgcgcggggcgcttccccgggtcgccgtcatggccgcggaggtggcacgcccgagcgg cctcgcctgagctccgggggtcgtcgccccgcagggattgctgtcacgtctaatgtggctgctgcc tcgtgtcacatctgaaactcatctgtacctcacttagaaagtggttctgattagacaagacttttc gttgcagtcgacagaaacctaatgggaccattgaagaattccaaacaggtatttgcataggaatca gaggagttaatcttgtctcttctcacaggtttgaatcttcagacaaacttctgggaggactcggtc cctgcctcgcagcagatgttccctgtcactcagtaggcatatg (Seq ID No: 222)
Homo sapiens phospholipase D2 (PLD2) :
tgctctcttggctccggaacccccgcgggcgctggctccgtctgccagggatg
(Seq ID No: 223)
Homo sapiens proteolipid protein 2 (colonic epithelium-enriched) (PLP2) :
cccccttcccggccagacggcgggcaagacagctgggtgtacagcgtcctcgaaaccacgagcaag tgagcagatcctccgaggcaccagggactccagcccatgccatg (Seq ID No: 224) Homo sapiens pinin, desmosome associated protein (PNN) :
cagtcctttcgcgcctcggcggcgcggcatagcccggctcggcctgtaaagcagtctcaagcctgc cgcagggagaagatg (Seq ID No: 225)
Homo sapiens phosphoribosyl pyrophosphate amidotransferase (PPAT) : ggtccttccacgtgctttcggcggcgacatg (Seq ID No: 226)
Homo sapiens protein phosphatase 1, catalytic subunit, gamma isozy me (PPP1CC) :
tgttcttctcgtggttccagtggggagagaaggaggaagtagggagcggggtggcaggggggggac ccgccgcggctgctgccaccgccgccaccaccgcctctgctcgtggcgtgggaaaggaggtgtgag tcccgggcgcgagccggcggcggcgccgctgcgggagggtcggcggtgggaaggcgatg
(Seq ID No: 227)
Homo sapiens protein phosphatase 1, regulatory subunit 8 (PPP1R8) : cggtcttccagtttcccggcgtgcttagggcgcgccaaatgggagggggagacgcaagatg (Seq ID No: 228)
Homo sapiens protein phosphatase 6, catalytic subunit (PPP6C) : cggcctccgccgctgccgccgccgctgctacagccgccgccgccgctgttgccgcggcttgttatt cttaaaatg (Seq ID No: 229)
Homo sapiens protein kinase C substrate 80K-H (PRKCSH) :
ctttctttctgcagcaggaaccgcggctgctggacaagaggggtgcggtggatactgacctttgct ccggcctcgtcgtgaagacacagcgcatctccccgctgtaggcttcctcccacagaacccgtttcg ggcctcagagcgtctggtgagatg (Seq ID No: 230)
Homo sapiens mitogen-activated protein kinase 6 (MAPK6) :
cgccccctcttcctcgccctctctcgcgggtcggggttacatggcggcgactgcggcaaagcgaga gcctcggagacgccgctgccgccagcacagccggagacctgagccgacactgggggcagtccgcga gccccgcactctctcgatgagtcggagaagtcccgttgtatcagagtaagatggacggtagctttg attgtgattgtggtgagctggagccacctgatcactaacaaaagacatcttctgttaaccaacagc cgccagggcttcctgttgaaataaatatatagcaacaaaggaaaaaaagaagcaaaacggaaatag tgcttaccagcaccttagaatgatgctgctcaggaccagtccaacactgaatgtatctgcactgtg aggagaatgttcatagaagcctgttgtgtgcatatttattcacatttttgttaaatgttaaatcgt ttagcacggtaatctgagtgcacagtatgtcatttcattccgtttgagtttcttgttttcgttaaa tgtctgcagagttgctgcccctttcttgaactatgagtactgcaatctttttaattctcaatatga atagagctttttgagctttaaatctaaggggaactcgacaggcctgtttggcatatgcaatgaaca tcaagaaaccatcttgctgtggaagcataattatttttcttctccctttttgaaagatctttcctt ttgatgccagttttcttccttgtttacacaagttcaatttgaaaggaaaaggcaatagtaagggtt tcaaaatg (Seq ID No: 231)
Homo sapiens phosphoribosyl pyrophosphate synthetase 2 (PRPS2) : cctccccttccctacatctagccgccgcgctttcccgctcccgcagcagcagcctcccgcgtcgct gtcgctgttgcctccgccacctcctccgccgccgcgcgcccctcggagttccgcgccccaccatg (Seq ID No: 232)
Homo sapiens phosphoribosyl pyrophosphate synthetase-associated pr otein 1 (PRPSAP1) :
ttgcctctggctctgaggcggcggcgccgggcgctgcgaaggctcggccgctgtagtcagtggtgt ggggtgcgcaagggcacggacctcggagctctccccgcttgcgccgagtttctcagcgccttcccc acccaaaccggggtctcgcagtcggaagcactcagagtgcagccccgcgcggggccggtcgtaacc gcgccgcgggccggacgatg (Seq ID No: 233)
Homo sapiens proteasome (prosome, macropain) subunit, beta type, 5 (PSMB5) : agttctttctgcccacactagacatg (Seq ID No: 234)
Homo sapiens proteasome (pro- some, macropain) 26S subunit, non-ATPase, 13 (PSMD13) :
tgttcttctgtgccgggggtcttcctgctgtcatg (Seq ID No: 235)
Homo sapiens protein tyrosine phosphatase, receptor type, N
(PTPRN) :
cagcccctctggcaggctcccgccagcgtcgctgcggctccggcccgggagcgagcgcccggagct cggaaagatg (Seq ID No: 236)
Homo sapiens RAB3A, member RAS oncogene family (RAB3A) :
ctccctttgcaggacgtcacggaggactgcaggggcctgagccgctgctgccgccgccgccgcgca gccccacatcaacgcaccggggtcctgtcaccgccaccgccaaaaaagtcaccgccgctagggtcg ccgttgcatcggtgcagggcaagatg (Seq ID No: 237)
Homo sapiens RNA binding motif, single stranded interacting protei n 2 (RBMS2) : ctctctctctctctctctcgctcgttccctaacattaaagagaaaatg (Seq ID No: 238)
Homo sapiens reticulocalbin 1, EF-hand calcium binding domain (RCN1) :
gcgcccctctgctccggctcggggcgggcactggcggagggactggccagtcccctcctccgcgcc ggccccaaccctgtcgctgccgccgcgctccgagtccccattcccgagctgccgctgttgtcgctc gctcagcgtctccctctcggccgccctctcctcgggacgatg (Seq ID No: 239)
Homo sapiens radixin (RDX) :
ccgccttttcccgcggaggcgccgagcggccatattgcggagctgtctgcggtggcggcggcgcct ctcgtctcccgcggcccagcgctcgcaccaccgcttctccctccctgtcgcagccgcgccgccgcg cagcgccccagccacacgccggcgggcagaagccgcccgctctccggaaagtgataacagaattca ttgaagtggagaatttttaaagaaggtaacaaaaagagaaagaaaatg (Seq ID No: 240)
Homo sapiens replication factor C (activator 1) 1, 145kDa (RFC1) : tcgccttcttgcacttcgcgggagaagttgttggcgcgaatggatcctgagcctcgataacagatt cctcaaccggcccacccgccagccagccagcgccttcatcctggggctgcgatg
(Seq ID No: 241)
Homo sapiens ring finger protein 4 (RNF4) :
gcatctttctcgaggagctctcctgggcggctgaagaaggagcttcttctccggagtgcgccggcg gtggcgcctgcggacctaactagctccaggttaggccgagctttgcgggaaagcagcggacttgaa aatactggaaatctgtccggatccaaattattttgcaagccagatgagtaaccagagggcatgaaa ggttgagaacatttgacttccctgcaaaccttggtatagatcacttccttttctgtaggaaaggaa aggcaccaaagagcacaatg (Seq ID No: 242)
Homo sapiens ribophorin I (RPN1) : tgctcttcccggtcatg
(Seq ID No: 243)
Homo sapiens ribosomal protein S27a (RPS27A) :
cgttcttccttttcgatccgccatctgcggtggagccgccaccaaaatg (Seq ID No: 244)
Homo sapiens secreted and transmembrane 1 (SECTM1) :
cttcctttagcgtgaaccgcgggtgcggtgcctcccgtgaaaataataaattcaccgtcacgcttg ttgtgaacgcgggtggttcccgaaacttggaggcttcccgtaaacccagctccttcctcatctggg aggtgggtcccgcgcgggtccgccgcctcctccctggcccctccctctcgtgtctttcattttcct ggggctccggggcgcggagaagctgcatcccagaggagcgcgtccaggagcggacccgggagtgtt tcaagagccagtgacaaggaccaggggcccaagtcccaccagccatg (Seq ID No: 245)
Homo sapiens small glutamine-rich tetratricopeptide repeat
(TPR) -containing, alpha (SGTA) :
ctttcttttgcgcaggcgtcgcgccctggggccggggccgggcggcaccgcggtgcgcaagcgcaa ccgtcggtgggtcggggatcggtcgcctgagaggtatcacctcttctgggctcaagatg
(Seq ID No: 246)
Homo sapiens SH3 domain binding glutamic acid-rich protein like (SH3BGRL) :
agttctccttccaccttcccccacccttctctgccaaccgctgtttcagcccctagctggattcca gccattgctgcagctgctccacagcccttttcaggacccaaacaaccgcagccgctgttcccagga tg (Seq ID No: 247)
Homo sapiens solute carrier family 1 (gluta- mate/neutral amino acid transporter) , member 4 (SLC1A4) :
cgccctcctacttccccgtctgcgtccgcgttcgcggctcccgtttgcatcatccccgtctgcgtc cgcgttcgcggctcccgtttgcatcatctccagccggcggctgctccagggaggctgggcgcgatc ctctccgcccgcggctccaacccgcactctgcgcctctcctcgcctttctcgcacctgctcctgcg ccaggcccggagacccccggggcggcttcccagaacctgcggagcacaactggccgaccgacccat tcattgggaaccccgtcttttgccagagcccacgtcccctgccacctctagctcggagcggcgtgt agcgccatg (Seq ID No: 248)
Homo sapiens small nuclear RNA activating complex, polypeptide 2, 45kDa (SNAPC2) : ctgcctctttctgagcggcatg (Seq ID No: 249)
Homo sapiens sorting nexin 1 (SNX1) : ctatctctcga- taaagttgttgttgcggcttccgccgcgggtggaagaagatg (Seq ID No: 250) Homo sapiens signal recognition particle 54kDa (SRP54) : ctatctctcatctttccgctcttagctgggagtgctccgcctagtcacttttcttaaggtggctcg tcgaggcctgacttcttccccgaaatcacgtccctagacagcctcctattttaccactaactttac tcctgcagttattcagcggtaggaaactgaaaccaaaaaccagtgtaagcaagtaaacatctaaac tgtttcaggagccgcgtagaaggaacgcggcggtgtgccccggaagcggaagtagattctcctata gaaaggctggactacgcggagtggtgacgtttcctcattgggcggaaggttcgctggcactccgtt ggtcttccagctggtgggagttgacgacgtggtgctgggcgttgggaccctactttatctagttcg ggaagttgggttgtggggtcatacctgtctgtctgctcccagctttcttgggtttcttccgacggc gtggggcctcgctaaggaattcccggcccctcagggccacggctttagcggtgtcttttgcgagtt cttcgtaagtacatcttaaagctgtcaagatg (Seq ID No: 251)
Homo sapiens signal sequence receptor, beta (translo- con-associated protein beta) (SSR2) :
cggtctttcggatgctgacgctctcttcctgtctttgtggctccggaaaggcgtttgggatgccaa cgatg (Seq ID No: 252)
Homo sapiens signal transducer and activator of transcription 6, i nterleukin-4 induced (STA 6) :
ttttctttttggtggtggtggtggaaggggggaggtgctagcagggccagccttgaactcgctgga cagagctacagacctatggggcctggaagtgcccgctgagaaagggagaagacagcagaggggttg ccgaggcaacctccaagtcccagatcatg (Seq ID No: 253)
Homo sapiens suppressor of Ty 4 homolog 1 (S. cerevisiae)
(SUPT4H1) : tgttcttcccatcggcgaagatg (Seq ID No: 254)
Homo sapiens transcription factor 7 (T-cell specific, HMG-box) (TCF7) :
ggtccttcccctaaaacttggcactgccgatactcccagcccgttccttcccaagtcaggaacttg caggggaccccttggcaattctttttctctcaagagcagacagccttcagtcccagccgctgccag ggctggtgtgtctgacccagctgtggtttttccaggcctgaaggccccggagtgcaccagcggcat g (Seq ID No: 255)
Homo sapiens TEA domain family member 4 (TEAD4) :
cagtctcctccccgaggtgccggtggccccgccgccactccctccggctccctccctcccgccgcg gcgcgcatctcattccagccctcattccgcgcattccagcgtcctcctcgcacactcgaggccagg gggcgggagggccgcagctccggcgccgccgcgtcccgccaggtgagaggcgcccgcgcccgccgc acccgccggcgccctcacgggccgcgcgccccacgccgccgcagccgaccgctcgcgccgcgtgct cggctgctcttttctttccgccgcccgcgttcccgccttggacctctgcgctccgacgcgctccgt cccgacctctggcttccctccgcgctccggcgctgctcgctgcccctctcccgcttccctcctgtc cgccccgcgctcccctcctcgctcccggttgactcactcctccaggaatagggatccccgtgtttt cccgtcagtcccattctgggaaaactcctccctccgcgcgctccgctccgctccgctgggcgcacc ggggccggtcggcgcggggtgggcttggccccgcggccccgccttcactgcgccgcccgtcggccc cggccggagcccggctctgcgcgctgacgccctgtcgtccccgcagaacgatcgccgcggccggaa gagttggcgctcggggcggactccttggaactggcttagcgcacccatcccaccttcccgcaccct gggaccggtcggaacgagctgattgcccgctacatcaagctccggacagggaagacccgcaccagg aagcaggtctccagccacatccaggtgctggctcgtcgcaaagctcgcgagatccaggccaagcta aaggaccaggcagctaaggacaaggccctgcagagcatg (Seq ID No: 256)
Homo sapiens G protein-coupled receptor 137B (GPR137B) :
ttttctttcctccagtctcggggctgcaggctgagcgcgatgcgcggagacccccgcgggggcggc ggcggccgtgagccccgatg (Seq ID No: 257)
Homo sapiens tumor protein, translationally-controlled 1 (TPT1) : cggccttttccgcccgctcccccctccccccgagcgccgctccggctgcaccgcgctcgctccgag tttcaggctcgtgctaagctagcgccgtcgtcgtctcccttcagtcgccatcatg (Seq ID No: 258)
Homo sapiens ubiquitin A-52 residue ribosomal protein fusion produ ct 1 (UBA52) : ctatcttctttttcttcagcgaggcggccgagctgacgcaaacatg (Seq ID No: 259)
Homo sapiens ubiquinol-cytochrome c reductase core protein II (UQCRC2) :
cggcctccgccaccatcttgctttcctttaatccggcagtgaccgtgtgtcagaacaatcttgaat catg (Seq ID No: 260)
Homo sapiens ubiquitin specific peptidase 1 (USP1) :
ctgcctttcgtgtctctgcagcgtggagactggaaccggcaatttcaaaggacgccacgttcaatc gcagcgctggcgcgggcggaggctaaaacacgggggtcctgagactgaggaaaacgcgccaagttc ccctcggtggcggagtgctaaagaccctagcggttcaggcgttcggcgagcggggccgctgcttgt tgcgctcctggctctcccggggcgggcgcagatgggcgccgctcccgggatgtagttggtgttggt gcaagacgggagcgagcggcggtcggggttcccgctcttgggagcggatggtcactcccccgcggg gagggcgagccgaccagattttcctggggccggggacccggcgggctcggggcagggactcacctg tcgcacccacactcattcgggttggacttgccggcgtcaccgccgcggacttcgctttgggccatg accagatataattggtgattacaactttcctctataaattaactcttgacactccttgggatttga agaaaaaaatg (Seq ID No: 261)
Homo sapiens voltage-dependent anion channel 2 (VDAC2) :
gtgtctccttcacttcgccctccagctgctggagctgcagcccgaccgcgagcgtgccaagcggct tcagcagctagcggagcggtggcggcggcccccctcaggacaccaccagattcccctcttcccgcg gcctcgccatg (Seq ID No: 262)
Homo sapiens vimentin (VIM) :
gcctcttctccgggagccagtccgcgccaccgccgccgcccaggccatcgccaccctccgcagcca tg (Seq ID No: 263)
Homo sapiens very low density lipoprotein receptor (VLDLR) :
ccccctccccgctgctcaccccgctctccggccgccgccggtgcgggtgctccgctaccggctcct ctccgttctgtgctctcttctgctctcggctccccaccccctctcccttccctcctctccccttgc ctcccctcctctgcagcgcctgcattattttctgcccgcaggctcggcttgcactgctgctgcagc ccggggaggtggctgggtgggtggggaggagactgtgcaagttgtaggggagggggtgccctcttc ttccccgctcccttcccccgccaactccttcccctccttctccccctttcccctccccgcccccac cttcttcctcctttcggaaggactggtaacttgtcgtgcggagcgaacggcggcggcggcggcggc ggcggcaccatccaggcgggcaccatg (Seq ID No: 264)
Homo sapiens wingless-type MMTV integration site family, member 10 B (WNT10B) :
agtcctttgctcgccggcttgctagctctctcgatcactccctcccttcctccctcccttcctccc ggcggccgcggcggcgctggggaagcggtgaagaggagtggcccggccctggaagaatgcggctct gacaaggggacagaacccagcgcagtctccccacggtttaagcagcactagtgaagcccaggcaac ccaaccgtgcctgtctcggaccccgcacccaaaccactggaggtcctgatcgatctgcccaccgga gcctccgggcttcgacatg (Seq ID No: 265)
Homo sapiens CCHC-type zinc finger, nucleic acid binding protein (CNBP) :
cagcctctaccttgcgagccgtcttccccaggcctgcgtccgagtctccgccgctgcgggcccgct ccgacgcggaagatctgactgcagccatg (Seq ID No: 266) Homo sapiens zinc finger protein 43 (ZNF43) :
gggcctttgtctctggctgcagttggagctctgcgtctcgtcttcgttcttctgtgtcctctgctg ctagaggtccagcctctgtggctctgtgacctgcgggtattgggggatccacagctaagacgccag gaccccccggaagcctagaaatg (Seq ID No: 267)
Homo sapiens zinc finger protein 74 (ZNF74) :
cagtccttttgtgggagtccggtctgtccacttgccggtccctcagaccgtcggcggtctctgtcc gcttcgggacctgtccgctggtcgctccgcgtccgatggctcctggccgcggaaccttaggcctgg ccctggtctccgagcgcgggttcgccgggaggagcgtgtggcgggggtgtgccggggcgtgagtgc gccgagcatggggctgagcctggtgtggggagtgggtatctgcggagccggcctgaaccccacctc agccgggcgcggggagggggctccgtgcgtgtgatcgtgcagctgtgagcgcgtggccgccccgcg gggctccgctgcaggcccctcagccccaggagcagtactcgctcttcagggcctgccctggatcct ggaggctacacagctgcccactcctcctggggaggctgccgtggaggccatg
(Seq ID No: 268)
Homo sapiens zinc finger protein 85 (ZNF85) :
gggcctttgtctctcgctgcagcctgagctctaggtcttgttttccctgctttgtgttttctgctc gtggacgcccagcctctgtggccctgtggcctgcaggtattgggagatccacagctaagacgccgg gaccccctggaagcctagaaatg (Seq ID No: 269)
Homo sapiens zinc finger protein 91 (ZNF91) :
gggcctttgtctctcgctgccgccggagtttccaggtctcgacttcactgctctgtgtcctctgct ccaggaggcccagcctgtgtggccctgtgacctgcaggtattggagagccacagctaagatg (Seq ID No: 270)
Homo sapiens zinc finger protein 141 (ZNF141) :
gggtctttgcgtctggctactaccagaccgcgggttaggggcttcatctctctgcgttctcagttg tgggaggccttggtgattcggccacagcctcagcctccgtcgctctgtgacctgcgggtattggat gattggtagctaagactcccgaatacttcagaagtggggaaatg (Seq ID No: 271)
Homo sapiens zinc finger protein 205 (ZNF205) :
tgttctttctagctctgaaatagaaaatg (Seq ID No: 272)
Homo sapiens transmembrane protein 187 (TMEM187) :
ctcccttttcggagatttgaatttcccccagcgaggcgagtgaggcgaaatacccgtatggtgata gctggccttttcgcgccaatactgaaaaaggcagaacgttcctccgctggcgccagccaatcagca ggactcctgccttccttcggggcaaggtcgcagcatctgcctcggaaatcacgaaatcacggggct tctttctgctggctcagccgggaggcccagagtgttctgcagaggctgcgtattgaaggctgctct ctgaagctccctgccccaggtcacgccgccggttccagatg (Seq ID No: 273)
Homo sapiens histone cluster 2, H2be (HIST2H2BE) :
acttcttttcttggctaagccgcgtttgtactgtgtcttaccatg (Seq ID No: 274)
Homo sapiens solute carrier family 25 (mitochondrial carrier; oxoglutarate carrier), member 11 (SLC25A11) :
ccgcctttgcgctgcgcgcctgcgcccgcgccggcttccagcgggtgtcggacctgagagctggag gggcgtgcgcgcgccctcgctctgttgcgcgcgcggtgtcaccttgggcgcgagcggggccgcgcg cgcacgggacccggagccgagggccattgagtggcgatg (Seq ID No: 275)
Homo sapiens tyrosylprotein sulfotransferase 2 (TPST2) :
cctcccccttccccggctggggcggctggagagccgggagtcgctgggtgcgtggggctgcctcgc cgcgtctcgccacgggctctgccagcagacagccttggcacacaggcacaagggctggagcccaga gatgagagtgcccaagggagatgtgagcctggcgggctgcccgctaacctgtcgctgaagccccag aagcgggccctcaggccaggcctaccctgcctccggcccagcatg (Seq ID No: 276) Homo sapiens sorbin and SH3 domain containing 2 (SORBS2) :
aagcctcttttatacatctcttcagggaagagagaagcaatgggcatgttagtatacaatgatcac agccacgcaggcctgcaagctgccttttggacaggctgttgactgccgttccaattagctgattgg agaatgtggaatgcagagtgataatgctgcatatctgctatcaggcagcagcaaaggtttttgtct tgggaaggcaagctttccctgcaatattatctcagcagctccctagctgcttaccctgaaaacgag ggatccaaacggagggtgttgcactctgctaacgctggtcctgtgcgtggctgtggcatatgagcg gcaggtctgaaaaagcaggtgtgtgctgggacgggcactggactggaacgcaggcggacgctctcg ggtttacctgcttcctgttaacagattgtgggctcccagggcatatgtctgcacgctgaggccgag gcggagaaggggcttcctgagcgtcccagtacactgacagagacacttggattggacttaatctta aacctctggagttcaagaccttttaaaaagggctaaataaacaatctctacatgtaaaaggccact gactcctacttcctctgtatagagcaactgttgaactcagctgcctgtaggaaaactgaagacttt aataacaaactctccaaggtgaaaatg (Seq ID No: 277)
Homo sapiens G protein-coupled receptor 65 (GPR65) :
gtttctcttcttgacttgatgcaggcacagatttatcaagctcctcagtcaacaaacacatcaccg gaagaaatatggaaggaaaggaattttaaaaggaaataccaatctctgtgcaaacaaagccttgta tattcatgtttgcaccaatctactgtgagatttatgaagaaaaacaaattgcggacaactctctat gtacacttacaaatgcctcagttgatgcttgtgggctgtttgtcagcgttctgtgataatgaacac atggacttctgtttattaaattcagttgacccctttagccaattgccaggagcctggatttttact tccaactgctgatatctgtgtaaaaattgatctacatccaccctttaaaagcattgatgaattaat tagaactttagacaacaaagaaaaattgaaaaagaattctcagtaaaagcgaattcgatgttcaaa acaaactacaaagagacaagacttctctgtttactttctaagaactaatataattgetaccttaaa aaggaaaaaatg (Seq ID No: 278)
Homo sapiens nipsnap homolog 1 (C. elegans) (NIPSNAP1) :
gggccttcctgcaacctttgcggctccaacatg (Seq ID No: 279)
Homo sapiens inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase complex-associated protein (IKBKAP) :
gcttctttgcagcgcttcagcgttttcccctggagggcgcctccatccttggaggcctagtgccgt cggagagagagcgggagccgcggacagagacgcgtgcgcaattcggagccgactctgggtgcggac tgtgggagctgactctgggtagccggctgcgcgtggctggggaggcgaggccggacgcacctctgt ttgggggtcctcagagattaatgattcatcaagggatagttgtacttgtctcgtgggaatcacttc atcatg (Seq ID No: 280)
Homo sapiens COP9 constitutive photomorphogenic homolog subunit 3 (Arabidopsis) (COPS3) : ctgccttcgccgctcgggccgcccgggggaaaacatg (Seq ID No: 281)
Homo sapiens pirin (iron-binding nuclear protein) (PIR) :
ccgcctcctctaggccgccggccgcgaagcgctgagtcacggtgaggctactggacccacactctc ttaacctgccctccctgcactcgctcccggcggctcttcgcgtcacccccgccgctaaggctccag gtgccgctaccgcagcgtgagtacctggggctcctgcaggggtccactagccctccatcctctaca gctcagcatcagaacactctctttttagactccgatatg (Seq ID No: 282)
Homo sapiens THO complex 5 (THOC5) :
ccttccttacttccggttctctatggtgcgcgggcaagctttgctccgcctccggcagtggcttac tcccggtgccaggttcttggagctgtgaggaggaacaaccatg (Seq ID No: 283)
Homo sapiens RuvB-like 1 (E. coli) (RUVBL1) :
gggcctttgcaaaattgccctagtaacggccgcatggtaactcaggcgccgggcgcactgtcctag ctgctggttttccacgctggttttagctcccggcgtctgcaaaatg (Seq ID No: 284) Homo sapiens Kruppel-like factor 7 (ubiquitous) (KLF7):
tttcctttttagttgactgaaacaaaacaaaacaaaagggccactggatgtctgccttcttggggg gtgagccagacagactgacaaacaaacagccccaactgtgttcgggggagggtttcgcctcccgtt ttgcccggcagcagcagcatg (Seq ID No: 285)
Homo sapiens USOl vesicle docking protein homolog (yeast) (USOl) : gctccccttttgccttcaaccttcgagccgccacgtaatgccacgtccccgcgcatgcgcatcttg gccgctgctggcggctgtttccgggcttagagggctggagtggccgccgagttggaggcggtggtg gcagcagtaggagtgtgtagagtgcgggattgggggccaggccctgcggagggcgggggaagttgt cttcttttttttccggaggggccggtaaacctggtggctgaacggcaagatg
(Seq ID No: 286)
Homo sapiens unc-5 homolog C (C. elegans) (UNC5C) :
cccccttttggcccctgcctttggagaaagtggagtgtggcgcttggttgtcgttatttcttcgga ctgcttcgcggtgcacggattcagcttctgcccagtggggctttcagctgtttgcgcgtctctctg tccccctcccctccccccggcacacctctgtctacgatg (Seq ID No: 287)
Homo sapiens RNA terminal phosphate cyclase domain 1 (RTCD1) :
gcttcttccgctttctcgtcaggctcctgcgccccaggcatgaaccaaggtttctgaactactggg cgggagccaacgtctcttctttctcccgctctggcggaggctttgtcgctgcgggctgggccccag ggtgtcccccatg (Seq ID No: 288)
Homo sapiens eukaryotic translation initiation factor 3, subunit A (EIF3A) :
ggctccttcctttccgtctctggccggctgggcgcgggcgactgctggcgaggcgcgtgggacctt acgctggttccccttcgtctcctctcccggcccgggccactagagagttcgctgacgccgggtgag ctgagcctgccgccaagatg (Seq ID No: 289)
Homo sapiens eukaryotic translation initiation factor 3, subunit D (EIF3D) :
gtttcctcttttcctggtttctcaagagtgctgctgctaacgcggtccccggcacgcaccatctgt tgccatcccggccggccgaggccattgcagattttggaagatg (Seq ID No: 290)
Homo sapiens eukaryotic translation initiation factor 3, subunit F (EIF3F) : ccgcctccttctttctcgacaagatg (Seq ID No: 291)
Homo sapiens eukaryotic translation initiation factor 3, subunit G (EIF3G) : cgctctctggccgggcttgggctgcgtggagaatactttttgcgatg
(Seq ID No: 292)
Homo sapiens eukaryotic translation initiation factor 3, subunit H (EIF3H) : gtttctctttcttcctgtctgcttggaaagatg (Seq ID No: 293)
Homo sapiens eukaryotic translation initiation factor 3, subunit I (EIF3I) : aaaccttttccggtcttactcacgttgcggccttcctcgcgtcacagccgggatg (Seq ID No: 294)
Homo sapiens eukaryotic translation initiation factor 3, subunit J (EIF3J) : ctccctctcacacacgctcacacccggctcgagatg (Seq ID No: 295) Homo sapiens poly (A) binding protein, cytoplasmic 4 (inducible form) (PABPC4) :
ccgcctctctccgccccgggtcgctgccgcctccgccgctttcgggcttcgcagcctgaggaaaaa aagagaaaaagataaaaaaaatctgaaaacgcttcaaaatcctgaaaaaaaaaaaggaaaagaaaa aacgaatcctcggagaacccgcggggaagtcactttcgtacgcttccggcctgccccgcgcccgcc gccgcagcgcttggcgtccgtcggtctccgtccgtcggtccgggggtgagccgcccgcccggcccg ccgtgccctccccccgctcgggccccgagccccgcgccccgcgcctgccccggcgcaccacgtgtc cgtgctgcccttcgccgcccgcccggggctcgccgagtcggcgcccacaaagatttggtttccctc tgccccggcggttgtaatcttaaaccgccggagcccgaggcctatatttatagagaaacgcgtgtc cccgaggccgccgtgggcagcgtccggtcgcctcttaaaggatttttacccttcggaaggggattc cccgtttaatttttttcctactttgattttttgaaatttggagcttcgcaccaggaccgcggagaa gtgcaaagtcgcggggagggccgtattgtgcggagagccttttgtctgcggtgctgcggccgtggg agccggcccccgcctcccgtttccgtcccgtctccaagcccgccgactccagctcgtcctcgccgc gccggtgccacctgtgagccgcggcgcgggcccgggctccgaaggcgcccctttgtcctgcggcgg gcccgataagaagtcctcctggcggggctcggggtggtggggggcggggagatg
(Seq ID No: 296)
Homo sapiens receptor-interacting serine-threonine kinase 2
(RIPK2) :
agctctttcgcggcgctacggcgttggcaccagtctctagaaaagaagtcagctctggttcggaga agcagcggctggcgtgggccatccggggaatgggcgccctcgtgacctagtgttgcggggcaaaaa gggtcttgccggcctcgctcgtgcaggggcgtatctgggcgcctgagcgcggcgtgggagccttgg gagccgccgcagcagggggcacacccggaaccggcctgagcgcccgggaccatg
(Seq ID No: 297)
Homo sapiens neuropilin 1 (NRPl) :
ctttcttttctccaagacgggctgaggattgtacagctctaggcggagttggggctcttcggatcg cttagattctcctctttgctgcatttccccccacgtcctcgttctcccgcgtctgcctgcggaccc ggagaagggagaatg (Seq ID No: 298)
Homo sapiens guanine monphosphate synthetase (GMPS) :
tggtcttctctcccgcggcgctggggcccgcgctccgctgctgttgctccattcggcgcttttctg gcggctggctcctctccgctgccggctgctcctcgaccaggcctccttctcaacctcagcccgcgg cgccgacccttccggcaccctcccgccccgtctcgtactgtcgccgtcaccgccgcggctccggcc ctggccccgatg (Seq ID No: 299)
Homo sapiens far upstream element (FUSE) binding protein 1
(FUBP1) :
ttttctttctttcttagctgttagctgagaggaagtctctgaacaggcggcagcggctcttatagt gcaaccatg (Seq ID No: 300)
Homo sapiens eukaryotic translation initiation factor 2B, subunit 5 epsilon, 82kDa (EIF2B5) :
gatcctttttgtcccctactgcgtgcggtggcagcttccttgcggaagtggtgaccgtgagagaag aagatg (Seq ID No: 301)
Homo sapiens eukaryotic translation initiation factor 2, subunit 2 beta, 38kDa (EIF2S2) :
gtttcctttcgctgatgcaagagcctagtgcggtggtgggagaggtatcggcaggggcagcgctgc cgccggggcctggggctgacccgtctgacttcccgtccgtgccgagcccactcgagccgcagccat g (Seq ID No: 302)
Homo sapiens adaptor-related protein complex 1, sigma 2 subunit (AP1S2) :
cctcccctctccgcctaagcctgccctatgccagccgggtgtcctccccacagcaccacggcttct cttcctcagcacggcgacaggggcttccccttcgccgccgccgccgccgccggccaagctccgccg cgcccgcggcccgcggccgccatg (Seq ID No: 303) Ί35
Homo sapiens suppression of tumorigenicity 13 (colon carcinoma) (Hsp70 interacting protein) (ST13) :
cgcccccttctgcgcggtcacgccgagccagcgcctgggcctggaaccgggccgtagcccccccag tttcgcccaccacctccctaccatg (Seq ID No: 304)
Homo sapiens solute carrier family 7 (cati- onic amino acid transporter, y+ system) , member 7 (SLC7A7) :
ctccctttcttaaatgcttggggtgagagagaagagaggctagggtggggcatggaggacacagag agagagagtgctgtgtattccttccccgctactgtcctgtcctcagctaacttgctctgggacagc ttccccagggctacagatactgcactcagctgactgtcctttcttctgggcccctggtcccagagc agagctgacaaaggagattcctgagagagcaccttcttatcacagaaagtgctgagccaagagctc ctagctgccccttttgcagatgtgaagggccagtgaaccttggacccagatggttgcttaatactc ctttccccctccctcactccttcctttgcgggctgcctcacctcctccacccttcttgcttaaatc cataggcatttgtctggccttcccttttactgctggctgggaaggaggagcatcagaccacagatc ctggaaggcacttctctccctgactgctgctcacactgccgtgagaacctgcttatatccaggacc aaggaggcaatgccaggaagctggtgaagggtttcctctcctccaccatg
(Seq ID No: 305)
Homo sapiens paired box 2 (PAX2) :
ctcccttttctcctcaagtcctgaagttgagtttgagaggcgacacggcggcggcggccgcgctgc tcccgctcctctgcctccccatg (Seq ID No: 306)
Homo sapiens 5-aminoimidazole-4-carboxamide ribonucleotide formylt ransferase/IMP cyclohydrolase (ATIC) :
agccctcctacctgcgcacgtggtgccgccgctgctgcctcccgctcgccctgaacccagtgcctg cagccatg (Seq ID No: 307)
Homo sapiens ATP synthase, H+ transporting, mitochondrial Fl compl ex, alpha subunit 1, cardiac muscle (ATP5A1) :
ccttctttgcggctcggccattttgtcccagtcagtccggaggctgcggctgcagaagtaccgcct gcggagtaactgcaaagatg (Seq ID No: 308)
Homo sapiens cyclin Gl (CCNG1) :
cggccccttcggctccgagctgaccctgatcagggccgagttgtctcggcggcgctgccgaggcct ccacccaggacagtccccctccccgggcctctctcctcttgcctacgagtcccctctcctcgtagg cctctcggatctgatatcgtggggtgaggtgagcaggcccggggagggtggttaccgctgaggagc tgcagtctctgtcaagatg (Seq ID No: 309)
Homo sapiens cadherin 16, KSP-cadherin (CDH16) :
agctctcttcttgcttggcagctggaccaagggagccagtcttgggcgctggagggcctgtcctga ccatg (Seq ID No: 310)
Homo sapiens cyclin-dependent kinase inhibitor IB (p27, Kipl) (CDKN1B) :
ttttcttcttcgtcagcctcccttccaccgccatattgggccactaaaaaaagggggctcgtcttt tcggggtgtttttctccccctcccctgtccccgcttgctcacggctctgcgactccgacgccggca aggtttggagagcggctgggttcgcgggacccgcgggcttgcacccgcccagactcggacgggctt tgccaccctctccgcttgcctggtcccctctcctctccgccctcccgctcgccagtccatttgatc agcggagactcggcggccgggccggggcttccccgcagcccctgcgcgctcctagagctcgggccg tggctcgtcggggtctgtgtcttttggctccgagggcagtcgctgggcttccgagaggggttcggg ctgcgtaggggcgctttgttttgttcggttttgtttttttgagagtgcgagagaggcggtcgtgca gacccgggagaaagatg (Seq ID No: 311) Homo sapiens chimerin (chimaerin) 2 (CHN2) :
tctcctcttcttcctttgtgtgtgcgcgagcggagttggggcggagggagaagggggaggtcgctc tgtctgtccgtctcccgccgcctctgcccggtctactcgaagtgcggcgggagaggcgggagccca ggagagggtgcgggagctggcggggcggctcggagctgccaggacgccctggtcccagccgcgcac aggggagcgtggacggcagaggggctcggcgggagccgagatccgcccgtcccggctgcccctcgg cctccctctgctcccacctaccccctgacacccatagaaaagcgtgcaaaggcgcggagcgggacg gaaaccacaaataaatagcggcggcggcagcgcgtcatctggtggagcaggaagtgcaggcagagt ccggaggctggtgctttctgcgcgtccccaggactttgccatgggctgggggccgcggaggctgcg agcggccgggcgagggcagcggcggcggcgtccgcaccggggctgagcgagcagcgacgcgagggg cgcgcggagatg (Seq ID No: 312)
Homo sapiens citrate synthase (CS) :
gggcctccttgaggaccccgggctgggcgccgccgccggttcgtctactctttccttcagccgcct cctttcaaccttgtcaacccgtcggcgcggcctctggtgcagcggcggcggctcctgttcctgccg cagctctctccctttcttacctccccaccagatcccggagatcgcccgccatggctttacttactg cggccgcccggctcttgggaaccaaggcacccagtggcaagtactagctgagcatttgggagatgc ttgtcttacttggctgttgcttctcctgctgctggggaaaaggaatgcatcttgtcttgttcttgc agcccggcatgccagtgcttcctccacgaatttgaaagacatattggctgacctgatacctaagga gcaggccagaattaagactttcaggcagcaacatggcaagacggtggtgggccaaatcactgtgga catg (Seq ID No: 313)
Homo sapiens cathepsin S (CTSS) :
atttcttttcaagtcaattgaactgaaatctccttgttgctttgaaatcttagaagagagcccact aattcaaggactcttactgtgggagcaactgctggttctatcacaatg (Seq ID No: 314)
Homo sapiens deoxynucleotidyltransferase, terminal (DNTT) :
cagtctccctcccttctggagacaccaccagatgggccagccagaggcagcagcagcctcttccca tg (Seq ID No: 315)
Homo sapiens dual specificity phosphatase 3 (DUSP3) :
cgctctccgcctcgcttgctcctgccgggcgtgcagggccccgccgccgccatg
(Seq ID No: 316)
Homo sapiens coagulation factor II (thrombin) receptor-like 2 (F2RL2) :
catcctttccctgcggaggaccagggcaagtttcctgcctgcacggcacaggagagcaaacttcta cagacagaccaaggcttccatttgctgctgacacatggaactgaggtgaaattgtgctccatgatt ttacagatttcataacgtttaagagacgggactcaggtcatcaaaatg (Seq ID No: 317)
Homo sapiens Fc fragment of IgG, receptor, transporter, alpha (FCGRT) : cgtcctctcagcatg (Seq ID No: 318)
Homo sapiens guanylate binding protein 2, interferon-inducible (GBP2) :
ttacctctttttcttgtctctcgtcaggtctctgacattgacagagcctggacgttggaggaagcc ccaggacgttggaggggtaaagtaaaagtccacagttaccgtgagagaaaaaagagggagaaagca gtgcagccaaactcggaagaaaagagaggaggaaaaggactcgactttcacattggaacaaccttc tttccagtgctaaaggatctctgatctggggaacaacaccctggacatg (Seq ID No: 319)
Homo sapiens G protein pathway suppressor 1 (GPS1) :
cgctctttctcccttcagcagccagccagctctgtgtcagggtcggggggtgcagaaagtcaggac agaatg (Seq ID No: 320) Homo sapiens general transcription factor IIF, polypeptide 2, 30kD a (GTF2F2) :
gttcctcttttcctcggttcccagtgttctggcaggtaaggaacgccggctcttcgcctctcagcg cggcttgtcctttgttccggacgcccgctcctcagccctgcggctcctggggtcgctgctgcatcc cgcacgcctccaccggctgcagacccatg (Seq ID No: 321)
Homo sapiens glycogenin 1 (GYG1):
cgctccctcccggtgccggcttctctgagtcaccaacctgaggctgccccggccgcctgcgcaccc ggcagcaccatg (Seq ID No: 322)
Homo sapiens heat shock 70kDa protein 9 (mortalin) (HSPA9) :
agctctttgccgtcggagcgcttgtttgctgcctcgtactcctccatttatccgccatg
(Seq ID No: 323)
Homo sapiens iron-responsive element binding protein 2 (IREB2) : cttccttctttcctcccttgccagtccgcctgtcttcctccccgtcttccctgcccggcctccccc ttcttcccccgctggccccctccccggagggataatatggtctccggcgatg
(Seq ID No: 324)
Homo sapiens origin recognition complex, subunit 1 (ORC1) :
ccaccttcttttcatttctagtgagacacacgctttggtcctggctttcggcccgtagttgtagaa ggagccctgctggtgcaggttagaggtgccgcatcccccggagctctcgaagtggaggcggtagga aacggagggcttgcggctagccggaggaagctttggagccggaagccatg
(Seq ID No: 325)
Homo sapiens RAB1A, member RAS oncogene family (RAB1A) :
cattcctttctttcgattacccgtggcgcggagagtcagggcggcggctgcggcagcaagggcggc ggtggcggcggcggcagctgcagtgacatg (Seq ID No: 326)
Homo sapiens cytohesin 2 (CYTH2) :
gagtcttttcagcgctgaggactggcgctgaggaggcggcggtggctcccggggcgtttgagcggg ctcacccgagcccgcgggccaacgcggatccaggcccgactggcgggaccgccccggattccccgc gggccttcctagccgccatg (Seq ID No: 327)
Homo sapiens C0P9 constitutive photomorphogenic homolog subunit 2 (Arabidopsis) (COPS2) : atttctcctccccctcccggccaagatg
(Seq ID No: 328)
Homo sapiens solute carrier family 9 (sodium/hydrogen exchanger), member 3 regulator 1 (SLC9A3R1) :
ggtcctctctcggctcctcgcggctcgcggcggccgacggttcctgggacacctgcttgcttggcc cgtccggcggctcagggcttctctgctgcgctcccggttcgctggacgggaagaagggctgggccg tcccgtcccgtccccatcggaaccccaagtcgcgccgctgacccgtcgcagggcgagatg (Seq ID No: 329)
Homo sapiens peptidase (mitochondrial processing) beta (PMPCB) : ctaccttccttctagcagaaatg (Seq ID No: 330)
Homo sapiens RAB3D, member RAS oncogene family (RAB3D) :
cggcccttcctccgccttctgggcggagcccgcgcgggatccgggtggctgcaggctgctggcttc tgcggctgcggggtcggggtcgcggccagggccaagccgcagcgagttcacaggcggaacccctgc aggcggcgccccctacgcgaggtcacccctgggaaggagcgcagcccacccggcccctccgcatcc gagcaggacgcccgtctcctctccctgaggatttcaggtctccctgtcccaggaggcttgtgccaa gatg (Seq ID No: 331) Homo sapiens ATP-binding cassette, sub-family B (MDR/TAP) :
tcttctctcggttcctctttcctcgctcaagatg (Seq ID No: 332)
Homo sapiens N-acylsphingosine amidohydrolase (acid ceramidase) 1 (ASAH1 ) : ggctcttctttgcctctgctggagtccggggagtggcgttggctgctagagcgatg (Seq ID No: 333)
Homo sapiens cytochrome c oxidase subunit Vic (COX6C) :
ttttcctttagtcaggaaggacgttggtgttgaggttagcatacgtatcaaggacagtaactacca tg (Seq ID No: 334)
Homo sapiens COX15 homolog, cytochrome c oxidase assembly protein (yeast) (COX15) :
gcttctcttttccttggcggaggagggagaccacagagccctgggttgtggaagaggtggctgttc cctgtcatcagtatg (Seq ID No: 335)
Homo sapiens c-src tyrosine kinase (CSK) :
cccccttcccccgcctttcttccctccgcgacccgggccgtgcgtccgtccccctgcctctgcctg gcggtccctcctcccctctccttgcacccatacctctttgtaccgcaccccctggggacccctgcg cccctcccctcccccctgaccgcatggaccgtcccgcaggccgctgatgccgcccgcggcgaggtg gcccggaccgcagtgccccaagagagctctaatggtaccaagtgacaggttggctttactgtgact cggggacgccagagctcctgagaagatg (Seq ID No: 336)
Homo sapiens versican (VCAN) :
gagcctttctggggaagaactccaggcgtgcggacgcaacagccgagaacattaggtgttgtggac aggagctgggaccaagatcttcggccagccccgcatcctcccgcatcttccagcaccgtcccgcac cctccgcatccttccccgggccaccacgcttcctatgtgacccgcctgggcaacgccgaacccagt cgcgcagcgctgcagtgaattttccccccaaactgcaataagccgccttccaaggccaagatg (Seq ID No: 337)
Homo sapiens dystroglycan 1 (dystrophin-associated glycoprotein 1) (DAG1) :
gcgcctcttaggcttggcggtggcggcggcggcagcttcgcgccgaatccccggggagcggcggtg gcggcgtcctggggccaggaggagcgaacacctgccgcggtcctcccgccggcgctgggctctgtg tgctccgggatggagcaggtgtgcagagggtgagaacccagctctgggaccaagtcacttgcttcc ttacttagcaagactatcgacttgagcaaacttggacctgggatg (Seq ID No: 338)
Homo sapiens DEAD (Asp-Glu-Ala-Asp) box helicase 5 (DDX5) :
ccccctcttttggttacagacgtgagggctctttggagacgtaaacatctccgagtggcgagggtg ggcggggctgggcttgggaaagggcggggtggcttgcttgaggtgtggaaagaccagaagaaggtg aggtcaagagagtgcagaatgaggcattccaatggtgggtgggccctgacctgagagagtggcgcg gggaggggtgaaagcgcggcgatcctggaacgccagcgggcgttgcggcctatgcgcgaggggcgg ggcgattaggtcatagagcggctcccagcgttccctgcggcgtaggaggcggtccagactataaaa gcggctgccggaaagcggccggcacctcattcatttctaccggtctctagtagtgcagcttcggct ggtgtcatcggtgtccttcctccgctgccgcccccgcaaggcttcgccgtcatcgaggccatttcc agcgacttgtcgcacgcttttctatatacttcgttccccgccaaccgcaaccattgacgccatg (Seq ID No: 339)
Homo sapiens desmoplakin (DSP) :
gctcctctgcgcccttgccgccctccgagccacagctttcctcccgctcctgcccccggcccgtcg ccgtctccgcgctcgcagcggcctcgggagggcccaggtagcgagcagcgacctcgcgagccttcc gcactcccgcccggttccccggccgtccgcctatccttggccccctccgctttctccgcgccggcc cgcctcgcttatgcctcggcgctgagccgctctcccgattgcccgccgacatg
(Seq ID No: 340) Homo sapiens glutamyl-prolyl-tRNA synthetase (EPRS) :
cttcctttcgcggggtcctccgtagttctggcacgagccaggcgtactgacaggtggaccagcgga ctggtggagatg (Seq ID No: 341)
Homo sapiens acyl-CoA synthetase long-chain family member 4
(ACSL4) :
gctcctcctcgtcccagcgctagcgggcacgcggttcctttttgcgagctttccgagtgccaggcg ccggccggctgcgaagacgcggtgggccgcccctccgattgaaatcacagaagatattcgtgttct tcttaagagaaaaagaggacattttagctttctcagttgaaggcgtactttattgtcggcttccaa agattactaacttttatctgtatcactaagattgaactgccttggctgtactgctattcttactgc tgcttctattattgccttcttcagcacaataaggctttcaaaagccaaagaataacaagaaataag caccattttagaagcctttccactatg (Seq ID No: 342)
Homo sapiens fibroblast activation protein, alpha (FAP) :
tggtccttttcaacggttttcacagatccagtgacccacgctctgaagacagaattagctaacttt caaaaacatctggaaaaatg (Seq ID No: 343)
Homo sapiens UDP-N-acetyl-alpha-D-galactosamine : polypeptide N-acet ylgalactosaminyltransferase 3 (GalNAc-T3) (GALNT3) :
ctgcctctccaggcaacgcgggaggcccagcgggaaggcaggaggcggcggcggaggaggagctct actgagccgcaactgtggcgacagcaaccggagtcgcagccgccgccacctgcacctggcgcctag cccacgtccagcgcctgcccggccgccgcttcccgccaccctgccctgcccacccgccaggtacta ccattaaagataccttcttctcagcaaatctatgataaaaaatataagtaacagaagaagaaataa ctgttatttgtcaagtgacaagcttttaatgtcagaatg (Seq ID No: 344)
Homo sapiens glypican 3 (GPC3) :
acgtctcttgctcctcagggccactgccaggcttgccgagtcctgggactgctctcgctccggctg ccactctcccgcgctctcctagctccctgcgaagcaggatg (Seq ID No: 345)
Homo sapiens interleukin enhancer binding factor 2, 45kDa (ILF2) : acgcctcttcagttgtctgctactcagaggaaggggcggttggtgcggcctccattgttcgtgttt taaggcgccatg (Seq ID No: 346)
Homo sapiens nucleosome assembly protein l-like 1 (NAP1L1) :
gggtcttttttagcgccatctgctcgcggcgccgcctcctgctcctcccgctgctgctgccgctgc cgccctgagtcactgcctgcgcagctccggccgcctggctccccatactagtcgccgatatttgga gttcttacaacatg (Seq ID No: 347)
Homo sapiens asparaginyl-tRNA synthetase (NARS) :
cgctctctgatgcaacgccggaatcgcggaaaccgccggtgcacgttggagtcataagacggcgtc ggtgttgcagtctgtgtccttggaggtgaccagggccactgcaggcatg (Seq ID No: 348) Homo sapiens NADH dehydrogenase
(ubiquinone) 1 alpha subcomplex, 10, 42kDa (NDUFA10) :
cgtccccttgggtccttgatcctgagctgaccgggtagccatg (Seq ID No: 349)
Homo sapiens NADH dehydrogenase (ubiquinone) Fe-S protein 2, 49kDa (NADH-coenzyme Q reductase) (NDUFS2) :
ttctccttcccgcagtctgcagccggagtaagatg (Seq ID No: 350)
Homo sapiens NADH dehydrogenase (ubiquinone) Fe-S protein 5, 15kDa (NADH-coenzyme Q reductase) (NDUFS5) :
catcctttacggcaggcgtccgcgtcgctagctagtcgttctgaagcggcggccagagaagagtca agggcacgagcatcgggtagccatg (Seq ID No: 351) Homo sapiens phosphoenolpyruvate carboxykinase 2 (mitochondrial) (PCK2) :
ccctcctttttaagcgcctcccgccagcctctgctgtggctcgcttcgccgcgctccctccttccc cgccttccatacctccccggctccgctcggttcctggccaccccgcagcccctgcccaggtgccat g (Seq ID No: 352)
Homo sapiens serpin peptidase inhibitor, clade B (ovalbumin) , member 6 (SERPINB6) :
ctcccttcgcgctccggacgggcgacggtagctcgagacccgggactccgcccgcctccccgcgag tatttgaggtccggggcggctccggcgcctctgcccgccgttctgctcgctcgctccccgctctgg agtctgccatcatg (Seq ID No: 353)
Homo sapiens Rab geranylgeranyltransferase, alpha subunit
(RABGGTA) :
ttctctcctcagacttcaagggctaccactggacccttcccctgtcttgaaccctgagccggcacc atg (Seq ID No: 354)
Homo sapiens Rab geranylgeranyltransferase, beta subunit
(RABGGTB) : ctctctcctttccctgttagacatg (Seq ID No: 355)
Homo sapiens small nuclear ribonucleoprotein polypeptide A
(SNRPA) :
agttctctccgcacgcgggctggagaagcgggtcctacgcacgctttgttgtcgcgctttgcctcc gtccttgcccctactcccgccttacctgacttccttttcggaggaagatccttgagcagccgacgt tgggacaaaggatttggagaaacccagggctaaagtcacgtttttcctcctttaagacttacctca acacttcactccatg (Seq ID No: 356)
Homo sapiens sterol regulatory element binding transcription facto r 2 (SREBF2) :
cgccctttctgtgcggcgcccgggcgcaacgcaaacatggcggcgggtggcacccgtcggtgaggc ggtgccgggcgggggttgtcgggtgtcatgggcggtggcgacggcaccgcccccgcgtctccctga gcgggacggcagggggggcttctgcgctgagccgggcgatg (Seq ID No: 357)
Homo sapiens translin (TSN) :
ctgccctttggacgcgcgcctcggttccgaacgcagcggacggcgcctcaggcagcgcggcggaca gcccgtcctccggcgcgccgcgagcctcggaggaccctagcgacggtcgtggcgtaagaccggggg gacgcggcggtagcggcggccgttgcgattgattgcgctggttgcctgcggcgtccacttccttgg ccgcccttgctacactggctgattgttgtgcagccggcgccatg (Seq ID No: 358)
Homo sapiens Fanconi anemia, complementation group G (FANCG) :
ccaccctttctcgaggctgtggcctccgcgagagccgagcgggccgcaccgccggccgtgcgactg ccccagtcagacacgaccccggcttctagcccgcctaagcctgtttggggttgctgactcgtttcc tccccgagtttcccgcgggaactaactcttcaagaggaccaaccgcagcccagagcttcgcagacc cggccaaccagaggcgaggttgagagcccggcgggccgcggggagagagcgtcccatctgtcctgg aaagcctgggcgggtggattgggaccccgagagaagcaggggagctcggcggggtgcagaagtgcc caggcccctccccgctggggttgggagcttgggcaggccagcttcacccttcctaagtccgcttct ggtctccgggcccagcctcggccaccatg (Seq ID No: 359)
Homo sapiens DEAD (Asp-Glu-Ala-Asp) box polypeptide 39B (DDX39B) : ttccctccttcgtcgctgttgctgccgccatacgcgctctccctgtttagctcttctgttagaaat agtatctttgttttcctttgctgttcctcaatcccctactcttcaccccttgttttcacctatttt gcgagaacccatccagatcccccttcccttcttcccctgccggcccagttatg
(Seq ID No: 360) Ί41
Homo sapiens RAB11A, member RAS oncogene family (RAB11A) :
ccgccctttcgctcctcggccgcgcaatg (Seq ID No: 361)
Homo sapiens SPARC-like 1 (hevin) (SPARCL1) :
agctctttcccttttggtttgcaagcactgcctgtaaagccctcgcatgagaggccagcctgctag ggaaatccaggaatctgcaacaaaaacgatgacagtctgaaatactctctggtgccaacctccaaa ttctcgtctgtcacttcagacccccactagttgacagagcagcagaatttcaactccagtagactt gaatatgcctctgggcaaagaagcagagctaacgaggaaagggatttaaagagtttttcttgggtg tttgtcaaacttttattccctgtctgtgtgcagaggggattcaacttcaatttttctgcagtggct ctgggtccagccccttacttaaagatctggaaagcatg (Seq ID No: 362)
Homo sapiens cyclin B2 (CCNB2) :
ctcccttttcagtccgcgtccctccctgggccgggctggcactcttgccttccccgtccctcatg (Seq ID No: 363)
Homo sapiens cytochrome c oxidase subunit Vila polypeptide 2 like (COX7A2L) : ggtccttctctggggcggtcgcgttggcagcggatgcgggaagccggactctg- ggcgtcatg (Seq ID No: 364)
Homo sapiens lysophosphatidic acid receptor 2 (LPAR2) :
cgccctctcagcaacccgcacagggcgcacccggacgctctaccgctcccgccgcagtcgccgggc catgggcctcgagcccgccccgaacccccgcgagcccgccttgtctgcggcgtgactggaggccca gatg (Seq ID No: 365)
Homo sapiens adaptor-related protein complex 4, mu 1 subunit (AP4M1) :
cgttcttttgttccggggccgcagggcggggcaggcccgactttcgccgtcttcttgtctactctc cagaacggccatg (Seq ID No: 366)
Homo sapiens budding uninhibited by benzimidazoles 3 homolog (yeast) (BUB3) :
cttcctctccgcctccttcgcctagcctgcgagtgttctgagggaagcaaggaggcggcggcggcc gcagcgagtggcgagtagtggaaacgttgcttctgaggggagcccaagatg
(Seq ID No: 367)
Homo sapiens DEAD (Asp-Glu-Ala-Asp) box helicase 21 (DDX21) :
ctacctcttcctctccacgcggttgagaagaccggtcggcctgggcaacctgcgctgaagatg (Seq ID No: 368)
Homo sapiens solute carrier family 33 (ace- tyl-CoA transporter), member 1 (SLC33A1) :
tgctctctgccgcattgatagcagcgagagctggaggtgttgggtcgggagaccagccgttcgatc ccgccgcaggtaggagctggtttccatcctggcaccacggcacacacctccagcctcgagcccggc gctgctgcccgggggtctccttcaggctctttgacgccgttccagggggcacctatccaggcatcc tctgggcctctagccagaggactggctcccggcttcagcactccgggctgcagtaagaagtgccct tatcgctctgagccctgccaccatcccgtgaaccaccgaaaccctggtccagcgcgacagccttgg acctgggactggacggatccaaaacgctcagcctcggccccccacagacggggctctgcatcgtct ctgatatg (Seq ID No: 369)
Homo sapiens G protein-coupled receptor 37 like 1 (GPR37L1) :
tgctcttcctgggctggctgtctcctgctcatccagccatg (Seq ID No: 370)
Homo sapiens neuronal regeneration related protein homolog (rat) (NREP) : ctgtctttctagcatgttgccctttttcaaccacatttgtgtttcaggtgtagagaggagagagag tgaacagggagcggggcttttgtctgttggtctccctggactgaagagagggagaatagaagccca agactaagattctcaaaatg (Seq ID No: 371)
Homo sapiens vesicle-associated membrane protein 3 (cellubrevin) (VAMP3) : gcttctctgctgaccctctctcgtcgccgctgccgccgccgcagctgccaaaatg (Seq ID No: 372)
Homo sapiens synaptosomal-associated protein, 29kDa (SNAP29) :
cctccttctgtttcccagaccgagagccgcgccggcaccatg (Seq ID No: 373)
Homo sapiens Ion peptidase 1, mitochondrial (LONP1) :
ccccctcttctccgcgtaggcccagctccctgaagcggctgtttcgagccacgcgcccatcgggta ccgaggcacgcgccgggcgtcacgtgcgtttcgcggcgagcggaaatgacgcgagttgtgtgagcc gccagtatggccgggctatg (Seq ID No: 374)
Homo sapiens kinesin family member 3B (KIF3B) :
ctgtctctccccatccggggcagcggggaatggctgagccaggggttcgccgcccccgccgccgcc gccgccgccgccgccgccgccgccgcccgctttcggctcgggcctcaggaccgtagcatcctgaga cattttgaattgacacttctcaagatttgactggatcagagttcatcatg
(Seq ID No: 375)
Homo sapiens transmembrane 9 superfamily member 2 (T 9SF2) :
cttcctttatctctggcggccttgtagtcgtctccgagactccccacccctccttccctcttgacc ccctaggtttgattgccctttccccgaaacaactatcatg (Seq ID No: 376)
Homo sapiens cytosolic iron-sulfur protein assembly 1 (CIAOl) : gagcctctgtcggccgcggaagcctggagtgggcggtacgcagacgcgcgcggtgagacccgctgt ctgctcagcggactctgcccgcccccacctccccctgcgtcgggccgacatg
(Seq ID No: 377)
Homo sapiens GRB2-related adaptor protein 2 (GRAP2) :
caccctctttcagagtggtacatggaagacagcacaaagtggatccatactctgaaatgcagtaac tctgatgcttgaatttgtctcccttcttgccagaaaggattctaataactcggtgtcaaagccaag acataaactcaaccccttctcttccaaaagcttcacgttacagcatg (Seq ID No: 378)
Homo sapiens leupaxin (LPXN) :
gtacctttctcggggtgtctgcgtaactgcccagacttgccttggtttggtcagatgacacctcct ctgggactggctagccagcgttcatg (Seq ID No: 379)
Homo sapiens SH3-domain binding protein 5 (BTK-associated)
(SH3BP5) :
tttcctctgctccgccgcggccggaggtatccgcatcggcgagctgcgtctcccgggtgtcggccc cggcggctccccgaccgtgcccggctgtggcgaggcggctccagcccagcctgtggcagccgcgac ccccggggcgctccggagcccactgcgcggcgcgcgtgccggctgcctgcatg
(Seq ID No: 380)
Homo sapiens phosphatidylinositol glycan anchor biosynthesis, clas s B (PIGB) : ctttcttccgccttaggaaggtggcggccagggatg (Seq ID No: 381) Homo sapiens lipopolysaccharide-induced TNF factor (LITAF) :
cggcccttttctcggggcgcccgagaggccagctcagacctcccggctcgacaggcggcgcgggcg gcggtgagtgcggcgcggggacgccggggcgcggggaccagcgggagacagcggggggccggtggc gccagcacctgctgggggccccgggcactgagcccttggctggggcctcctgggatgccagggggc gcgggtcgggtcgcgggcatcgaggcgcggcggagggcgtgggggcccggccggggcggggtccgg cctcccagcgctggtcccggccgcgtctccggttgggttcagctcctgcgtcccagagtggcccga tcgcgcgtggcggggtcgtccggcccccacccgaacgagcgcccttcgcggcccgccgcgtccccc tccccggagaggacggcccctgggctttttagaaaaaggcgcgattctctctagtgactcaggttg agatttccagaaatatcccccgggggttcagaaacaaaaccaaaacaaacaaaaaaaccccaacga attcccaaatgctatttgccaaacatttgacttctaggggcgcgggtacccgcgtttctctccctg cccccgcgacttcgcgcaagatccgggaaggacacccgaggcccctgggagaccctggggaggtga aaatcagagagcgaagcgggccgtggcccctaggcctgacccctccccgcggggtaaggcgggcac cccgcgagcgcaggggtcctcttactgctgatggcacccagctctgggcccagacgccgctcaccg tccaccgccggtgctgggtaaaatg (Seq ID No: 382)
Homo sapiens etoposide induced 2.4 rriRNA (EI24) :
ccaccccttcggctctgggccccgcctcgtggtgccggctggttcttcgcgctcgcccgacttccc agcggccccgtgcggcccgggcatgcccagtgcgggcgcagcggccccggccctggaagcgccccg gcggagctggcctgcggtgggctaggggcagggccggagccgcggcggcggagctgtggatccttc atgatgagagatttggggacacttctctctcctgtgtgtagttgatagtttggtggtgaagagatg (Seq ID No: 383)
Homo sapiens chromosome 14 open reading frame 2 (C14orf2) :
tgacctttccgagttggctgcagatttgtggtgcgttctgagccgtctgtcctgcgccaagatg (Seq ID No: 384)
Homo sapiens peroxiredoxin 6 (PRDX6) :
attcctccgcgcgctgggacaggctgcttcttcgccagaaccaaccggttgcttgctgtcccagcg gcgccccctcatcaccgtcgccatg (Seq ID No: 385)
Homo sapiens solute carrier family 29 (nucleoside transporters) , member 1 (SLC29A1) :
ctctcttccgcccggcggcccacaccggtcaggcccggcgcgggctgcgctctccagctgtggcta tggccccagccccgagatgaggagggagagaactaggggcccgcaggcctgggaatttccgtcccc caccaagtccggatgctcactccaaagtctcagcaggcccctgagggagggagctgtcagccaggg aaaaccgagaacaccatcaccatg (Seq ID No: 386)
Homo sapiens heterogeneous nuclear ribonucleoprotein F (HNRNPF) : cgaccttcctgccgggccgggcggtccgaggctgctggagtgccgtgagcaggccgcgggaacgtc gccgtcaccttgtctcggggcctcggcgctgcttcccgccaaaacacgtttaccgcgcgcccgggc ctcccaccttgcggaagggaccccaccaccacttggatttctgttgcaggttgagaacaaaaacat gcacctggagtttccccggagccctctgcgtggttgagcttcggtggaatttcggggctcttggct gccagccgcgcttgcctggtagcaacagaaaccagtcctgctcgcctccgtggacatttcattacc atccagaagtgtctcccactgaaggcatccgtggttgtttttaagccacaaaaaagccacacccaa gatcacctgacacccaccctgacaagtgtccatg (Seq ID No: 387)
Homo sapiens islet cell autoantigen 1, 69kDa (ICAl) :
ccgcccctttccctcgccttcggctgacgctgacgtcggatgagtgatccggagggacgctccgac cgcggccgggaggctcctgggggccggggctccgaggttataatataacttatcctctcatgcttt tttcctgccccttctccccaaatcatcaacaatagaagaagaagaaaacatg
(Seq ID No: 388)
Homo sapiens PWP2 periodic tryptophan protein homolog (yeast)
( PWP2 ) : gtgtctctgtgggcggccgccgggttgagctgcggcacacgtgcgacggccgtgatg
(Seq ID No: 389)
Homo sapiens glutaminyl-tRNA synthetase (QARS) :
gtttcttttagtttccggtgtctctgcaatg (Seq ID No: 390) Homo sapiens stearoyl-CoA desaturase (delta-9-desaturase) (SCD) : cggcctctgtctcctccccctcccgcccttacctccacgcgggaccgcccgcgccagtcaactcct cgcactttgcccctgcttggcagcggataaaagggggctgaggaaataccggacacggtcacccgt tgccagctctagcctttaaattcccggctcggggacctccacgcaccgcggctagcgccgacaacc agctagcgtgcaaggcgccgcggctcagcgcgtaccggcgggcttcgaaaccgcagtcctccggcg accccgaactccgctccggagcctcagccccctggaaagtgatcccggcatccgagagccaagatg (Seq ID No: 391)
Homo sapiens fragile X mental retardation, autosomal homolog 1 (FXR1) : cggcctttgcggttccaacatg (Seq ID No: 392)
Homo sapiens musculin (MSC) :
tagccttttcaaaaggcgcagcttaccgcggtgcgcgcggattctggacttgggcgccaactcgta gtccacgctccccggggtcagcagaggggcgctcacgctctcgccacccacctcgctttctcaccc cgcgcttcccggcctgggtttttagtcttccttggagcgctctctggcctccgcctccgccaggga gcggaaggcggagacagcgagactggccaggggggaggaaagaggacgcgtgtgggcaagggggac aacgggatg (Seq ID No: 393)
Homo sapiens RNA binding motif protein 8A (RBM8A) :
cgacctttcccctctgcgacagtttcccgaggtacctagtgtctgagcggcacagacgagatctcg atcgaaggcgagatg (Seq ID No: 394)
Homo sapiens heparan sulfate (glucosamine) 3-O-sulfotransferase 1 (HS3ST1):
ggtcctctgcgccctggcagccaggagtcgccgccacgaccgccgggtctcagtgggtgcctgcgc cttctccccgcccgcctgccccgggccatccagaaacttgctctacccgccgcgggtgctcggcag tgctgcccatggcccagcccaggagcctatttagggcgccggacgggctggacagaggcgcggctc agtaattgaaggcctgaaacgcccatgtgccactgactaggaggcttccctgctgcggcacttcat gacccagcggcgcgcggcccagtgaagccaccgtggtgtccagcatg (Seq ID No: 395)
Homo sapiens solute carrier family 12 (potassium/chloride transporters) , member 6 (SLC12A6) :
ctgtctcttgtaggcagggatcacagtctgaaacgacagcaaggaagaggtaggcagggaaaacta actggaaggaagtttaaatacagaaagagcaaagtattatctaactataacaatg
(Seq ID No: 396)
Homo sapiens apelin receptor (APLNR) :
cttcctccagggtctggagaacccagaggcagctcctcctgagtgctgggaaggactctgggcatc ttcagcccttcttactctctgaggctcaagccagaaattcaggctgcttgcagagtgggtgacaga gccacggagctggtgtccctgggaccctctgcccgtcttctctccactccccagcatg
(Seq ID No: 397)
Homo sapiens calpain 1, (mu/I) large subunit (CAPN1) :
cgctcttcctggttgggccctgccctgagctgccaccgggaagccagcctcagggactgcagcgac ccccaaacacccctcccccaggatg (Seq ID No: 398)
Homo sapiens cyclin C (CCNC) :
cttcctttcgccgtcgccgccgcggagcggagtcgagccgagctgatttgatcgaggagcgcggtt accggacgggctgggtctatggtcgctccgcgggccgctccgccggctggtgcttttttatcaggg caagctgtgttccatg (Seq ID No: 399)
Homo sapiens glutamate dehydrogenase 1 (GLUDl) :
cttcctccctagtcgcggggagtctgagaaagcgcgcctgtttcgcgaccatcacgcacctcccct ccgcttgtggccatg (Seq ID No: 400) Homo sapiens guanine nucleotide binding protein-like 1 (GNLl) : cctccttcctcgccgccggggcgccctctcggtgccactggctctcacgtgccagtagcccacccc gcatcatcctctcgcctcgctcctggagggaagtgactatatctcccccgtccgccttccatcgcc gccgcggcggtaattctgtcgggcccgcccgctgacgtcacctgctagccccgcctcctctagggt cccgggcccctgcggcgggggctgccccggggggcagtcagttgaggcggcgggagctcggcggag ggcgggccaggtgactggtccgggccatg (Seq ID No: 401)
Homo sapiens lysophosphatidic acid receptor 4 (LPAR4) :
aggcctttttgtgtcctgtttgctaaaggcatgcgggctacagcattcaagagagggagtcgttaa caaagggaaagagataaatgtaaataagctcacatttacagaatgagcggtttgcagtaaaaagct gcggcagcccagagtctgctactttaggctgggctaacctttccctgtaaaaaaaaaaaaaaaaaa aaaaaaaaaaaaatggataaaaatatgcacttccaaagggcgagttgcccatttacatgtttatta gctaattatctacaggcatcagcacattctctcatctagcacactctttcttggggaggaaaatat ttcctaccggtccatagtgtcagagtggtgaacccctgcagccagcaggcctcctgaaaaaaaagt ccatg (Seq ID No: 402)
Homo sapiens G protein-coupled receptor kinase 5 (GRK5) :
gctcctctttgcagagggggaaactcttgggctgagagcaggaataatgcggtaggcaaggcgggc tgctggctcccccggctccggcagcagcggcggcagcccgagcagcggcagcagcagcggcagcac cccaggcgctgacagccccgccggccggctccgttgctgaccgccgactgtcaatg
(Seq ID No: 403)
Homo sapiens glutamic-pyruvate transaminase
(alanine aminotransferase) (GPT) :
agccctttctgtccctcccagtgaggccagctgcggtgaagagggtgctctcttgcctggagttcc ctctgctacggctgccccctcccagccctggcccactaagccagacccagctgtcgccattcccac ttctggtcctgccacctcctgagctgccttcccgcctggtctgggtagagtcatg
(Seq ID No: 404)
Homo sapiens hydroxyacyl-CoA dehydrogenase (HADH) :
gggtctcctcgctgtcgccgccgctgccacaccatg (Seq ID No: 405)
Homo sapiens high density lipoprotein binding protein (HDLBP) : tcttctcctttaccaagatggcggcttgtccctgtttcgccacagttcctaccttatgagctcggt tttcttatgcttataagagtggaacagcaaaagctggcaggctgacagaggcggcctcaggacgga ccttctggctactgaccgttttgctgtggttttcccggattgtgtgtaggtgtgagatcaaccatg (Seq ID No: 406)
Homo sapiens histidine triad nucleotide binding protein 1 (HINT1) : gttcctcccttcttccgagcctctcctctggccgccgcgcgggagagaggccgagatg
(Seq ID No: 407)
Homo sapiens heat shock 70kDa protein 1A (HSPA1A) :
ctacctttttcgagagtgactcccgttgtcccaaggcttcccagagcgaacctgtgcggctgcagg caccggcgcgtcgagtttccggcgtccggaaggaccgagctcttctcgcggatccagtgttccgtt tccagcccccaatctcagagcggagccgacagagagcagggaaccggcatg
(Seq ID No: 408)
Homo sapiens nucleolin (NCL) :
cagtctttcgcctcagtctcgagctctcgctggccttcgggtgtacgtgctccgggatcttcagca cccgcggccgccatcgccgtcgcttggcttcttctggactcatctgcgccacttgtccgcttcaca ctccgccgccatcatg (Seq ID No: 409) Homo sapiens nuclear factor, interleukin 3 regulated (NFIL3) :
ccgcccctttctttctcctcgccggcccgagagcaggaacacgataacgaaggaggcccaacttca ttcaataaggagcctgacggatttatcccagacggtagaacaaaaggaagaatattgatggatttt aaaccagagtttttaaagagcttgagaatacggggaaattaatttgttctcctacacacatagata gggtaaggttgtttctgatg (Seq ID No: 410)
Homo sapiens protein phosphatase 1, regulatory subunit 3C
(PPP1R3C) :
cagtctctcccagcgaccgccgcgggggcaaggcctggagctgtggttcgaatttgtgcaggcagc gggtgctggcttttagggtccgccgcctctctgcctaatg (Seq ID No: 411)
Homo sapiens protein tyrosine phosphatase, non-receptor type 14 (PTPN14) :
agttctttccaactttttctcggcggagtgagcgcagcgggcgcagactcgggggcaggttgctgt gcttctccgggctcagccgcctgctctcctggctcaggtcctcggggagccctagacagacatcaa gtggccactggcgctccttcccctcccagctgagccatcctccccggcctcctcgggcgggacagc cccgtgcttaggtttttctccttttctcccccggtgcgcctctgctcggactctcgcgccgggatc gcggcggaaacctccctcccctttcgcctcctgcggctccttcccttcgcccctcctccgccagtc actggaatcaattccgtggggaatcggctccgccgccgcgaaggacagcctttccgcgcgggactc cggggcgccacgggggccatgtaagcagctatcttccagagggccacactgggcatggacaccctt ttccctgcctggaggagcacaggtgatagtgtaattttccagtcacgaaactgctaaggccatctc aggggcgtgtgcgccaggataggcgggcggcgtccgaggaccacatagccatg
(Seq ID No: 412)
Homo sapiens selenoprotein P, plasma, 1 (SEPP1) :
ctttcttttaagttgataacaatcagctcaggggtttgctctgcttgcaaggtcactgcaagaatg aacattgaactttggactatacctgaggggtgaggtaaacaacaggactataaatatcagagtgtg ctgctgtggctttgtggagctgccagagtaaagcaaagagaaaggaagcaggcccgttggaagtgg ttgtgacaaccccagcaatg (Seq ID No: 413)
Homo sapiens serine hydroxymethyltransferase 2 (mitochondrial) (SHMT2) :
agctcttctcgcgcatgcgttctccgaacggtcttcttccgacagcttgctgccctagaccagagt tggtggctggacctcctgcgacttccgagttgcgatg (Seq ID No: 414)
Homo sapiens tyrosine kinase with immunoglobulin-like and EGF-like domains 1 (TIE1) :
tttcctcttcctccccagcaccgacccacactgaccaacacaggctgagcagtcaggcccacagca tctgaccccaggcccagctcgtcctggctggcctgggtcggcctctggagtatg
(Seq ID No: 415)
Homo sapiens coiled-coil domain containing 6 (CCDC6) :
cctcctttccccagcccgccgcggccatg (Seq ID No: 416)
Homo sapiens nuclear receptor coactivator 4 (NCOA4) :
ggacctttcgcactcgggtcaggggtaaagcagcctgtcgcttgccgggcagctggtgagtcggtg acctggcctgtgaggagcagtgaggagaatg (Seq ID No: 417)
Homo sapiens chromatin assembly factor 1, subunit B (p60)
(CHAF1B) :
gtgcctctgactgtccgggtccctccagcattttgcagctttctcctgtcttgaagaagtagaacg gtgcccgagaaacgtttttccccttcgagactcaggaggatgaaagtcatcacttgtgaaatagcc tggcacaacaaggagcccgtgtacagcctggacttccagcatg (Seq ID No: 418) Homo sapiens 3 ' -phosphoadenosine 5 ' -phosphosulfate synthase 1 (PAPSS1) :
agccccgccccgctcgctggcctgccctcctcttgctaccctcccggcgcagagaaccccggctgc tcagcgcgctccgcggtcatg (Seq ID No: 419)
Homo sapiens Fas apoptotic inhibitory molecule 3 (FAIM3) :
tgccctcctcttgctaccctcccggcgcagagaaccccggctgctcagcgcgctccgcggtcatg (Seq ID No: 420)
Homo sapiens N-acetylated alpha-linked acidic dipeptidase 2
(NAALAD2) :
cagcctcctgccagcgcgctctctgtttctctgcagccccgaagctcgcgaatgtagcaggcgccc caagctcggtcctcaagaagccatggcggaatccaggggccgtctgtacctttggatgtgcttggc tgctgcgctggcatctttcctgatgggatttatggtgggtaagt (Seq ID No: 421)
Homo sapiens abl-interactor 1 (ABI1) : ctgtctctttaacgcgagaggaag- cgatgcagaggggtggaaaatg (Seq ID No: 422)
Homo sapiens potassium voltage-gated channel, Isk-related family, member 3 (KCNE3) :
cttccttttctgccttctctcctgctttctagctctgggctttcccagctccgaagtcaatactga gatcccagatgtgtccagagacatcctgaagaggctcgggggtggaggagccttagtgtgtccaca aagggactcctgaaactgactgagagccagt (Seq ID No: 423)
Homo sapiens target of mybl (chicken) -like 1 (TO 1L1) :
ggccctctggcgctaccatg (Seq ID No: 424)
Homo sapiens ubiquitin-like modifier activating enzyme 2 (UBA2) : cgcccttcccccacccgcttccggccgcggctcggttctcccgcctccgcctccgccgcggctcgt ggttgtcccgccatg (Seq ID No: 425)
Homo sapiens scavenger receptor class B, member 2 (SCARB2) :
ctccctccttgcagttggatccctggcgggtgcggcccggcccggcccgtgagcggcgcacagaat g (Seq ID No: 426)
Homo sapiens insulin induced gene 1 (INSIG1) :
actcctcctttcccccgccccgcctccgttcggagagccggcgggcgggcgcctctcggccaggaa gcgcctcttggacgcgtgtgaccgatg (Seq ID No: 427)
Homo sapiens kinesin family member C3 (KIFC3) :
aggcctcttctgaggctctaggtgccccagtagcagggccttctgcagcaaggccgggaactgctg caccattggtgtgttttaccttaagggactccaggcagcttccttgctgggaagatattcatttgc tggggtggggctgggggtgcagaggtaggaagtgctgtggctagaaggcggcctggccagcgagta ggtggtggagcgagtgagagcgtgtgcgctgtaaacagtgtgagtgcatg
(Seq ID No: 428)
Homo sapiens LIM domain kinase 2 (LIMK2) :
aggcctcttctgaggctctaggtgccccagtagcagggccttctgcagcaaggccgggaactgctg caccattggtgtgttttaccttaagggactccaggcagcttccttgctgggaagatattcatttgc tggggtggggctgggggtgcagaggtaggaagtgctgtggctagaaggcggcctggccagcgagta ggtggtggagcgagtgagagcgtgtgcgctgtaaacagtgtgagtgcatgtgcgccagcgcgtgca aggacacggtaagggatgtacatgtattgtctcgtgagtaagagcttgtgtgtgtgttgggatggg aagacacgtactggtatgagagcccgcgtgagaagtgtatgtgtgagtactcgcgtggaagttttg cactcgggtttgaggctgtgcaaaagtacgcatggctcaccaggtgtggggctgtgtgggctgcct cgtgtgtgccagcccgtgtgcaggcctgttttgtgagagccttcagggaacgcatgagcacgtgtg ccagtgcgagtgcgggacgcggggaggcgggagagaccgagtgggaggccccgcgaaggagtggga gtgggagtgggagtgccggcgggagacctgcgggggcgcgcccgggctgacgcgtgcgcgccagtg cgcgtgagtgcgggcgcgcgccgccgccccccgccggggtcggagccggttgccatgggaacgcgc cgcggcccgagttaatcatttcctgtggaaagtgtgcgggaggggcgcgagcgggctggccgagga ggaggcggcggcgtggagctgcctcctgccggcgggccgggccgggccgagccccgggcgctgcgg cgacgcctggatcctgcctccgccaggccggctgcctggtgccccgaggaggctgctgagccccag gccatg (Seq ID No: 429)
Homo sapiens lectin, mannose-binding, 1 (LMAN1) : cctcctccgcgttcca- gaatccaagatg (Seq ID No: 430)
Homo sapiens RE11 meiotic recombination 11 homolog A
(S. cerevisiae) (MRE11A) :
cgttctctcccgcggaattcaggtttacggccctgcgggttctcagaggcaagttcagaccgtgtt gttttcttttcacggatcctgccctttcttcccgaaaagaagacagccttgggtcgcgattgtggg gcttcgaagagtccagcagtgggaatttctagaatttggaatcgagtgcattttctgacatttgag tacagtacccaggggttcttggagaagaacctggtcccagaggagcttgactgaccataaaaatg (Seq ID No: 431)
Homo sapiens nascent polypeptide-associated complex alpha subunit (NACA) :
cttccttctgcaacaggcgtgggtcacgctctcgctcggtctttctgccgccatcttggttccgcg ttccctgcacagtaagtactttctgtgccgctactgtctatccgcagccatccgcctttctttcgg gctaagccgccccggggactgagagttaaggagagttggaggctttactgggccacagggttccta ctcgcccctgggcctccggacaaaatggggtctgcggttggtgtcctggcaaaagcagggtagaag ggctgcggggcgggcccagaatccgagcctgcagagatgggagcagttgcagtgttgagggcggaa gaggagtgcgtcttgttttgggaactgcttcacaggatccagaaaaggaaatg
(Seq ID No: 432)
Homo sapiens claudin 11 (CLDN11) :
cgcccttcgccgctgagctcgcagcctccggcgcccacctccacctccagtgtcccgcctcgggcc gtcgccctccagcggctcgcgagcgtgggagacgtacctgggcaggcactgtccagcccaggccca ggcacagccgtgaggggcgaggcacggggacatcctggcggccaccatg (Seq ID No: 433)
Homo sapiens retinoblastoma binding protein 4 (RBBP4) :
ccgcccctcccgcaacgctcgaccccaggattcccccggctcgcctgcccgccatg
(Seq ID No: 434)
Homo sapiens acyl-CoA synthetase medium-chain family member 3 (ACSM3) :
ccctcttctttagactgccacgaggaaaaagcagatgtgagaactcaaggttcagggctgctcttc taagaaacaagtctgccataatctccatctgtgttggaatctgttaactaatgaactggtctctgt gcaaatcctgagtgctaaagcttccaacaagactgatg (Seq ID No: 435)
Homo sapiens syndecan binding protein (syntenin) (SDCBP) :
cgctctcttacactcgggcctcagaagtccgtgccagtgaccggaggcggcggcggcgagcggttc cttgtgggctagaagaatcctgcaaaaatg (Seq ID No: 436)
Homo sapiens serum/glucocorticoid regulated kinase 1 (SGKl) :
agtccttctcattccttgcccccgcccaaggctctcttcaccttccccgcgggggtcctctcgttt tctgtctcccaaatgctggcttcccgcctttcctcccccgcttatttacttaattaaggccctggg gctgcaccccaccggcagctccttcgggggtgtggccgaagagctccgagggcggggctgaccgag ccatattcgggcgtggccggtggtgattggtgagggcggggcctgccgcagggggcggggcctgca ggtttggcccccgcagggagcgcagctggcgccgctgggagctggtggcgcggcgcaggtcccggc cgagtgtggcgcagcagtggcggcgcttcccattcgccatgcgccgggggtgggtgcccgaaggtt gcatgatggaatttgaacattacttcaagaggttttgtattttggattagttaattgggtttgtcc tctgctgactgtttcttcggatgcattttttggtgtgctcttgagggattaaatg
(Seq ID No: 437)
Homo sapiens Wolf-Hirschhorn syndrome candidate 2 (WHSC2) :
cgtccttccggctctcggctttgccacaaagcttcccgaagacgcggccgctacccggagacgcgg tcgccacccagaagcgctctcccgggaagccccgctcgtgggaccgcgccacctgcgccgcctctg cggcccgcagcccgacgggcgccgccatgttggggtcctagcgagggacgcgtaggtgtcttcata agatg (Seq ID No: 438)
Homo sapiens nuclear receptor subfamily 1, group H, member 3 (NR1H3) :
cagtccttttgcaagagctgctaagagcgctgggtaaggagaggaaggggagagacatggaacttg gctggtctgcagggaaatgccactgttttggccgggagtagggggcgggagtggcgggagaggggg tggccggctggggaggagccagcctggtggagaagctgccctgtgggcgggggtgaggaggggagg gctgtggtcaccaggcaggaaggaggggtggcctgacccctcggcagtccctcccctcagcctttc cccaaattgctacttctctggggctccaggtcctgcttgtgetcagetccagctcactggctggcc accgagacttctggacaggaaactgcaccatcctcttctcccagcaagggggctccagagactgcc cacccaggaagtctggtggcctggggatttggtgggtctgctccttag (Seq ID No: 439) Homo sapiens glypican 6 (GPC6) :
cctcctttctccttccctcttgcctccagtgactgtctccaggatttctctcttcctatttcagga ggactctcacaggctcccacagcctgtgttaagctgaggtttcccctagatctcgtatatccccaa cacatacctccacgcacacacatccccaagaacctcgagctcacaccaacagacacacgcgcgcat acacactcgctctcgcttgtccatctccctcccgggggagccggcgcgcgctcccacctttgccgc acactccggcgagccgagcccgcagcgctccaggattctgcggctcggaactcggattgcagctct gaacccccatggtggttttttaaacacttcttttccttctcttcctcgttttgattgcaccgtttc catctgggggctagaggagcaaggcagcagccttcccagccagcccttgttggcttgccatcgtcc atctggcttataaaagtttgctgagcgcagtccagagggctgcgctgctcgtcccctcggctggca gaagggggtgacgctgggcagcggcgaggagcgcgccgctgcctctggcgggctttcggcttgagg ggcaaggtgaagagcgcaccggccgtggggtttaccgagctggatttgtatgttgcaccatg (Seq ID No: 440)
Homo sapiens peptidylprolyl isomerase F (PPIF) :
cggccttctgggcgcgcgcgacgtcagtttgagttctgtgttctccccgcccgtgtcccgcccgac ccgcgcccgcgatg (Seq ID No: 441)
Homo sapiens ARP1 actin-related protein 1 homolog A, centractin al pha (yeast) (ACTR1A) : agttccttccccagaaggagagattcctctgccatg
(Seq ID No: 442)
Homo sapiens tripartite motif containing 28 (TRIM28) :
ggctctttctgcgagcgggcgcgcgggcgagcggttgtgcttgtgcttgtggcgcgtggtgcgggt ttcggcggcggctgaggaagaagcgcgggcggcgccttcgggaggcgagcaggcagcagttggccg tgccgtagcagcgtcccgcgcgcggcgggcagcggcccaggaggcgcgtggcggcgctcggcctcg cggcggcggcggcggcagcggcccagcagttggcggcgagcgcgtctgcgcctgcgcggcgggccc cgcgcccctcctccccccctgggcgcccccggcggcgtgtgaatg (Seq ID No: 443)
Homo sapiens aminoadipate-semialdehyde synthase (AASS) :
cggccttccatcccagtttcttctaggaattcggagcctcccctgcagcgactcggaagattcgag gcggcgggggacaagtcggcgccccagagcggacgagtcaccaggtgtcaagatg
(Seq ID No: 444) Homo sapiens cornichon homolog (Drosophila) (CNIH) :
ccgcctttctccgctggcaacggcgccgctccccgctcctcctccccagccatg
(Seq ID No: 445)
Homo sapiens M-phase phosphoprotein 10
(U3 small nucleolar ribonucleoprotein) (MPHOSPH10) :
ctcccttcccttgcatgctgcattgtgtcgggagttgctgacagccatg (Seq ID No: 446)
Homo sapiens ubiquitin specific peptidase like 1 (USPLl) :
ccgccttcctagtggagacgcgagtgggggaggagcagtccgaggggaacgtgggttgaacgttgc aactagggtggagatcaagctggaacaggagttccgatcgacccggtaccaagaaggggagtgccc gcggcagggttcattgaaaaaatccttagtgatattgacatgtctcaagtgacataaattagccaa tgactcggaatg (Seq ID No: 447)
Homo sapiens solute carrier family 23 (nucleo- base transporters) , member 1 (SLC23A1) :
tggcctttgtcaagtcatcccctcttctcctcaggaactgctcaaacctgtgccccaaagatg (Seq ID No: 448)
Homo sapiens splicing factor 3b, subunit 4, 49kDa (SF3B4) :
ggatctctttcgccatg (Seq ID No: 449)
Homo sapiens DnaJ (Hsp40) homolog, subfamily A, member 2 (DNAJA2) : ctgtctccctcggcctgtgccgccgccgacgccgcttgtgggcccgactccgctctgtctgcttcg ccaccttctccccgagcactgcccggccggccgccatg (Seq ID No: 450)
Homo sapiens calicin (CCIN) :
catcctctcttccaccctctcttctccctggtcaaccgctctgcaaacaaccatcaatctgatccc acaggcctgagaaagtctgctctccagtacctgctgctgatctgtttcagccgacaagaggcacca tg (Seq ID No: 451)
Homo sapiens mannosidase, beta A, lysosomal ( ANBA) :
ctgcctttcgatctctccacatctcggtggcgcgggatctcaagatg (Seq ID No: 452)
Homo sapiens microtubule-associated protein IB (MAP1B) :
aatcctttctcctgccgcagtggagaggagcggccggagcgagacacttcgccgaggcacagcagc cggcaggatg (Seq ID No: 453)
Homo sapiens malate dehydrogenase 1, NAD (soluble) (MDHl) :
gagccttttctcgctaacaccgctcgccctctccgagtcagttccgcggtagaggtgacctgactc tctgaggctcattttgcagttgttgaaattgtccccgcagttttcaatcatg
(Seq ID No: 454)
Homo sapiens microfibrillar-associated protein 1 (MFAP1) :
gtttctctatcagtcgcgcagctgtgttcgcggactcaggtggaaggaatttcttctcttcgttga cgttgctggtgttcactgtttggaattagtcaagtttcgggaatcaccgtcgctgccatcaacatg (Seq ID No: 455)
Homo sapiens chaperonin containing TCP1, subunit 3 (gamma) (CCT3) : ggttctctctctccagaaggttctgccggttcccccagctctgggtacccggctctgcatcgcgtc gccatg (Seq ID No: 456)
Homo sapiens tubulin, alpha la (TUBA1A) :
caacctctcctcttcgtctccgccatcagctcggcagtcgcgaagcagcaaccatg
(Seq ID No: 457) Homo sapiens CD164 molecule, sialomucin (CD164):
ctttctcccgaacgccagcgctgaggacacgatg (Seq ID No: 458)
Homo sapiens cysteine-rich secretory protein 3 (CRISP3) :
ctctctctgcaccttccttctgtcaatagatg (Seq ID No: 459)
Homo sapiens SMYD family member 5 (SMYD5) :
cggcctccatgtgcgacgtgttctccttctgcgtgggcgtggcgggccgcgcgcgggtctccgtgg aagtccgtttcgtgagcagcgccaaggtgaggtcggggcgggtcctgccgggagcctctccccagt ccggccatg (Seq ID No: 460)
Homo sapiens kelch repeat and BTB (POZ) domain containing 10 (KBTBD10) :
ctgcctttttacagctagacctgtgtgctgcaaggagctaaggccttcagtgtccccttccttacc caggtttctcacagaatg (Seq ID No: 461)
Homo sapiens aldo-keto reductase family 1, member Al (aldehyde reductase) (AKR1A1) :
ccgccccttgcaccgcccacgtggccagcgccacctgcctcattgtgcccaggagttctccaaacc cgcgctgcggagtgagtgaccaagttccggccagttcgacctcgaggatccagaggtggagacggt actacctcccagctctgttttccatccccttcaggtccttcctcgggaggcggcgaaggcggtcca ccctgcgcgtgatcctttatgcccggcccctgcccctccctccgggtggaacttccccctcaccgc cagacttaagctgaggatcgttggatctctggcggggtgcagaactgagcccaggccacagtaccc tattcacgctctgtgcttgtgccaaggtttcaagtgatcctcccgcctcagcctgcccaggtgctg agattacatgtatgagccactgcacctggaaaggagccagaaatgtgaagtgctagctgaaggatg agcagcagctagccaggcaaagggggcaatg (Seq ID No: 462)
Homo sapiens TRK-fused gene (TFG) :
tgttcttcccccacctgccacgtacagagcccaagttctcgctaggcttgttgggtcagcgcgatt ggccggggcccgcgcgagcctgcgagcgaggtgcggcggtcgcgaagggcaaccgagggggccgtg accaccgcctccccgcgacgccccagtccagtggcctcgcgtccgcccattcagcggagacctgcg gagaggcggcggccgcggcctccgcaagccgtctttctctagagttgtatatatagaacatcctgg agtccaccatg (Seq ID No: 463)
Homo sapiens 3' (2'), 5 ' -bisphosphate nucleotidase 1 (BPNTl) :
catccttctcaaaagacttattgacagtgccaaagctcggtactggacacaacgagggacctgggt ctacgataacgcgcttttgctcctcctgaagtgtctttggtccaacgttgttccagagtgtaccat g (Seq ID No: 464)
Homo sapiens guanine nucleotide binding protein (G protein) :
ttttctctctctctttcactgcaaggcggcggcaggagaggttgtggtgctagtttctctaagcca tccagtgccatcctcgtcgctgcagcgacacacgctctcgccgccgccatg
(Seq ID No: 465)
Homo sapiens major histocompatibility complex, class II, DM alpha (HLA-DMA) :
caccctctcggggagggagttggggaagctgggttggctgggttggtagctcctacctactgtgtg gcaagaaggtatg (Seq ID No: 466)
Homo sapiens transmembrane protein 50B (TMEM50B) :
tctccttcctgcgcgcgcgcctgaagtcggcgtgggcgtttgaggaagctgggatacagcatttaa tgaaaaatttatgcttaagaagtaaaaatg (Seq ID No: 467) Homo sapiens lactoperoxidase (LPO) :
cagtctttcctgctaagcctcagcgtctcctccaagccacatcaaaatctttccttctgggccttt cccagaagtgaattcttgctggaaggtataaaagaccagctcctccaagcagagcaactccctggc tgccgtgaaaagacaaggcactgggcagtgatg (Seq ID No: 468)
Homo sapiens NEL-like 2 (chicken) (NELL2) : ctgcctttacaacagaggga- gacgatggactgagctgatccgcaccatg (Seq ID No: 469)
Homo sapiens nucleobindin 1 (NUCB1) : cgccctctgcggtgaaggagagacca- cactgccatg (Seq ID No: 470)
Homo sapiens paired box 9 (PAX9) :
aagcctctttcatcggggcacagacttccttttacttcttccttttgccctctcgcctcctcctcc tgggaagaagcggaggcgccggcggtcggccgggatagcaacaggccgggccactgaggcggtgcg gaaagtttctgtctgggagtgcggaactggggccgggttggtgtactgctcggagcaatg (Seq ID No: 471)
Homo sapiens cyclin-dependent kinase 16 (CDK16) :
cgccctttattcttgctcggcctcgccacagagagcaaatcagattggctgggcgacaacctcaaa gggcggggctgcacacgttcactacgggaatgaggtagcggtggagggggcagttgggcggggata ggccgtcctagctaaggtggtaaaggccaataactcttcaggctgcctctcctcgaaaagtcatct tctcgcgaacctttaaaatgccttcctccccaagcacctcaagggactagaactgagtgcttcatt tgtcttttttcctccttgcaaaagtcccgtttgccaccatggggatgtaccaagtgagaccgagta gggggaacgagtggtgattgacgcgccaggttactggccactgetcacctaggcgctagcaaactt ctgccaagatcggaactgagtactaaacagcctccacagttctccctggtgccgtctccggcttgg cgccgcatcctcctctgggctcgcgatggccgcgtcccctcccgctgcggacgggtcctttggtac atg (Seq ID No: 472)
Homo sapiens serpin peptidase inhibitor, clade E
(nexin, plasminogen activator inhibitor type 1), member 2 (SER- PINE2) :
ctgcctctttccggctgtgaccctcctcgccgccgccgcttggctgcgtcctccgactccccgcgc cgccgagaccaggctcccgctccggttgcggccgcaccgccctccgcggccgccccctggggatcc agcgagcgcggtcgtccttggtggaaggaaccatg (Seq ID No: 473)
Homo sapiens pancreatic lipase-related protein 1 (PNLIPRPl) :
aactcctttccccctgctgtgacgtacaggtgaggtaaacagtactgaagtccagggcgtcggtgc tcactgctctggcaatgcccggtgagactgaattatgtttaaatttattgtagatg
(Seq ID No: 474)
Homo sapiens peripherin (PRPH) :
ggctccttcccagcccccggcctagctctgcgaacggtgactgcccatccttggccgcaatg (Seq ID No: 475)
Homo sapiens RAD21 homolog (S. pombe) (RAD21) :
gacccttttcccctccccgggccacccagcccgcccaactcccagcggagagcaaggttttcttct gttttcatagccagccagaacaatg (Seq ID No: 476)
Homo sapiens signal sequence receptor, delta (SSR4) :
ttttcttttcctctaggcagagaagaggcgatg (Seq ID No: 477)
Homo sapiens tissue factor pathway inhibitor (lipopro- tein-associated coagulation inhibitor) (TFPI) :
ctccctctttgctctaacagacagcagcgactttaggctggataatagtcaaattcttacctcgct ctttcactgctagtaagatcagattgcgtttctttcagttactcttcaatcgccagtttcttgate tgcttctaaaagaagaagtagagaagataaatcctgtcttcaatacctggaaggaaaaacaaaata acctcaactccgttttgaaaaaaacattccaagaactttcatcagagattttacttagatg (Seq ID No: 478)
Homo sapiens ubiquinol-cytochrome c reductase binding protein (UQCRB) : gcttctctttctggtcaaaatg (Seq ID No: 479)
Homo sapiens mitogen-activated protein kinase kinase kinase 12 (MAP3K12) :
ccgccttttgtgctgcggccgcggagcccccgagggcccagtgttcaccatcataccaggggccag aggegatg (Seq ID No: 480)
Homo sapiens sushi-repeat containing protein, X-linked (SRPX) : tggtctcttcggtctcctgccgcccccgggaagcgcgctgcgctgccgaggcgagctaagcgcccg ctcgccatg (Seq ID No: 481)
Homo sapiens aminopeptidase puromycin sensitive (NPEPPS) :
ccccctctccctccctccttgcgggccctcctccccttccctcccctccgcccccttccccgtagg cagcccgcccgccagtccgcccgcaccgcctccttcccagcccctagcgctccggctgggtctctc ccccgccccccaggctcccccggtcgctctcctccggcggtcgcccgcgctcggtggatg (Seq ID No: 482)
Homo sapiens fibulin 5 (FBLN5) :
tcgccttctgcccgggcgctcgcagccgagcgcggccggggaagggctctcctcccagcgccgagc actgggccctggcagacgccccaagattgttgtgaggagtctagccagttggtgagcgctgtaatc tgaaccagctgtgtccagactgaggccccatttgcattgtttaacatacttagaaaatgaagtgtt catttttaacattcctcctccaattggtttaatgctgaattactgaagagggctaagcaaaaccag gtgcttgcgctgagggctctgcagtggctgggaggaccccggcgctctccccgtgtcctctccacg actcgctcggcccctctggaataaaacacccgcgagccccgagggcccagaggaggccgacgtgcc cgagctcctccgggggtcccgcccgcgagctttcttctcgccttcgcatctcctcctcgcgcgtct tggacatg (Seq ID No: 483)
Homo sapiens lysophospholipase I (LYPLA1) :
cgctcttccttccgcttgcgctgtgagctgaggcggtgtatg (Seq ID No: 484)
Homo sapiens high mobility group nucleosomal binding domain 4 (HMGN4) :
tcgtcttctctgtcttagggctggtgctggccctgcccacgcctagggctccggcgcgtcacgggc ctcagctgggattcccgcgcccctcggacggccacgagactcggacatctttccaggaacagcgtg aggaggacagaagcacccaacaggactgctcaagccacctgcgaacactgctgctaccatg (Seq ID No: 485)
Homo sapiens eukaryotic translation initiation factor 3, subunit (EIF3M) :
agttcccttttccggtcggcgtggtcttgcgagtggagtgtccgctgtgcccgggcctgcaccatg (Seq ID No: 486)
Homo sapiens Sec23 homolog A (S. cerevisiae) (SEC23A) :
cctcctcttgacgtggcagaggcggcgccagccatg (Seq ID No: 487)
Homo sapiens cartilage associated protein (CRTAP) :
cgtcctctttcctttccttctccctccccttttcccttccttcgtcccttccttccttcctttcgc egggegegatg (Seq ID No: 488) Homo sapiens vesicle amine transport protein 1 homolog (T. californica) (VAT1) :
ccgcccctcccgctggatcccgcagccgcggctcttcccgacgcgttccgccttccccagctgtgc actctccatccagctgtgcgctctcgtcgggagtcccagccatg (Seq ID No: 489) Homo sapiens importin 7 (IP07) :
gcttctctttcctttcgcgccggttgccgctgcggagcgcggcgggtccatgtgcgcagtgagtgg cgctattcctggcccagtagcacccgagccccgggtttgaccgagtccgcgctgcgatg
(Seq ID No: 490)
Homo sapiens ATG7 autophagy related 7 homolog (S. cerevisiae) (ATG7) :
gctcctttgcgcacgcgcgccgcttcccagtggcaagcgcgggcaggaccgcgttgcgtcatcggg gcgcgcgcctcagagagagctgtggttgccggaagttgagcggcggtaagtgagccgcggcgggcg agggtgtagtggggtcttgctgggccggttttggaggcctggagtcaaggggcgagctcgccaggg agggcgagggtcacagcaagtctcaggatcctcctctgccagtttctgggtggtccttcctcctcc agggactcactgattccggctggcgcccttcgtctgtagccgcgtcccctcagactggttcagtcc ggggtcttctgacttggaagctcgtgctgatttcctaagtcagcccctcctgtcctcttggtaggc agtgctcagaatcttcagtgttggaacacgggagatgggacatttggattcccagcctggctgtgt ctggatttgctgtctctggcacgttccttccccatctaagctgcttttccatctgcaaaatgggaa tgataatccgccatttgtttaagtgaggaggttaaataagtttactttctgagaaagaagattctc gattccttggttacagggttagaaactaatg (Seq ID No: 491)
Homo sapiens dynactih 2 (p50) (DCTN2) :
cgctccctttgccgccgccttagcccgggacccgaacccagcctctcccctacccgaacaccggcc ccggctccaccgaggcccgggtcccccagcccgtctcgccgccgccatg (Seq ID No: 492)
Homo sapiens acidic (leu- cine-rich) nuclear phosphoprotein 32 family, member B (ANP32B) : agcccccttttccctccatggtttctctccgctcccgtgagtaacttggctccgggggctccgctc gcctgcccgcacgccgcccgccacccaggaccgcgccgccggcctccgccgctagcaaacccttcc gacggccctcgctgcgcaagccgggacgcctctcccccctccgcccccgccgcggaaagttaagtt tgaagaggggggaagaggggaacatg (Seq ID No: 493)
Homo sapiens protein C receptor, endothelial (PROCR) :
acttctcttttccctagactgcagccagcggagcccgcagccggcccgagccaggaacccaggtcc ggagcctcaacttcaggatg (Seq ID No: 494)
Homo sapiens actin related protein 2/3 complex, subunit 1A, 41kDa (ARPC1A) :
cgctccctctgggcttccgtcctccgcccgcgcccgacggagcctgttcgcgtcgactgcccagag tccgcgaatcctccgctccgagcccgtccggactcccccgatcccagctttctctcctttgaaaac actaagaataatg (Seq ID No: 495)
Homo sapiens chaperonin containing TCP1, subunit 4 (delta) (CCT4) : aggcccccttctccgcctccgcctcctcccgacgccggcgccgctttctggaaggttcgtgaaggc agtgagggcttaccgttattacactgcggccggccagaatccgggtccatccgtccttcccgagcc aacccagacacagcggagtttgccatg (Seq ID No: 496)
Homo sapiens Niemann-Pick disease, type C2 (NPC2) :
gcttctttcccgagcttggaacttcgttatccgcgatg (Seq ID No: 497)
Homo sapiens phosphoribosylaminoimidazole carboxylase, phosphoribo sylaminoimidazole succinocarboxamide synthetase (PAICS) : acccctcttttctagagttctgcctcgcttcccggcgcggtcgcagccctcagcccacttaggata atg (Seq ID No: 498)
Homo sapiens ST6 (al- pha-N-acetyl-neuraminyl-2 , 3-beta-galactosyl-l , 3) -N-acetylgalactosa minide alpha-2, 6-sialyltransferase 2 (ST6GALNAC2) :
ctcccttctgcctgggacgtcagcggacggggcgctcgcgggccggggctgtatg
(Seq ID No: 499)
Homo sapiens polymerase (RNA) III (DNA directed) polypeptide C (62kD) (POLR3C) :
aagccctttccgaggatggcaaaggatctgggaatgcttctccaaagatatgtggatggacgaaat aggtctctggtgatactgaggcggggtggggacggggaggcaaagacttggcttcttaggaattgg aagaaataagtaaacaatgtttggtagcaatttgtaataaggaagtaatcataaaattaactacgt ccgtttctgattgtgtcaactttgtcaaggagtagaagtttaagaattgaatactgtcctgcaaac aacgtaacctcatctcctgtttgacacaccctgttgagaagcagtcctttacctcctaaatttctt tttcgaaattatcatttcctttatggactgagaataacactgcctgttcactcccaccgagctgtg aacagtgaccttaattcttccaagcagggaagtgtagaaactaaggtctgtgacagaccgcaaaat catctcccaatctttaaggaaaatcagaatcacgcataatcccatagagataaatttgatgcatag tcttttcctatgcatacatttttcctttttttttacaataattgaatttttatattttttcagctt gcttctgtcacttaatatattatgagtaattttttttggttttttttgttttggagacagaatctc gcactgtcgcccgggttggagtgcagtggcgcgatctcggctcactgcaacctctgcctcccggct tcaagcgattctcctgtctcagcctccctagtagctgggattacaggcacccgccaccacgcccag ctaatttttttgtgtgtttttagtagagaaggggtttcactatattggccaggctggtctcaaact cctgacctcatgatacgcccacctcggtctcccaaagtgctaggattacaggcctgagccaccgcg ccagcctattatgaataattttctacatgaatacgcatcgtactaaataactttaaatgttggtgt agtatgccattgtatgggtatggcatcatttattgttagacgttagattgtttccactaagtcggt attataaagagaactaatgacttcattattattagctttttctttctttggacacaatatccaaaa agaaattgttgtttcaaagatatgcaagatttttaaggctttttgatatgtattgtcaaattgccc tccagaaagaatacatgaatttacactcagcagctctgcttccagcgtgaaagactttctattgta ccattttggtgttttttccctagctctcagactccccagtacaatg (Seq ID No: 500) Homo sapiens influenza virus NS1A binding protein (IVNS1ABP) :
gtgtctcccggtcgcgcgtggaggtcggtcgctcagagctgctgggcgcagtttctccgcctgctg cttcggcgcggctgtatcggcgagcgagcgagttcccgcgagttctcggtggcgctcccccttcct ttcagtctccacggactggcccctcgtccttctacttgaccgctcccgtcttccgccgccttctgg cgctttccgttgggccgattcccgcccgcttcctcctgcttcccatcgaagctctagaaatgaatg tttccatctcttcagagatgaaccagattatgatgcatcattatcacagaagaaattcgtgtctat agcttttaaggacttgattacatcattttcaagcctgatagttttggaatcaecattagagcttaa gacacacctgccttcatttcaaccacctgtcttcataccctgacgaagtgcaccttttaacactcc tttgtccttggattacttaagagttcccagaaatacatttgccaccaacagagtagccaaatttat aaggaaaaatg (Seq ID No: 501)
Homo sapiens thioredoxin interacting protein (TXNIP) :
acccctctttttctccaaaggagtgcttgtggagatcggatcttttctccagcaattgggggaaag aaggctttttctctgaattcgcttagtgtaaccagcggcgtatattttttaggcgccttttcgaaa acctagtagttaatattcatttgtttaaatcttattttatttttaagctcaaactgcttaagaata ccttaattccttaaagtgaaataattttttgcaaaggggtttcctcgatttggagctttttttttc ttccaccgtcatttctaactcttaaaaccaactcagttccatcatg (Seq ID No: 502)
Homo sapiens ecotropic viral integration site 2B (EVI2B) :
ttttcctttcttagccaaatcaccaaaatgtccagttagaacaagaatttagcattctgcaaaaga agttaacagctgagataacgaggaaatattctgaaatg (Seq ID No: 503) Homo sapiens guanine nucleotide binding protein
(G protein) , alpha inhibiting activity polypeptide 3 (GNAI3) :
ggttcttctgggcgctaagggagctgacggagagggccaccgcccagcaatagacggtgcctcagc ctgccgagccgcagtttccgtggtgtgagtgagtccgggcccgtgtcccctctcccgccgccgcca tg (Seq ID No: 504)
Homo sapiens polymerase (DNA directed) , eta (POLH) :
cggcccttcgcagcgggcgcgctgtcagacctcagtctggcggctgcattgctgggcgcgccgctc tcgtctgatccctgctggggacggttgcccgggcaggatcctttacgatcccttctcggtttctcc gtcgtcacagggaataaatctcgctcgaaactcactggaccgctcctagaaaggcgaaaagatatt caggagcccttccattttccttccagtaggcaccgaacccagcattttcggcaaccgctgctggca gttttgccaggtgtttgttaccttgaaaaatg (Seq ID No: 505)
Homo sapiens solute carrier family 2 (facilitated glucose transporter) , member 1 (SLC2A1) :
cgctctctggcaagaggcaagaggtagcaacagcgagcgtgccggtcgctagtcgcgggtccccga gtgagcacgccagggagcaggagaccaaacgacgggggtcggagtcagagtcgcagtgggagtccc cggaccggagcacgagcctgagcgggagagcgccgctcgcacgcccgtcgccacccgcgtacccgg cgcagccagagccaccagcgcagcgctgccatg (Seq ID No: 506)
Homo sapiens zinc finger protein 138 (ZNF138) :
gggtctttgtctcgctgcagcgggtgctgcaggtctggccttcacttttctgcgtcctcttactcc tagaggcccagcctctgtggcgctgtgatctggttattgggagattcacagctaagacgccaggat cccccggaagcctagaaatg (Seq ID No: 507)
Homo sapiens ubiquitin specific peptidase 3 (USP3) :
ctttctttgacgcaagggctcgagacgcagccgccgtcggccgagcgcccggctagaagcgacacc agacggagcctccggagttcctccgcccccacctcgccgggtcctggagccgcagtcctcccagct gccctcctcgtggccatg (Seq ID No: 508)
Homo sapiens calcium channel, voltage-dependent, gamma subunit 3 (CACNG3) :
ctgtcttttctccagtttgagcgggggtgtcgggagcaggcggagagctttcctgcgaggctgtgg aagcagtgaacactcttctcagcggctcgcctcccagcagtgctattttttgccatccgccctcac ccccagcacacgcgctcgcacacacacgcacgcacgcacacacacacacacacacactcacacaga gacctctctgggtttctttgccttgagtctcccggggctgtgagaagccaggcgcatctcaaaccg agctggcagctccaggctccggagccatgccctgcacggaccctcgtctttaccacgctcctgagg aatgaaaggaacccagggaccctcagaaggcagcagtgatgcggaccaaccccccggagcctgcac ccttccgagggccataggcgacccagggaactggagagagctccagaaaggaaatcccagctttcc caaagtccctgtggatgctgacaaaaggagacctgaatttttggaagagcctgtactaggttaccc ggctgcagagtgattttcccctccggcactgactctccccctccaacccccagccgtccagagtac catgaagaattatg (Seq ID No: 509)
Homo sapiens guanine nucleotide binding protein
(G protein) , beta 5 (GNB5) : ttccctctccgctgcgtccccgcgcgaagatg (Seq ID No: 510)
Homo sapiens chaperonin containing TCP1, subunit 8 (theta) (CCT8): cttcctccgcggtcttccgagcggtcgcgtgaactgcttcctgcaggctggccatg
(Seq ID No: 511)
Homo sapiens prostaglandin E synthase 3 (cytosolic) (PTGES3) :
cgctctttccgcgcggtgcattctggggcccgaggtcgagcccgccgctgccgccgtcgcctgagg gaagcgagaagaggccgcgaccggagagaaaaagcggagtcgccaccggagagaagtcgactccct agcagcagccgccgccagagaggcccgcccaccagttcgcccgtccccctgccccgttcacaatg (Seq ID No: 512)
Homo sapiens zinc finger protein 266 (ZNF266) :
ttttcttcctggtggcgtttgggcttaatacagctttggcgaggtcggatgacgggtgggagccag cggtggaaggggtggcgaaagtaccggtttgccccaggccgccgaggggcctccttagagagacct tgcctgctccgctcgcgtccgccggggccgcgcgggtcctcctggcgccgccaggttcaaaaagcc actcgagttgtcactgcgacggccctgggccaggagccgtttcgggatctgtcaaacaacgagttt tcgtcgttcgaatcaggttgactggtccttcatccccccaatctcccgtacctggcgagtccagct cgtcgcggcaatgctaagaaaagagtgatatgcaagctgagaccaaaaatatggtatgatttagcc atactgaaggggaaggaaataagagctgggcaaagcattctgtgaattggctgactccacttctat ggtgagagagaggagtgcatcaaagattactcccagtagagatggtttcagcatgttggccagtct ggtctcagactcctgacctcaagtgatccacccacctcggcctcccaaaatgctgggattacaggt ataagccactgtgcctggccaaagataccgttaaccctggataaagagaatggaggttacctctgt ccgtgtagattcctaagctgtcctggagtgatccttggagtaaaggaaaggtgctttgaagcacat tcagccatcagccctgtgggatggcagccactgatttgtcctatggtctttacagggacccagtct gccttcaagaaaagacagaagtagaaagggtggtggctgactgtctgacaaattgttatcaggtat gcaggaagtatatccttctccaaaatatcatacttgcatcaccaggtagacacatttccttctaca cagaattatcttcagagcttcttaaagcaaataaagcctgcttcaaggactgagtccctagtcgaa ttcccggaaggagtggagcctgtcatattgtgtttatctagcatctgctcaagagtgtgctgcagt ggagggaaatcagatgacctcccagtctggttgtgttacatacaatcatgtgtaagaagtgccatt caagccgtgtcactggaggggactgacagtgagattcagtgacttttgatgatctggctgtggact tcaccccagaagaatggactttactggacccaactcagagaaacctctacagagatgtgatg (Seq ID No: 513)
Homo sapiens methylenetetrahydrofolate dehydrogenase
(NADP+ dependent) 2, methenyltetrahydrofolate cyclohydrolase
(MTHFD2) : gcttccctcccggcgcagtcaccggcgcggtctatg (Seq ID No: 514)
Homo sapiens chemokine (C-C motif) receptor 9 (CCR9) :
cttcctttctcgtgttgttatcgggtagctgcctgctcagaacccacaaagcctgcccctcatccc aggcagagagcaacccagctctttccccagacactgagagctggtggtgcctgctgtcccagggag agttgcatcgccctccacagagcaggcttgcatctgactgacccaccatg
(Seq ID No: 515)
Homo sapiens heat shock 105kDa/110kDa protein 1 (HSPHl) :
cctccccttttgggtcggtagttcagcgccggcgccggtgtgcgagccgcggcagagtgaggcagg caacccgaggtgcggagcgacctgcggaggctgagccccgctttctcccagggtttcttatcagcc agccgccgctgtccccgggggagtaggaggctcctgacaggccgcggctgtctgtgtgtccttctg agtgtcagaggaacggccagaccccgcgggccggagcagaacgcggccagggcagaaagcggcggc aggagaagcaggcagggggccggaggacgcagaccgagacccgaggcggaggcggaccgcgagccg gccatg (Seq ID No: 516)
Homo sapiens StAR-related lipid transfer
(START) domain containing 10 (STARD10) :
tggtcctttcttttatgattcacaaggaatgaccctcttcatcgcctctcctaattcagtcctcac aacagtccttttacaaatgggacaacaggttagaggaagtcaggcagatttccagcatcatagaga gtaaaggaccagggaaggatcaggattcaaggactgcacccaggctctgcttccagcttgctgtgt gactttgggtaattttgttcccttagggaactgagctttctcatttgtaaatgcaaacaggctgtt gggaggatcaaatgagatccaggggtgaaaacagcttagtttactttcaggaatttacccacgcgg tatataaaggcaaaatattattatagtcaggtgattgtagattgaggaacccatttcctcattctg caaattgcaaacctgagggcccaaagagggacaggggcttgccccaggtctcagcaggctgtgagc aagagctaaagcctaatcctcctgcctttgggcctggagcccttccttgtaccccaggggtcagtg tctttgttggatacaggcttagattgactgactgtaccctgagaacctaggggagtccctgttccc aattcttctcctacccccaccttggcctgatggaggaagaccctgctgtgttgagatgagcaccag agccaagaagctgaggaggatctggagaattctggaggaagaggagagtgttgctggagctgtaca gaccctgcttctcaggtcccaggaaggtggcgtcagcatctgcagccgcgtcgacgttgtcggagc ctccgcggaggacccaggagagccggactaggaccagggccctgggcctccccacactccccatg (Seq ID No: 517)
Homo sapiens UTP14, U3 small nucleolar ribonucleoprotein, homolog A (yeast) (UTP14A) : ctttccttcggcttccgttcttggtccatgtgagagaagctggct- gctgaaatg (Seq ID No: 518)
Homo sapiens SUB1 homolog (S. cerevisiae) (SUB1) :
ggttctctgtcagtcgcgagcgaacgaccaagagggtgttcgactgctagagccgagcgaagcgat g (Seq ID No: 519)
Homo sapiens minichromosome maintenance complex component 5
(MCM5) :
ccgcctcttgtttttcccgcgaaactcggcggctgagcgtggaggttcttgtctcccctggtttgt gaagtgcggaaaaccagaggcgcagtcatg (Seq ID No: 520)
Homo sapiens RNA binding motif (RNP1, RR ) protein 3 (RBM3) :
tactctttatcaatcgtcttccggcgcagccccgtccctgttttttgtgctcctccgagctcgctg ttcgtccgggttttttacgttttaatttccaggacttgaactgccatg (Seq ID No: 521) Homo sapiens KDEL
(Lys-Asp-Glu-Leu) endoplasmic reticulum protein retention receptor 1 (KDELR1) :
ctccccctctcgctctcctccctcttcccggctccagctccgccgccagctccagcctttgctccc cctcccaaagtcccctccccggagcggagcgcacctagggtccctcttccgtccccccagcccagc tacccgttcagaccagcagcctcggggggcacccccccgccagcctgcctccctcccgctcagccc tgccagggttccccagccatg (Seq ID No: 522)
Homo sapiens StAR-related lipid transfer
(START) domain containing 3 (STARD3) :
agatcttcttccgctctgaggcgctactgaggccgcggagccggactgcggttggggcgggaagag ccggggccgtggctgacatggagcagccctgctgctgaggccgcgccctccccgccctgaggtggg ggcccaccaggatg (Seq ID No: 523)
Homo sapiens heterogeneous nuclear ribonucleoprotein AO (HNRNPA0) : cggcctctttgtgtggtgcccagataggggagcggaggtggcggcggcggcggtagcggtggcctt ggttgtcttccagtctcctcggctcgccctttagccggcaccgctccccttccctcccccttcctc tcttccttccttccctccccttccctttttcccttccccgtcggtgagcggcgggggtggctccag caacggctgggcccaagctgtgtagaggccttaaccaacgataacggcggcgacggcgaaacctcg gagctcgcagggcgggggcaaggcccgggccttggagatg (Seq ID No: 524)
Homo sapiens chromobox homolog 1 (CBX1) :
ggctcttttgttcggctgaggggagggccgttggccggggcctgcggtacgccgcttcagtgaggg acgccactgcggccacccggcttgctgccttcctgggcgccactcccccaggcgacccgacgcgac gcgccagcagcgcagcaccgattcctctcgggctcttgggcgctgctctgaggtgaggagcccgct ggaggcgggagagctgggggagggggcgcggcggcggcggcggcgggagccctgcgtgagggaacg cgctttcgaggcggaggttaggagcggggagcgcgcccgggtccagcgtcctgcttctccgcttcc cgcgctgagctcttcgcctgtcgctgaggcgtcggtgccagctgcgtgaaggatggagagggcggg gcgcgaatcctgagccagagactgagtgcttgggggtgggccgagcacttgggggccgctcttcgg ggcccgggtggtctggaacaatgttgcttggctgggcggctgcgggatagggcggaaggggacagg cttgaggcttggataggcgtgaggaggcgcatacgaccgcacaacccgaggtttgtaactgtattc ggaagacgccgggtccggctgggactgccagaggaacctggctttgcaggactacggaggagtaac gtcgagtgaattggaagagggcccagggccgcacaagcagcgtcaccctttacaccagaaagctgg cgggcactatg (Seq ID No: 525)
Homo sapiens myeloid/lymphoid or mixed-lineage leukemia (tritho- rax homolog, Drosophila) ; translocated to, 11 (MLLT11) :
cgcccttcttaggaggggctgcattgcagggggagagtgaactgacagactcagtcactgaagagg gaaaaggagtgagaagacaaagccgtcaaagccccaacagctttgtatttctccagcccggcgcag accccggagctcccgaggcactccctccatctttggaacacgccagtaattgattgataacaggaa gctatg (Seq ID No: 526)
Homo sapiens interferon-induced protein 44-like (IFI44L) :
ttttctttctttcctagagtctctgaagccacagatctcttaagaactttctgtctccaaaccgtg gctgctcgataaatcagacagaacagttaatcctcaatttaagcctgatctaacccctagaaacag atatagaacaatg (Seq ID No: 527)
Homo sapiens cyclin I (CCNI) :
acttcttcctcccttcccctctcttcccctccctccccagccttccccgcgagcggacgcggcagc gcctctgtctcgctttttcttatttttcccccctttcccctttctttttttttttttcttttcttt tctcccctccccccctttcaecatttcccctcggaggcgctttccccgggeaggggcagagccggt ctcaccccccgcctctccccggcccccgccgccctatggcgagagggagccccctcccaacccggg ctcgagcggcggcggcctcaggccgggggtcatcatggaactaattcgctgaccgacccagcggcc gcagccgtgcgtcccgctcgagcgccagcgcccgcgcccgcgccccccgatccgcttcccctttct ccctcctcagttggccgagtcgtcccgcgcgcaccgcctccgcgcgcctatgagaatgaggtggta acgggcccccggatgaccccgcgtcaccactgtgaggcctacagctctgccggggaggaggaggag gaggaagaggaggagaaggtagctacagcaagctgggtagcaggcagatccaaaggatatcatg (Seq ID No: 528)
Homo sapiens methionyl aminopeptidase 2 (METAP2) :
cattccctcgcgctctctcgggcaacatg (Seq ID No: 529)
Homo sapiens leukocyte immunoglobulin-like receptor, subfamily B (with TM and ITIM domains), member 4 (LILRB4):
gtctctttgtcctgccggcactgaggactcatccatctgcacagctggggcccctgggaggagacg ccatg (Seq ID No: 530)
Homo sapiens destrin (actin depolymerizing factor) (DSTN) :
gggtctctcggtcccgcagccgtgaggaggacggtctgcatactcgctgcccgccggctccctccc ccgcgtccctgcgaccgccgcggcgaagatg (Seq ID No: 531)
Homo sapiens eukaryotic translation initiation factor 2D (EIF2D) : gggcccttttcgcggccgggccccagcatggctgcccccacggctgagggcctggcagctgctgcg ccctcgctttcttgacattccctggcttctgtgctctcttccccaggccaccccagcagacatg (Seq ID No: 532)
Homo sapiens histamine N-methyltransferase (HN T) : ctgtctttctca- gaaaaccaaatatg (Seq ID No: 533)
Homo sapiens ras-related C3 botulinum toxin substrate 1
(rho family, small GTP binding protein Racl) (RAC1) :
gtttctctgcagttttcctcagctttgggtggtggccgctgccgggcatcggcttccagtccgcgg agggcgaggcggcgtggacagcggccccggcacccagcgccccgccgcccgcaagccgcgcgcccg tccgccgcgccccgagcccgccgcttcctatctcagcgccctgccgccgccgccgcggcccagcga gcggccctgatgcaggccatcaagtgtgtggtggtgggagacggaaacaagaatctcagtgtaacc cgagcaaaatcgcgcgtctcagcgttgcttgtatagagctgtaggtaaaacttgcctactgatcag ttacacaaccaatgcatttcctggagaatatatccctactgtctttgacaattattctgccaatgt tatg (Seq ID No: 534)
Homo sapiens signal recognition particle 72kDa (SRP72) :
tcgtctcctccaagatg (Seq ID No: 535)
Homo sapiens zinc finger protein 33B (ZNF33B) :
ccgcctttccttttgtttgtctcacgttttgcgtgggaggcggtcccgggatttcaggggtctacc ggctctcttatggcgaatgcaacccgaagagagagtgagctgtatcttcagagttgtctccgtctt tccaagaacagaacaaaatg (Seq ID No: 536)
Homo sapiens zinc finger protein 16 (ZNF16) :
gcctcctttccaagcgcgacccgttgaggtccttgtcatg (Seq ID No: 537)
Homo sapiens zinc finger protein 33A (ZNF33A) :
ccgcctttccttttgtttttctcaggttttgcgtgggaggcggtcccgggatttcaagggtctacg cgcttttctatggcgaatgcaacccgacgagggagtgggctgtatcttcagagttgtctccgtctt tccaagaacagaacaaaatg (Seq ID No: 538)
Homo sapiens butyrophilin, subfamily 3, member A3 (BTN3A3) :
ctttctttttcctttcttcggaatgagagactcaaccataatagaaagaatggagaactattaacc accattcttcagtgggctgtgattttcagaggggaatactaagaaatggttttccatactggaacc caaaggtaaagacactcaaggacagacatttttggcagagctgctcactccttgctcagctcagtt ttctgtgcttggaccctctgggcccatcctggccatg (Seq ID No: 539)
Homo sapiens butyrophilin, subfamily 2, member A2 (BTN2A2) :
ctctttgggatgctttgttgtctggtggtgactgtgcccatgggtgagttgtatcggaaaatcgtc atgtgaggatcagaggggaaaagaaaacagaggcctctggtctctgcctgccctgggtgctcatg (Seq ID No: 540)
Homo sapiens nudix (nucleoside diphosphate linked moiety X) -type motif 21 (NUDT21) :
acgcctcctcttgcgctgtcctgttaatggcgggcagtagccgctgaggggattgcagataaccgc ttcccgcacggggaaagtctaccctgcctgccactttctgctcgccgtcagcgccggagctcgcca gcatg (Seq ID No: 541)
Homo sapiens stathmin-like 2 (STMN2) :
tgctctttctctagcacggtcccactctgcagactcagtgccttattcagtcttctctctcgctct ctccgctgctgtagccggaccctttgccttcgccactgctcagcgtctgcacatccctacaatg (Seq ID No: 542)
Homo sapiens katanin p60 (ATPase containing) subunit A 1 (KATNA1) : caccctcttccgccgctcccgcccagcgacctcgctcccggggcgacgccccgcgtgcgccagagt cgccgaggtcgtccccggcaccggaagtgaccctggcgggtttgtcttcaaattctcggcgagcag gagccgcgccggcaggtggtgttgacgattgaactgggcagtactggggccgtgagcggagagcaa agtgggctggactgggtcaggccctccttcctcgctgccgggatctccactccgccaatcccctgt gcctggcgttgggcggtttcccgaggagcttgggccgccgcagcttacagttgaacatg
(Seq ID No: 543)
Homo sapiens butyrophilin, subfamily 3, member A2 (BTN3A2) :
ctttctctttttcctttcttccggatgagaggctaagccataatagaaagaatggagaattattga ttgaccgtctttattctgtgggctctgattctccaatgggaataccaagggatggttttccatact ggaacccaaaggtaaagacactcaaggacagacatttttggcagagcatagatg (Seq ID No: 544)
Homo sapiens CLK4-associating serine/arginine rich protein
(CLASRP) :
cggcctttcatttccgcttccggtgcgggccgcgcgcgagcgcagcggtgggaggcggcgaccagc cggttgaggccccaggcttggcctcaccacaatg (Seq ID No: 545)
Homo sapiens clathrin, light chain A (CLTA) :
ctccctcctggcgcttgtcctcctctcccagtcggcaccacagcggtggctgccgggcgtggtgtc ggtgggtcggttggtttttgtctcaccgttggtgtccgtgccgttcagttgcccgccatg (Seq ID No: 546)
Homo sapiens NADH dehydrogenase (ubiquinone) flavoprotein 1, 51kDa (NDUFV1) :
gcgtctctatcgcgccagttcctcagcctcagtgctatgaaggtgacagcgtgaggtgacccatct ggcccgccgcgatg (Seq ID No: 547)
Homo sapiens signal sequence receptor, gamma (translo- con-associated protein gamma) (SSR3) :
gggcctttgcccgccttggcggccggctctacgttccctgttctcgcctgcagctccgccatg (Seq ID No: 548)
Homo sapiens valosin containing protein (VCP) :
gcttcccttccgatgattcggctcttctcggctcagtctcagcgaagcgtctgcgaccgtcgtttg agtcgtcgctgccgctgccgctgccactgccactgccacctcgcggatcaggagccagcgttgttc gcccgacgcctcgctgccggtgggaggaagcgagagggaagccgcttgcgggtttgtcgccgctgc tcgcccaccgcctggaagagccgagccccggcccagtcggtcgcttgccaccgctcgtagccgtta cccgcgggccgccacagccgccggccgggagaggcgcgcgccatg (Seq ID No: 549) Homo sapiens zinc finger protein 195 (ZNF195) :
gggcctttgtcccgacagagctccacttcctgtccccgcggctctgtgtcccctgctagccgtagg tcgtgtgacccgcaggcaccgggagatccagaagtgaaacgccaggctctctggaggccaggagat g (Seq ID No: 550)
Homo sapiens testis-specific kinase 2 (TESK2) :
cagtctttcgcggcccgggagctcagcagagctaccagctgccctgttggcttcgctggtcggatc gtcctcctggccccgccaaacaggcggggggagcggccccgactgtggggccatggcagtagtctc ctcgttcgccgccgccgctagcctagctgagtcgccggcttctgcgctaggggctcccaccgcctc cgcaggctaaggagccgctgccaccaacgagctgtgagggttactatgctccctctttgccgccgt ctcctcctcttgcccgcgcaggcacccctctggctgctcagtcctgcctcagtgtcaaaccagaag agaagtaaaattcaacaaaaatttatgtgtggagttccttcttaaaagaagaaaaaagtgattatt tagactatg (Seq ID No: 551)
Homo sapiens family with sequence similarity 107, member A
(FAM107A) :
agccctccttgctagtctgggacttcccggtggagtgaggaacccagcaacacgctcctgacttcc cttcccaaggactcgacctgagaaggacacagcagtctctgaatttcatgctctcctctttgatgt gaagaaaatgaaaagctgaacagttgtggaactgtggatagagttagacaataaggccgccatg (Seq ID No: 552)
Homo sapiens serine/threonine kinase receptor associated protein (STRAP) :
ccctccctccctttccctccctcgtcgactgttgcttgctggtcgcagactccctgacccctccct cacccctccctaacctcggtgccaccggattgcccttcttttcctgttgcccagcccagccctagt gtcagggcgggggcctggagcagcccgaggcactgcagcagaagagagaaaagacaacgacgaccc tcagctcgccagtccggtcgctggcttcgccgccgccatg (Seq ID No: 553)
Homo sapiens mitochondrial ribosomal protein L3 (MRPL3) :
ctttctttccgtcgcagagagcatcggccggcgaccgttccggcggccattgcgaaaacttcccca cggctactgcgtccacgtggcggtggcgtggggactccctgaaagcagagcggcagggcgcccgga agtcgtgagtcgagtcttcccgggctaatccatg (Seq ID No: 554)
Homo sapiens zinc fingers and homeoboxes 1 (ZHXl) :
ctcccttccccctccgcccccggacggccgctggggcgcgcgcctctcctcgcacccccaccctga gtccccacactccgcggggccaccgagctgctgaggcccctttgcgggcccgccgagcggttccgg gtttagggttcacaggtcagagttgactccctgaaaagtgcagccggtttgaaatgcaagatggcg gcggcgtggcgctgagaggcgcggcggcccctgcaggagaagacagactgctgctttggacctgtt ggtaatgatggcctgagctaaacatctaactagaagggatacccttccatttcaaagaacagaatg ctaaggaagctgtggcaagtgattggagttgtgcttcaaaaatttcagaaattcagcagtatttta tctgccaacaataagctctttacttgattgcaccatgagaaagctgctaatgagacttgttgagca caaaaatggacttgaagaaccaaaagccattgttttcaaatgaagaacactgaacagttttaagcc tcgatgctttttaatcaccactgagcttttcctcataacatcagaatg (Seq ID No: 555)
Homo sapiens calcium binding protein P22 (CHP) :
ccttccttccctccctccttccctcctgtcgccgtctcttctggcgccgctgctcccggaggagct cccggcacggcgatg (Seq ID No: 556)
Homo sapiens ecdysoneless homolog (Drosophila) (ECD) :
ctttctctcaggatttccgctggcttcaggttccggtcaggcgtcgggacagagcctgatccaggc ttcggcggccggtggcagctctcgatcagctctcgcagtcggagaggcggctaaggaaaggtgcca cagcagagacgcgaaggagaggccctagaaccttttcaaagaagaatg (Seq ID No: 557) Homo sapiens V-set and immunoglobulin domain containing 4 (VSIG4) : gagcctctttggtagcaggaggctggaagaaaggacagaagtagctctggctgtgatg
(Seq ID No: 558)
Homo sapiens prohibitin 2 (PHB2) :
tgccctttctttcgccagccttacgggcccgaaccctcgtgtgaagggtgcagtacctaagccgga gcggggtagaggcgggccggcacccccttctgacctccagtgccgccggcctcaagatcagacatg (Seq ID No: 559)
Homo sapiens signal transducer and activator of transcription 1, 9 lkDa (STAT1) :
ctgccttttctcctgccgggtagtttcgctttcctgcgcagagtctgcggaggggctcggctgcac cggggggatcgcgcctggcagaccccagaccgagcagaggcgacccagcgcgctcgggagaggctg caccgccgcgcccccgcctagcccttccggatcctgcgcgcagaaaagtttcatttgctgtatgcc atcctcgagagctgtctaggttaacgttcgcactctgtgtatataacctcgacagtcttggcacct aacgtgctgtgcgtagctgctcctttggttgaatccccaggcccttgttggggcacaaggtggcag gatg (Seq ID No: 560)
Homo sapiens heat shock protein 90kDa alpha (cytoso- lic) , class B member 1 (HSP90AB1) :
agctctctcgagtcactccggcgcagtgttgggactgtctgggtatcggaaagcaagcctacgttg ctcactattacgtataatccttttcttttcaagatg (Seq ID No: 561)
Homo sapiens cancer susceptibility candidate 3 (CASC3) :
cgttctccgtaagatg (Seq ID No: 562) Ί63
Homo sapiens nuclear cap binding protein subunit 2, 20kDa (NCBP2) : gcttctctgcactatg (Seq ID No: 563)
Homo sapiens non-POU domain containing, octamer-binding (NONO) : cgctcttttctcgggacgggagaggccgtgtagcgtcgccgttactccgaggagataccagtcggt agaggagaagtcgaggttagagggaactgggaggcactttgctgtctgcaatcgaagttgagggtg caaaaatg (Seq ID No: 564)
Homo sapiens lectin, galactoside-binding, soluble, 9 (LGALS9) : atttctttgttaagtcgttccctctacaaaggacttcctagtgggtgtgaaaggcagcggtggcca cagaggcggcggagagatg (Seq ID No: 565)
Homo sapiens chaperonin containing TCP1, subunit 5 (epsilon) (CCT5) : cggtctccgccggttggggggaagtaattccggttgttgcaccatg
(Seq ID No: 566)
Homo sapiens haloacid dehalogenase-like hydrolase domain containin g 1 (HDHD1) : cttcctcctcgcccccacccagacccagaaggcgccaccatg
(Seq ID No: 567)
Homo sapiens glutamate dehydrogenase 2 (GLUD2) :
cttccttcctagtcgcggggagtctgagaaagcgcacctgttccgcgaccgtcacgcacccctcct ccgcctgccgcgatg (Seq ID No: 568)
Homo sapiens general transcription factor IIIC, polypeptide 3, 102 kDa (GTF3C3) : ggttctctgtcccggttcctggggttgcacagacagaccctgtaaacatg (Seq ID No: 569)
Homo sapiens general transcription factor IIIC, polypeptide 5, 63k Da (GTF3C5) :
gggtccctcgctggctagtaggagagactggtgcttgccccgcccggtggactaactcgcttaatt ttaaataaaaagtcgaggacacggcggtcgttttcccgaagacatgggccctcccatgggccattt gctccctggaggccctcgcgtcttgctgagcccggggagttaggatgacgcgagcggtgagggagc ccggaacgattccttcgcggaacaattgaggcgaggcctttgggagtactttgtgggacggaccct ggcgggccctgccagacgcacagggatg (Seq ID No: 570)
Homo sapiens ancient ubiquitous protein 1 (AUP1) :
ccgccttcccaagagcccctgcggccgggcgcgaaaatggcggcggcggcgacggccgggcgctcc tgaagcagcagttatg (Seq ID No: 571)
Homo sapiens coatomer protein complex, subunit gamma 2 (COPG2) : cggccttcctgcagcctcttccgctcgccggctgcggcgcctgggacggttgcggtgggtctgggc gctgggaagtcgtccaagatg (Seq ID No: 572)
Homo sapiens apoptosis antagonizing transcription factor (AATF) : cggtctctggcggagtcggggaatcggatcaaggcgagaggatccggcagggaaggagcttcgggg ccgggggttgggccgcacatttacgtgcgcgaagcggagtggaccgggagctggtgacgatg (Seq ID No: 573)
Homo sapiens integrator complex subunit 6 (INTS6) :
tctcctctttctccaccacctcgggccccggtgtccccggccagcactatg
(Seq ID No: 574)
Homo sapiens F-box and leucine-rich repeat protein 4 (FBXL4) :
tcttccttccgggtcgcgctaggccgggcttgcggcggttgtgccgcatctagagagtcggggagc cgcccccgcacccaggccttctcgcgctgcctggtcgctggtgaagcccgcggcgcgcgcctctcc cggaccctgcagggtaaaagaatgtcacatgtcagcatttgtacctgaagtcagcatgcaaagttc agggtacctggatgaatgccaacttttgcatttcccatgtgtatcctgtgaccattctatctggga acatccttcaaagagttcatgcatcttactgaggacacctgaccttttgaagcttcataattcaca tctagatg (Seq ID No: 575)
Homo sapiens guanine nucleotide binding protein
(G protein) , gamma 3 (GNG3) :
gctccttctagcatccttcatccttcaggtaccagccatccagacagtgcttgagctgcagaaact gagaccagacctctggcctggccctccccaggggcctcctttcgtatagtcactgcttctgcatca gatactttcagctgcaactccctactgggtggggcacccatttcaggcagaaggttttggtaccct ccactgaccctacacccagggctgctactgccgcttgtggcttcaggatg
(Seq ID No: 576)
Homo sapiens histidyl-tRNA synthetase 2, mitochondrial (putative) (HARS2) : aggccttttgttcctgtcccggaaagccggcgtcctgccgcgcgatg
(Seq ID No: 577)
Homo sapiens interleukin enhancer binding factor 3, 90kDa (ILF3) : cctcctcctcctcttctcgccattgcagttggacccagcagcccggcgcgcaccgcgtggcttttg ggggcagaccccggcgggctgtggcaggagggcggcggcggcggctgcggtcgaagaaggggacgc cgacaagagttgaagtattgataacaccaaggaactctatcacaatttgaaaagataagcaaaagt ttgatttccagacactacagaagaagtaaaaatg (Seq ID No: 578)
Homo sapiens polymerase I and transcript release factor (PTRF) : gtttcctctgctctccgctctcgcccgctagctctcctcccttccgctcctgcttctctccgggtc tcccgctccagctccagccccacccggccggtcccgcacggctccgggtagccatg
(Seq ID No: 579)
Homo sapiens 5 '-3' exoribonuclease 2 (XRN2) :
tgccctctgccgctgctcccgtctctttggttacgctcgtcagccggtcggccgccgcctccagcc gtgtgccgctatg (Seq ID No: 580)
Homo sapiens 2-hydroxyacyl-CoA lyase 1 (HACL1) :
ccgcctcttccttcccgttgtttaaggcagttggttgccctcctgtccgtcagaggtgcagtacca gaggtggcgtgctgccgatttcgcgtttgccttgctggatgattccgcttgtttgccggctgcgtg agtgcttagagcttttcggtggaagatg (Seq ID No: 581)
Homo sapiens zinc finger protein 346 (ZNF346) :
ggctctctaccggtgagggtttgcggggaagatg (Seq ID No: 582)
Homo sapiens microtubule-associated protein, RP/EB family, member 3 (MAPRE3) :
cagtctctgtgcgttgaagccggagaccgcggcggcctcagcgaggaccctccgccccggagccgc cggccggagccgcagcctctgccgcagcgcccccgccacctgtcccctccccctccgcctccgccg gagccgcctcgtgcactctggggtatg (Seq ID No: 583)
Homo sapiens splicing factor 3b, subunit 3, 130kDa (SF3B3) :
gtgcctttttccgccgcgcgccaccagaatgtccctgtcttgaggtctaatggcggacgccagtat gttggagttggtggtggcttaagttttgaagggaggtagcatccgttggatatccacaccatcctt ctcgctgcaggctttcttggactccgtactgttggtgtaaccaaggcctggaggtctgggtggctc aggtttcctgcagccatg (Seq ID No: 584) Homo sapiens spondin 2, extracellular matrix protein (SPON2) :
ctgcctctcgctggaggccaggccgtgcagcatcgaagacaggaggaactggagcctcattggccg gcccggggcgccggcctcgggcttaaataggagctccgggctctggctgggacccgaccgctgccg gccgcgctcccgctgctcctgccgggtgatg (Seq ID No: 585)
Homo sapiens solute carrier family 13 (so- dium/sulfate symporters), member 4 (SLC13A4) :
ttttcttttctgctttgcaggcccaggctcaaggcaaattataagtagggaaccaatttgagggaa agacatgtgaacagagttaaggtaccacgtcctgggagcgaccagcagccccacctgaagtccgca tgcaactctgacaagctcaggtgcttgttttaaggaaaggggctactagagtcttaccaacagcga gcccaggtgggagatgaaacaggtactccccaaaataggtcatccgagggaggaaaactgatggag agcacaatgtgctctgagcgtttttaatgtttttaagcttttaaatgatttcttcaaggccgagca gcagcagcaaaggtgtggcttaaaggattaagggggtttctgctgacacctagaatgaagttactc tattactaatcaagccgagaggaggcccactatgcccccgtttatcatcctttcccagttcctttt tgctggtcacaaaacgatgctcatcaatcccacctaaagcaggaggccaggagcccagcctcttgt agaaacagcgagggtataactgccctcccgttctgcccccaagacgaaggaggactctcggaagcc aagaaaggtttaagaagtctttctggatagagagcagtgcccaggcaggaagcctttcgccggcag agcggggtccaaggacgagctggagaggacagaggcgcgatg (Seq ID No: 586)
Homo sapiens PRP6 pre-mRNA processing factor 6 homolog
(S. cerevisiae) (PRPF6) : attcctttccttcctagccttggtcgtcgccgccaccatg (Seq ID No: 587)
Homo sapiens eukaryotic translation initiation factor 3, subunit K (EIF3K) :
ccacctcttcctgttcccgtccttgaggacgccgtgccgggtcagtgttagcctccagccctggtt gtggaaggcgacagaagtcatg (Seq ID No: 588)
Homo sapiens ataxin 10 (ATXN10) :
ccccctcccccgcggcgccgtctcctcctcccgcctgaggcgagtctgggctcagcctagagctct ccggcggcggcgcagcttcagggcagcgcgggctgcagcggcggcggcggttagggctgtgtaggg cgaggcctcccccttcctcctcgccatcctactcctccctcctcgtcatcctcccccttcgtcctc ctcgccttcctcctcctcgtcaggctcgacccagctgtgagcggcaagatg
(Seq ID No: 589)
Homo sapiens secretogranin III (SCG3) :
cttccttcctcacttcctctgcaggagggagcgagagtaaagctacgccctggcgcgcagtctccg cgtcacaggaacttcagcacccacagggcggacagcgctcccctctacctggagacttgactcccg cgcgccccaaccctgcttatcccttgaccgtcgagtgtcagagatcctgcagccgcccagtcccgg cccctctcccgccccacacccaccctcctggctcttcctgtttttactcctccttttcattcataa caaaagctacagctccaggagcccagcgccgggctgtgacccaagccgagcgtggaagaatg (Seq ID No: 590)
Homo sapiens polymerase (DNA directed) , mu (POLM) :
cttccttccgtctcgctcggagtttccctctgcgttcgctccgcgctgctggaggctgtcgtccca atg (Seq ID No: 591)
Homo sapiens epsin 1 (EPN1) :
cctccttctgttgcttcccgtctcctcggcggctcccctcccccgcccggctctccgcgccccttc tgggcggcggggcggcggagccgtcggcgtgcggccctccttgcgttcgtgcgtgcgcccgtggcc cggcgcacgtcccgcgacaccgaggccgagcggggcagggggctgaccgccatgaccccccagagc ccggcgtgagggggccgagatgcggtgacctgccagcacctgccgcagccttcgtccgggagtcgc cccatctctccacgcatcggggccctgtgccccttgctgctgcagccgggcaccatg
(Seq ID No: 592) Homo sapiens Sec61 alpha 1 subunit (S. cerevisiae) (SEC61A1) :
gtgtctctcggcggagctgctgtgcagtggaacgcgctgggccgcgggcagcgtcgcctcacgcgg agcagagctgagctgaagcgggacccggagcccgagcagccgccgccatg
(Seq ID No: 593)
Homo sapiens Obg-like ATPase 1 (OLA1) :
cgttctctcctccttcctccccgcctccagctgccggcaggacctttctctcgctgccgctgggac cccgtgtcatcgcccaggccgagcacgatg (Seq ID No: 594)
Homo sapiens sorting nexin 12 (SNX12) :
aggcctctgtcccccaccccctttccccggtcccaggctctccttcggaaagatg
(Seq ID No: 595)
Homo sapiens LAG1 longevity assurance homolog 2 (S. cerevisiae) (LASS2) :
cggcctttttttcccggctgggctcgggctcagctcgactgggctcggcgggcggcggcggcggcg ccggcggctggcggaggagggagggcgagggcgggcgcgggccggcgggcgggcggaagagggagg agaggcgcggggagccaggcctcggggcctcggagcaaccacccgagcagacggagtacacggagc agcggccccggccccgccaacgctgccgccggctactccctcttgatgccctcccctttgcccctc actcaggatg (Seq ID No: 596)
Homo sapiens cytohesin 4 (CYTH4) : tcatcttttccccagaggcgtcggaatg (Seq ID No: 597)
Homo sapiens transportin 2 (TNP02) :
aattctctctctttggctccctccttccgcgcgagtctctggagaagccgcagcgcgagttgccgc cgctgctgcccggggccgggtaagtgggcctcactcagagcccgaccctcttggccccggcttgcg tcgacccccgccgggcaccgagcctgcgccgcgcgcggcccgggcgtcggggccgcgcccgaccgg gaaaggccgggaagccggttgggcccgatcctcctggcagctagaacgggccgggcgggggagggg ggaaccgagcagagcttagggggtggggcctcggagccaggccatgtcggggctcctcaagaagag ggccagtgggactgctggggtcgggctggaggggatctgattgggggaagcgtctggggactgctt ggggcctgattgggggacgtcgcgaggatcggcttgccttgcgccatg (Seq ID No: 598)
Homo sapiens makorin ring finger protein 1 (MKRN1) :
gggcctttgctgtgtgggataaacagtaatg (Seq ID No: 599)
Homo sapiens vinculin (VCL) :
ctgtctcttcgccggttcccggccccgtggatcctacttctctgtcgcccgcggttcgccgccccg ctcgccgccgcgatg (Seq ID No: 600)
Homo sapiens DEAH (Asp-Glu-Ala-His ) box polypeptide 38 (DHX38) : cctccttttcctgcccccagactagaggcgggatgtagtctcttaggctaagagtgattggtcaca aggagactcggaagtgtctgatcagagccccagaggaggccttgagagcctgttggcgtaccgttc cacacttggatccaggaatcgggcgtgttccaggctgctctctatggtagctttgggcggatagag ggggcgcgcaaagtattaagggacaataatggccgctttcaaggtgtggattttggctccttgagc ctgtctgagcgaggggtggcagcgccggcgccccagaatccgggacagaagggtcccaagagtcgc gcttggtgagagaaatcccagatcctgtgatg (Seq ID No: 601)
Homo sapiens osteoglycin (OGN) :
catcctctaagcttttaaatattgcttcgatggtctgaatttttatttccagggaaaaagagagtt ttgtcccacagtcagcaggccactagtttattaacttccagtcaccttgatttttgctaaaatg (Seq ID No: 602) Homo sapiens NIN1/RPN12 binding protein 1 homolog (S. cerevisiae) (NOB1) : gctcccctctcacgcagccaacatg (Seq ID No: 603)
Homo sapiens nudix (nucleoside diphosphate linked moiety X)-type motif 5 (NUDT5) :
catccttttagcaccgcgagaggcgccggtgtttcgagccgtggcaccggcatcggctgacactgc tgcctccagctagttatttcgtcctcttccgttcttcacccctacaccttggaggtgaacttctca cctgagggctgtaaagactcgtttgaaaatg (Seq ID No: 604)
Homo sapiens WD repeat domain 91 (WDR91) : cgtccctcaccgcac- cacccctaaagacgctagcgctgcgatg (Seq ID No: 605)
Homo sapiens nuclear transcription factor Y, gamma (NFYC) :
gggcctctgcattgcccgactccgtaggagcgcgggggcggctcctgctcttcctggactcctgag cagagttgtcgagatg (Seq ID No: 606)
Homo sapiens protein phosphatase 2, regulatory subunit A, alpha (PPP2R1A) :
ccgcccttccttcttctcccagcattgccccccccacgtttcagcacagcgctggccgcagtctga caggaaagggacggagccaagatg (Seq ID No: 607)
Homo sapiens vesicle-associated membrane protein 2 (synapto- brevin 2) (VAMP2) :
ccatctttccgtcccgggcagccagcgccagtcggagccagcgcgagccgccgccgccatcactgc cgctgccaagtcctccacccgctgcccccgccatg (Seq ID No: 608)
Homo sapiens transmembrane protein 5 (TMEM5) :
gattctctttccgcccgctccatggcggtggatgcctgactggaagcccgagtgggatg
(Seq ID No: 609)
Homo sapiens UDP-GlcNAc:betaGal beta-1 , 3-N-acetylglucosaminyltrans ferase 3 (B3GNT3) :
aactctttcttcggctcgcgagctgagaggagcaggtagaggggcagaggcgggactgtcgtctgg gggagccgcccaggaggctcctcaggccgaccccagaccctggctggccaggatg
(Seq ID No: 610)
Homo sapiens SEC11 homolog A (S. cerevisiae) (SEC11A) :
gcgccctttcccctgccggtgtcctgctcgccgtccccgccatg (Seq ID No: 611)
Homo sapiens RUN and SH3 domain containing 1 (RUSC1) :
ctccctccccgcgccccgtcctctcccgccctacaggccctagcagggcaggcgggaggtgagcgc ggccatcccgctcccggagttccgggatcctggagtccgtagttcgtggtccttcgccggtgtccc cggagcccagcggctgtggatg (Seq ID No: 612)
Homo sapiens aryl hydrocarbon receptor interacting protein-like 1 (AIPL1) : cctccctttctcctgcagccatg (Seq ID No: 613)
Homo sapiens tumor necrosis factor, alpha-induced protein 8
(TNFAIP8) :
cctccttttctcccgccggctctaacccgcgcttggctaaggtccgcgggaacccgtgagccaccg agagagcagagaactcggcgccgccaaacagcccagctcgcgcttcagcgtcccggcgccgtcgcg ccactcctccgatg (Seq ID No: 614)
Homo sapiens staphylococcal nuclease and tudor domain containing 1 (SND1) : gcgtctctttcgctccgtgtcccgctgctgctcctgtgagcgcccggcgagtccgtcccgtccacc gtccgcagctggtagccagcctgcccctcgcctcgactccctttcaccaacaccgacacccacatt gacacctccagtccggccagccgctccactcgttgcctttgcatctccacacatg
(Seq ID No: 615)
Homo sapiens DNA segment on chromosome 4
(unique) 234 expressed sequence (D4S234E) :
cgccctcttttggtcgccccctccccaacccagcactaaggagcaccctgctctggtctccgccac cacccagcgcctcctggacccatccccccaaacccttgaacgtcctcaggacccccaggtgagcgc ggcgcgctgcgggcggggaccctctctgcacctccccgcacccctgggggtcgctctgtccctacg gtccccgcctcccctttctcctttctaagcgcctcgcgcccaggccgccgcccggggtggcgcagc ccgcagccctcccgctccgggcgccctccgccgctccgagaccccctgggggcgcgtcctctcccg ctcccctgttccctcccccggctcagggcgggcgcgtggtcccaggggaggctcccgcccagcccc gcactcctttgtgcggccgggcgggcgctgcgtcaaggtggaggcgcggccacacgcgcgcaccca cccgcgcgcacccagcccccgggagaggcaggaagggaggcggcggcgcgaggaggagggagcggc cgtggagcccaatcgttcgctccccttcccgggtccgcgcgcggcgccgcctccgccattgctgcg agcaggagcaggagacgcggagctcggagcgctcagctgacctgccggagccgggcgtgggctgca gcctcggagctcccggaacgatg (Seq ID No: 616)
Homo sapiens growth hormone inducible transmembrane protein
(GHITM) :
acgtcctttcgatgttgcgtcatgcagtgcgccggaggaactgtgctctttgaggccgacgctagg ggcccggaagggaaactgcgaggcgaaggtgaccggggaccgagcatttcagatctgctcggtaga cctggtgcaccaccaccatg (Seq ID No: 617)
Homo sapiens stress-associated endoplasmic reticulum protein 1 (SERP1) :
tttccttcctctttcactccgcgctcacggcggcggccaaagcggcggcgacggcggcgcgagaac gacccggcggccagttctcttcctcctgcgcacctgccccgctcggtcagtcagtcggcggccggc gcccggcttgtgctcagacctcgcgcttgcggcgcccaggcccagcggccgtagctagcgtctggc ctgagaacctcggcgctccggcggcgcgggcaccacgagccgagcctcgcagcggctccagaggag gcaggcgagtgagcgagtccgaggggtggccggggcaggtggtggcgccgcgaagatg
(Seq ID No: 618)
Homo sapiens ADP-ribosylation factor interacting protein 1 (AR- FIP1) :
cggtctcctcacttccggcttcgctgctcttggttctggttctggaggctgggttgagaggtcgcc ggtccgactgtcctcggcggttggtcagtgtgaatttgtgacagctgcagttgctccccgcccccg agcagccgaggagtctaccatg (Seq ID No: 619)
Homo sapiens tumor necrosis factor receptor superfamily, member 21 (TNFRSF21) :
ccgccccttcggcgccaccacgtgtgtccctgcgcccggtggccaccgactcagtccctcgccgac cagtctgggcagcggaggagggtggttggcagtggctggaagcttcgctatgggaagttgttcctt tgctctctcgcgcccagtcctcctccctggttctcctcagccgctgtcggaggagagcacccggag acgcgggctgcagtcgcggcggcttctccccgcctgggcggccgcgccgctgggcaggtgctgagc gcccctagagcctcccttgccgcctccctcctctgcccggccgcagcagtgcacatggggtgttgg aggtagatgggctcccggcccgggaggcggcggtggatgcggcgctgggcagaagcagccgccgat tccagctgccccgcgcgccccgggcgcccctgcgagtccccggttcagccatg
(Seq ID No: 620)
Homo sapiens sushi-repeat containing protein, X-linked 2 (SRPX2) : ccccctcttctgcagcagacggactgagttcctctaatccctgtgttccttctcccccatctttct aaaacccttctctgagagaggaataactatagcttcagggataatatagctttaaggaaacttttg gcagatgtggacgtcgtaacatctgggcagtgttaacagaatcccggaggccgggacagaccagga gccactcgttctaggaatgttaaagtagaaggttttttccaattgatgagaggagcagagaggaag gagaaagaggaggagagagaaaaagggcacaaaataccataaaacagatcccatatttctgcttcc cctcacttttagaagttaattgatggctgacttctgaaagtcactttcctttgccctggtacttca ggccatatacatcttttcttgtctccataatcctccctttcaaggatg (Seq ID No: 621)
Homo sapiens HIV-1 Tat specific factor 1 (HTATSF1) :
acctccctttctctgctcagctccagcgtcatttcggcctcttagttcttctgaaccctgctcctg agctaggtaggaaacatg (Seq ID No: 622)
Homo sapiens trafficking protein particle complex 2 (TRAPPC2) : gggtctcttccgcggaaactgacattgcgtttccgttgtcggcctcccactgcaggagccatatat tgaagaccatg (Seq ID No: 623)
Homo sapiens UDP-N-acetyl-alpha-D-galactosamine : polypeptide N-acet ylgalactosaminyltransferase 5 (GalNAc-T5) (GALNT5) :
ccaccttttcttgggcttgtaggaaggtggacatgggctcccggagacaagacaagtgatatgttg aactgttcggtggctggaatcaactgctcctggagtgacctaaggccagtgtttatcagaacttag ccagggccagccaagcaggcacagatgctctgctatgaaatgccacgcaggcagagactgacaagc ggtaggaactgagctttccccttggactgctgcttcctgctgtgttcaggggagggggtcactttc tggcaactctgctgctgctgctgctgctgctgctacttcagcttcctctccactcaaggtaagcag gctaagggagggcaggctgctagggaaagctttgtaccatg (Seq ID No: 624)
Homo sapiens transmembrane protein 97 (TMEM97) : tggcccctcttctca- catcagcgggtccaggcccaaccgacagactatg (Seq ID No: 625)
Homo sapiens EH-domain containing 2 (EHD2) :
cgtcctccccgctccgggccccacccggctcagacggctccggacgggaccgcgagcacaggccgc tccgcgggcgcttcggatcctcgcgggaccccaccctctcccagcctgcccagcccgctgcagccg ccagcgcgccccgtcggcagctctccatctgcacgtctctccgtgaaccccgtgagcggtgtgcag ccaccatg (Seq ID No: 626)
Homo sapiens tubulin tyrosine ligase-like family, member 4
(TTLL4) :
cgccctcttcttccagactctcggtctgtccgctgggggcgcgcgcggtgtgtggcaggcggcagc ggcgctggcggccgagtgcgcttgtcacgcgtggcggtgcgtggttgctaggggcgcctgaggctg ccgggtagcccagcaggccgagggaggaagtagcgtggagccggtgccgagccggggcgaagctgg atcccctagatagactgtcttcaagctcactgatattttcctctgcttgatccattgtgctgttga gagcctctagtaaatttttcagactgacagacttcaaggatgcagctgctactaccggaggtgtgt ggcaccttacctcagcaaggccatgagaccgtgtggccatgatgtgggcccctcatg
(Seq ID No: 627)
Homo sapiens basic leucine zipper and W2 domains 1 (BZWl) :
acctctccctcctcctggcgttagttccggtcgcagaggagacaccgccgcagttgccggtacatc ggggatttctggctctttcctcttcgccttaaattcgggtgtcttttatg
(Seq ID No: 628)
Homo sapiens centrosomal protein 57kDa (CEP57) :
ttgccctttctgtgtaagctgtgagcgtaggcggccctgagggggtgtgttgcaggggtttccaag cccagcaccagcacccttgcccttttccatcaggggttcagcctagggtccccgctggtgggcggc tcccgagtcttggagaagagcacgagaacctagaccgcccccgaagtgcggagaccccctgggcag gctgaaagatg (Seq ID No: 629) Homo sapiens family with sequence similarity 115, member A
(FAM115A) :
ctgccctttgcctcctgggcggagaagctgcttcctcctgggaacaaccgcctcccgctcctagca ggttgctactgccccgaacccgcgctgcagggaacagcggggcaaacagtgagtggggttcagcgt agactctggaccaggagaggcccgcggtgaccgaggcctgggccccggaaaccaatagagccatg (Seq ID No: 630)
Homo sapiens ATG13 autophagy related 13 homolog (S. cerevisiae) (ATG13) :
agccctctttcaccccccccccccggccattaccgaagcggatgaaaacaaacactaacgatggcg gcgccgggaagcgaccggctgctgggcttaaggcgggagtgaccgcttaaccagtgagggaagcac tgaagagcgccagtcgacgtgggtgcgacaactcgcggagtcttaggagcaaaacgtctggggcct gcgagccaggacccttctgaagccttaggtgtctatcggcgacgtgtacggtcactgcagctccgg agcgcggaaccctcagccaggaggcgcggctggtcggtcccaggtcccggcctccgtaatgagagc ccggaaccactctttgtgccgcagcttcgcagcatcttggactcaagtgattctcctgcctcagcc tcctgagtagctgggactacagattcctataggcaatg (Seq ID No: 631)
Homo sapiens sorting nexin 17 (SNX17) :
ccgccttcccacatcggatcgcagggctcccaaaatggcgagtgaggctgcggggactcgctgagc agcggagggggagcgtgcagagccgctgcggccctcacagtccggagcccggccgtgccgtgccgt agggaacatg (Seq ID No: 632)
Homo sapiens phytanoyl-CoA 2-hydroxylase interacting protein (PHY- HIP) :
cgttctttctcccttctctgcctctctctcctccacgctgctttgatttcgctcttgcctctcttc ttgcgctgctcagctgggaacatcgtctcaccaggggcagcagcgacgcgctgcacagccagacag gagctggctgcggggcatggaagcagcctccttggcagccgggagaggagcaagcgcacgccactg cccgtgacccaggcgtccggctgctgtcccctgccggggagctcatccacgcagaggtctctccct gtcctccctgcgagcttttcctctgcagagcccagtggagccagtccccacaggagacaaccctga cgggagcatg (Seq ID No: 633)
Homo sapiens translocase of outer mitochondrial membrane 20 homolo g (yeast) (TOMM20) :
cggcctttctgtgttcctggcccgcggccgtcgggtgtgagctgcgccgaccgctctgagggttcg tggcccaccgctccttcgcggtccctgccgccaccgtccacgctcagcgttgtagagaagatg (Seq ID No: 634)
Homo sapiens KIAA0141 (KIAA0141) :
cggcctttctagccgctgtcccaagggttggtctcgcgctttcggctgcgagctctctgtggtgct ggcagcgacatg (Seq ID No: 635)
Homo sapiens janus kinase and microtubule interacting protein 2 (JAKMIP2) :
ctccctcctttaaacagcttctccgggtctcagcatgggcttccagggcagcgattgaggagacct taccaaggagcaccacacagtagatgctgagacatcgtactccaggataagaaacagtaacatggc agcacctgcttgaaagaaattaaaaaccaacagactccatttagaaaggaacaatg
(Seq ID No: 636)
Homo sapiens EPM2A (laforin) interacting protein 1 (EPM2AIP1): cctcctctccccttgcggcctttctaacgttggccctgctcttgtggcctcccgcagaatg (Seq ID No: 637)
Homo sapiens centrosomal protein 170kDa (CEP170) :
cggtctttgccgttaccgctatgtgtggggcgtgtgtggaataacgttattgcccagcggagctga gggccccggagctcgaccgcagcggcagcgacgacaacagcggcgacgacgacgacgacgaggtgg ggggaggacggcgtgcgagagactcacgggacgcgacgcgccccgcctcccccgtccggtccctct ctccacggtaaggggatgacgtagctttgccaaagacttagaagctaagcagaaaatg
(Seq ID No: 638)
Homo sapiens suppressor of Ty 7 (S. cerevisiae) -like (SUPT7L) : aggcctctcgaggtccagacagccgcccagcccgctctgcgacgcagcagtgaatagtgtggtacc tccttgtctcggttcaggtccagacctccccgtcttccggctgccctgaacgtcaggcgacctcag gaccctgtgattggcgcctgcgccggcggaccgtgaccgaggaaacccctggagggacttgggcat tccttgggctccgtgcctgttcttcgtgctcctttcgggcaaggatctcacattatcagtctttga ccgacacagaatgcctggcatttgataaatgtttgttgaacttgaagagacatatggacaatg (Seq ID No: 639)
Homo sapiens non-SMC condensin I complex, subunit D2 (NCAPD2): ttttccttttcatttcagcctgactgccggaatcagagccgcgggtgagatccccagccctgtgag cctgtaggagtagaatg (Seq ID No: 640)
Homo sapiens ring finger protein 10 (RNF10) :
ggttctttgagatgctgtttggcgactcgtcgccattcccggagcaggtcggcctcggcccagggg cgagtatccgttgctgtgtcggagacactagtccccgacaccgagacagccagccctctcccctgc ctcgcggcgggagagcgtgtccggccggccggccggcggggctcgcgcaacctccctcgcctcccc ttcccccgcagcctccgccccgccaggcccggcccggactcccgagccccggcctcctcgtcctcg gtcgccgctgccgccgggcttaacagccccgtccgccgcttctcttcctagtttgagaagccaagg aaggaaacagggaaaaatgtcgccatgaaggccgagaaccgctgccgccgccgacccccgccggcc ctgaacgccatgagcctgggtccccgccgcgcccgctccgctccgactgccgtcgccgccgaggcc cccgttgatg (Seq ID No: 641)
Homo sapiens PAN2 poly (A) specific ribonuclease subunit homolog (S. cerevisiae) (PAN2) :
agcccttcttgattggaagaagcgcctcggaccccggtccttggcgccgtagtggttaggttgagc cctaggcgtgggggagaactggggaaactggaatttcccgcggagctgacagcgcttgcgctcccc ctactcgttctaattccacgcgctccaaaatatccgccatggagaaatcttggccaggatgtccat tctaggcccatcggtgctgtcttgctgaaggttgggtcaggcatctaaagggactgtggtaaggga gggtgtgacacaggtgtaagctgccatcgtcatcatg (Seq ID No: 642)
Homo sapiens CD302 molecule (CD302) :
gctcctctccggccgcgcagccgctgccgcccacccgcacccgccgtcatg
(Seq ID No: 643)
Homo sapiens NSA2 ribosome biogenesis homolog (S. cerevisiae) (NSA2) :
gactctttcctgtcccggcctgcgtggtgtgggcttgtgggtctttgagacccgaaaattgagagc gttttcgcactccagcggctgctcctggcggctctgcggccgtcaccatg
(Seq ID No: 644)
Homo sapiens DIS3 mitotic control homolog (S. cerevisiae) (DIS3) : acgccttttgctggaagagcgctgctggggttaggattctgcgcggcgaggcaagatg
(Seq ID No: 645)
Homo sapiens caspase recruitment domain family, member 8 (CARD8) : cctcctctgcgagcgttatttcaaaagaagttgagaaccagagaaaccgacctaaggggattctcc catttggcccgtcctaccctaaagtcaccacctgctgcttttctggagcgcttaccagtgaccaag aggaacagaacacagagcagcctggcagtgtccaagcaacaagcctccgctcctccttcctgcacc ctggggctcctgaaactcacatgggtaaaaaagatacagtaaagacataaataccacatttgacaa atg (Seq ID No: 646)
Homo sapiens epsin 2 (EPN2) :
ccgcctctcgagcgctgccggtggccgcagcggcgcacccacgccggcccggaggagcagagtgtt catttctgtgtcgggcacagtgctaagtgctgggtgctcactggtgatgaggcagatgaaggttac caaacttgtggacaggagcctcatatcagagacgtggacctcactgtagcctggtcatggcttcca gcttttcgaatctgaggctccaaaggaggaaatgaccattcagggatcttactccagcttgattac ggagactgaaccttcatagggtgcgcacttaccaaggacaggaaggtttctctgtttgaagggctt taaacttataacaaagaaaataaaaatg (Seq ID No: 647)
Homo sapiens pyridoxal-dependent decarboxylase domain containing 1 (PDXDC1) :
ccgcctctcaaccatcaggttcggcagcccgcggcgccgcctggcagctcctcctcttctccgccc cgccggccgcgggcgcgggggacgtcagcgctgccagcgtggaaggagctgcggggcgcgggagga ggaagtagagcccgggaccgccaggccaccaccggccgcctcagccatg (Seq ID No: 648) Homo sapiens nicotinamide nucleotide adenylyltransferase 2
(NMNAT2) :
ccttcctttctccctctgcagacacaacgagacacaaaaagagaggcaacccctagaccaccgcga aggacccatctgcaccatg (Seq ID No: 649)
Homo sapiens mitochondrial ribosomal protein S27 (MRPS27) :
tgttccttttggtacgctccaagatg (Seq ID No: 650)
Homo sapiens leucine-rich repeats and calponin homology
(CH) domain containing 1 (LRCH1) :
tcccctecttccagcgcctttcggtggagcactgcggcactcagcccgagctgccgttttcccctc gcggggaacgctgtgacccccccgcaggagcggcggggcggggtgggggggcccgggagaagatg (Seq ID No: 651)
Homo sapiens PAS domain containing serine/threonine kinase (PASK) : gctcctttccgtggtgtgtagccggcttggcgtgaccctcgcctgatccagttgttagagttggaa gcttggcagttggcctcccttcttcccatg (Seq ID No: 652)
Homo sapiens megalencephalic leukoencephalopathy with subcortical cysts 1 (MLC1) :
cttcctttcctagttgggttctgacagctccgaggcagtggtttacacaaccaacacgaaacattt ctacgatccacccgattcctcccctcattgatattcaggaagcagctctccttcccctgccttcag ctcaagtttgctgagcttttgtttcatttgtgaatacttcttgctggaagtccctcacccagagac cagtgctcccaacggcagagcagcgggggagataaagaactggtgacacgtggctgtacattcagc acagctgtggtgtccccaagtgccatg (Seq ID No: 653)
Homo sapiens RRS1 ribosome biogenesis regulator homolog
(S. cerevisiae) (RRS1) :
ctttcttttccggattgggcatcccggcatctgcacgtggttatgctgccggagtttgggccgcca ctgtaggaaaagtaacttcagctgcagccccaaagcgagtgagccgagccggagccatg
(Seq ID No: 654)
Homo sapiens formin binding protein 4 (FNBP4) :
cgctctctgctcgcgcttgggctcgcgatg (Seq ID No: 655)
Homo sapiens peptidylprolyl isomerase domain and WD repeat contain ing 1 (PPWD1) : gcgccttttctgacgatgcgaacaacatg (Seq ID No: 656) Homo sapiens sorting and assembly machinery component 50 homolog (S. cerevisiae) (SAMM50) :
ccgccttctgccctcagcagcagacgctctgtcccgcccgggcagctctgcgaggcagcggctgga gagggaaccatg (Seq ID No: 657)
Homo sapiens Yipl domain family, member 3 (YIPF3) :
gcttctcctttttgtgttccggccgatcccacctctcctcgaccctggacgtctaccttccggagg cccacatcttgcccactccgcgcgcggggctagcgcgggtttcagcgacgggagccctcaagggac atg (Seq ID No: 658)
Homo sapiens tectonin beta-propeller repeat containing 1 (TECPRl) : caccctcttgcccggtccccgggagggccggtccgctcctcccggacgccgaggacctaccaccgc gacttcgccccgcccggcgcgggcccaggaccctgatgtcgcttttgaacagcccctgcacctggc agccagcgagctactgtagtaggcattgccgactgtttgcataccggatgggagtgacagtgtaat agaaaaacaagcaagaaaccttttaggtaggactcctaaggctcagaggaagttacctccagccgc tgccatg (Seq ID No: 659)
Homo sapiens DDB1 and CUL4 associated factor 12 (DCAF12) :
ccttccctttcccggctcaagtccttcctctctctttcctttctttccgcctatcttttttctgct gccgctccgggtccgggccattttccgggccgggcgcactaaggtgcgcggccccggggcccagta tatgacccgccgtcctgctatccttcgcttcccccgccccatgtggctgcggggccgcggcggcgc tgcccactatg (Seq ID No: 660)
Homo sapiens chromosome 3 open reading frame 17 (C3orfl7) :
ccgcctttcgtaagtccccccgcctcgcatg (Seq ID No: 661)
Homo sapiens LETM1 domain containing 1 (LETMD1) :
caacctcttctctcccgcttctctcgctgtgaagatg (Seq ID No: 662)
Homo sapiens chordin-like 2 (CHRDL2) :
ctcccttctgctggaccttccttcgtctctccatctctccctcctttccccgcgttctctttccac ctttctcttcttcccaccttagacctcccttcctgccctcctttcctgcccaccgctgcttcctgg cccttctccgaccccgctctagcagcagacctcctggggtctgtgggttgatctgtggcccctgtg cctccgtgtccttttcgtctcccttcctcccgactccgctcccggaccagcggcctgaccctgggg aaaggatg (Seq ID No: 663)
Homo sapiens CCR4-NOT transcription complex, subunit 10 (CNOT10) : actcctctagccggaacctgggggcccggagccggggtaggcacagagttgtcctcggaggtccag gacagcggccagcccggcggcgggagtcagggccacgccacctgcagggaagaacccgagtcgaag cgggaagatg (Seq ID No: 664)
Homo sapiens THUMP domain containing 3 (THUMPD3 ) :
cttcctcttgcagttgaggccggcgccgagccggacttcaggcggatctcgtggcggagcccatct tgctccctctcccaggcctttacccgctccctaggattcccgggccctgtaggtgggagttgggag acgacagtactgcttttaaagagacagtgttagggatcttggaagcacagccaacatg
(Seq ID No: 665)
Homo sapiens nipsnap homolog 3A (C. elegans) (NIPSNAP3A) :
gctcctttccactcgggaaaccttcagaggagtctcagaaaggacacggctggctgcttttctcag cgccgaagccgcgccatg (Seq ID No: 666)
Homo sapiens CAP-GLY domain containing linker protein 3 (CLIP3) : gcccctccctctccgcccccaccccctgtcggcgtctgggcctcgtccccttctctctgtctccct tgcctcccccatcacgtcccctgacaccgacaccccattgctcccacagtctccccagtctccact ttggtccccagcgctgtctgcccgaggatttgcctgaaggctgcccccaactctgcacccgccccc cgagggccaccgaggaccatg (Seq ID No: 667)
Homo sapiens ring finger protein 167 (RNF167) :
cacccttcccgaagtttttctgtcacctgtgttaggctccgtcccctttccgcgttttatccccgt accagaaaaggatacatttagtgcctcccacccagctccactaaacgggttggatatctcattctt tgagttggtgttccttccccggcgcccccatgtagctgggaagtgggacctgggggtggttggacc cctgggatcctaaaggaggggcagggagggcgcagaactccgcttctgctccttgctaccaggacg cgcggcctcctcagcctctttcctcccgctgccatg (Seq ID No: 668)
Homo sapiens polymerase (RNA) II (DNA directed) polypeptide M (POLR2M) :
cgttcttccgggaaaatggcgactcccgctcgtgccccggagtcaccgccgtccgcggatccggcg ctagtageggggcctgccgaggaagccgagtgcccgccgccgcgccagcctcagcccgcgcagaat g (Seq ID No: 669)
Homo sapiens dihydroxyacetone kinase 2 homolog (S. cerevisiae) (DAK) :
tcgcctctttccgccagcgcccgcaggacccggatgagagcgcacgcttcggggtctccgggaagt cgcggcgccttcggatgtggcggatgcggccgtgagccggcgggggaggtgctgctgctgcctcca ctgtactcagacccaggtagcacaggattgtccatcctccagcagctcagtgcaacggtgtgaact cagcctgtttcagagcctccacaccatg (Seq ID No: 670)
Homo sapiens RNA polymerase II associated protein 1 (RPAP1) :
cgatctctgcggggcaagatggcggcgcccagacaggcctggagcacggatgaataagagggaacc cccacacggagacactgctggagagagtcgtactggggaggcagctggagcagcaagatg (Seq ID No: 671)
Homo sapiens torsin A interacting protein 1 (TOR1AIP1) :
cctcctctttggtgcctccagccaggaggcgggagcgatccacagcagctgacccagctcaggcac tgcctctctcacagccctcaagacacaccatgggcccagaggcaggtttgctacacagcagcgacg acgcaggcggcggccccagcgactcgcaactgcctccctgaccacagcggccaccgcccaacaccc ccgagaagccatcgccaccaccggcaggagaacctagggtccataaagccatcttcgcgatcgact aaagctacgtcaacaactatg (Seq ID No: 672)
Homo sapiens SERPINE1 mRNA binding protein 1 (SERBPl) :
ccccctctctcggcccggccatcttgtgggaagagctgaagcaggcgctcttggctcggcgcggcc cgctgcaatccgtggaggaacgcgccgccgagccaccatcatg (Seq ID No: 673)
Homo sapiens N-acetyltransferase 9 (GCN5-related, putative)
(NAT9) : caccctttctgcgggggacgatttcgtcggtggtaggctgctaccatg
(Seq ID No: 674)
Homo sapiens ribosomal LI domain containing 1 (RSL1D1) :
gcgcctcttcacgaggtggaaacaagatg (Seq ID No: 675)
Homo sapiens SH3 domain containing, Ysc84-like 1 (S. cerevisiae) (SH3YL1 ) : cttcctcttcctgggcagcctcgggacggggcgccgcggccgggcgggcagcatg (Seq ID No: 676)
Homo sapiens methylmalonic aciduria (cobala- min deficiency) cblD type, with homocystinuria (MMADHC) :
acttcctttgcctgctcaccgccagcgtaggtgctaccaccgctgccgtcgccgccgccattttga tggcaggaagagtccggttctgggacagctggagacagtggtggtgactgaaataactttaccaaa ggaaagctattttgcgaactatcttctccagcggagatg (Seq ID No: 677)
Homo sapiens glioma tumor suppressor candidate region gene 2 (GLTSCR2) : agttcttcctttgacaagatg (Seq ID No: 678)
Homo sapiens DDB1 and CUL4 associated factor 8 (DCAF8) :
cagtcttctcgagcacatcgtcgcaaacggggccggaaagcgtggcagcgcaggcgcaagcgcaga gagcggaggcggtggtggtggcggccgctggccagttccttcagtgaatctacagacctattttct caggagctcagcctggccttacttcagtgataaaaggaggaaaggctggctacagcaaacatcatt caagatg (Seq ID No: 679)
Homo sapiens UBX domain protein 1 (UBXN1) :
ctttcttctcgtcggtgttcccggctgctatagagccgggtgagagagcgagcgcccgtcggcggg tgtcgagggcgggttgcctcgcgctgacccttcccgccctccttctcgtcacacaccaggtccccg cggaagccgcggtgtcggcgccatg (Seq ID No: 680)
Homo sapiens antizyme inhibitor 1 (AZIN1) :
ccgccttctcacactttcaggctctgatcgcggccgcagtttttccttttttcttctgccgtcgcc ttctctgcctcttctcatcctttctcgctctgctgctctgcagtgtgacgagtccgaatcctcttc ccacccagcccgcgcctttcttcttttgcctgcgctgttctatttctccttcggccgccgccgcca ctgctgcacacagctggtgtcggtgccgcgcttttacccccaagtcgttcccgcagcctatggccc aggccgccttgggtatttctgctcaaggtaaccacatccctctttaaaaattccgccgaaaaagag aagacgctttacccgactctttgggccgttatctcacggcgaactttctgaccaagtatacaacta cccagagggcctaggagaagtgctgtatagagagcagttcgacttcaacgctgagccaccttggga acctagctgatgataggggggttccatctcccaacttgtccatggaggtcttcacttcagaaatcc aagactcatattcatccagcttggtgtcaagtgggctgttgctgccagaattatcttgtgattatt tgagagatgtatcagtttcttctgaagtacaatcaactgtagaagcctttgtagcagtttgttgca tattctaaggacccagacataggcttggtggcccgtctcttgtctttcctggtttatgactttcgg ctttgtggaatacggctgagatg (Seq ID No: 681)
Homo sapiens cell division cycle 40 homolog (S. cerevisiae)
(CDC40) : gcctcttcttcttccgccctggcagggtctccgcagaagatttgttgccgtcatg (Seq ID No: 682)
Homo sapiens stathmin-like 3 (STMN3) :
gcgcctctccagcctccgcaggcccaaccgccgccagcaccatg (Seq ID No: 683)
Homo sapiens nudix (nucleoside diphosphate linked moiety X)-type motif 13 (NUDT13) :
tttcctcttttgtgctgattcctgaggactaggaaggtgccccgaaaagaattcagagacctgaca atg (Seq ID No: 684)
Homo sapiens calcium homeostasis modulator 2 (CALH 2) :
ctctcttttctggagttagattagtctgaagccgccaccagccccaggcccccgtgcagaagaaaa gcgggagggaacggcggaggccgccgctgccctgcaccgccctcctggaggccacttggagagtcc ggccccgaggaggccatggccacaagtgcccacagctggccccaggttgccagcgtcgctacagcc cagaccaaggcagaataatctccggatgagctggtggcaccgctgagcctttggtctcaccagggc ttcctgttgctggcaggcggggtggagcggagctgctgggaggctgctggataggagaggggtcac ggctgcggaagaggaggttcttcgggacacccgtggatggacacggcaaggaaacaccaggccaac cacagctggggataaaatagcacaaccacaccctgccgtccagcgcctcccagcctgtgccccttc ctagtaccaccagcaaccatcaatcccgtctcctcctgcctcctctcctgcaatccaccccgccac gactatcgccatg (Seq ID No: 685) Homo sapiens NMD3 homolog (S. cerevisiae) (NMD3) :
tcttctctgtggcggagacagccaggttggcagctgacgggacagccggggtctattttgttgcgg gttttcagcaaatccagggctggtctggaggcgcgaaaacttaaggcatacagaacgatg (Seq ID No: 686)
Homo sapiens ATPase, H+ transporting, lysosomal 50/57kDa, VI subun it H (ATP6V1H) :
gcgcctctgtcattctactgcggccgccctggcttccttctacctgtgcggccctcaacgtctcct tggtgcgggacccgcttcactttcggctcccggagtctccctccactgctcagacctctggacctg acaggagacgcctacttggctctgacgcggcgccccagcccggctgtgtccccggcgccccggacc accctccctgccggctttgggtgcgttgtggggtcccgaggattcgcgagatttgttgaaagacat tcaagattacgaagtttagatg (Seq ID No: 687)
Homo sapiens DPH5 homolog (S. cerevisiae) (DPH5) :
gggccttttctctgcacggagccggcgcttttgcagttgcttctgcggaaaggtggtagttaagaa tttgtaaaggccagagaactacctacgattctctcagcggtctctcttctcctcaagtttgaaatg (Seq ID No: 688)
Homo sapiens polymerase (RNA) I polypeptide D, 16kDa (POLR1D) : cctcctccctccttccgtcctccgcgccttccgtcggtcggtccttgcttcctgcttcgcctccgc gcctcgcgctatgggacagagcccccgatccgccagcaccacctgaggatccagaaaccgccccag cgatg (Seq ID No: 689)
Homo sapiens HMP19 protein (HMP19) :
ctgtcctttcagcaccacaagctcgggctgaggagggaggactcctggccgtcctcctoctettea aattggcttgaatcttctctgaccccccacgagtgcagcacagtctgggaagaaaggcgtaaggat g (Seq ID No: 690)
Homo sapiens adiponectin receptor 1 (ADIPOR1) :
gcgccccttccggcgcggggagggcgctgaagatcggggccgctcggccgcaggccgcctccagcg ccgcgggatgtagcgcgggggaccgcggcccccagcagagcccgcctgcccggcttgtctaccatc agagggagatctctgccccctggggctgagagaccccaacctttccccaagctgaagctgcagggt attgaggtaccagccagatg (Seq ID No: 691)
Homo sapiens SH3-domain GRB2-like endophilin Bl (SH3GLB1) :
ttttcccttgggacccgggtccacacggcggggtcgcccgtccatctccggctcgcccgcggggcc catcgtcgacgttagcggccgttctccgagccgactgacccatccttggcgctgccgccgcgcgct tgttctcctccctcgccccgccttcatcctccccgttcacggaaacgacagctgcggctgcggggc tggcgccgcctccctccacctaccacgtctgccctcgccgctctagccctgcgccccagcccggcc gcggcacctccgcctcgccgccgctaggtcggccggctccgcccggctgccgcctaggatg (Seq ID No: 692)
Homo sapiens anterior pharynx defective 1 homolog A (C. elegans) (APH1A) :
gtcccctcttcggcttccgtagaggaagtggcgcggaccttcatttggggtttcggttccccccct tccccttccccggggtctgggggtgacattgcaccgcgcccctcgtggggtcgcgttgccacccca cgcggactccccagctggcgcgcccctcccatttgcctgtcctggtcaggcccccaccccccttcc cacctgaccagccatg (Seq ID No: 693)
Homo sapiens RNA binding motif protein, X-linked 2 (RBMX2) :
ctgcctttcccgggcgctgattcctgagtgctgagcgcgaacccgaggagatg
(Seq ID No: 694) Homo sapiens family with sequence similarity 82, member B
(FAM82B) :
atctcctttagccccgcccgcctccgtagctgcctgaagtagtgcagggtcagcccgcaagttgca ggtcatg (Seq ID No: 695)
Homo sapiens UTPll-like, U3 small nucleolar ribonucleoprotein, (yeast) (UTP11L) : tgatcttttccaaggctgtacagacatg (Seq ID No: 696)
Homo sapiens chromosome 14 open reading frame 166 (C14orfl66) : cgccctctcgccgcgtcgccggtgcctgcgcctcccgctccacctcgcttcttctctcccggccga ggcccgggggaccagagcgagaagcggggaccatg (Seq ID No: 697)
Homo sapiens transmembrane emp24 protein transport domain containi ng 5 (TMED5) :
gcttctctttcggagggagtgttcgccgccgccgcggccgccacctggagtttcttcagactccag atttccctgtcaaccacgaggagtccagagaggaaacgcggagcggagacaacagtacctgacgcc tctttcagcccgggatcgccccagcagggatg (Seq ID No: 698)
Homo sapiens coatomer protein complex, subunit zeta 1 (COPZl) : gtttcttttgcggctccacgtcggcaccagctgcggggcaagat (Seq ID No: 699)
Homo sapiens mitochondrial ribosomal protein S16 (MRPS16) :
ggttctttctgtgtttgttctctgccctgccaaggccgtagagctggtgcgtgcgggtagcggggc tctccgaggagccgcacgccggcggcaccatg (Seq ID No: 700)
Homo sapiens charged multivesicular body protein 3 (CHMP3) :
ctacctccttttccgcgggccccgcccaggcggctgcccgtgacctgcctgggcgcggggaactga aagccggaaggggcaagacgggttcagttcgtcatggggctgtttggaaagacccaggagaagccg cccaaagaactgatatccaaagagaagaagaaaaagtgaaacgatctgtgaaagatgctgccaaga agggccagaaggatgtctgcatagttctggccaaggagatg (Seq ID No: 701)
Homo sapiens RNA binding motif protein 7 (RBM7) :
cgaccttttggccaggttagggagggggcgacgctgagatg (Seq ID No: 702)
Homo sapiens eukaryotic translation initiation factor 3, subunit L (EIF3L) : cgctctttccggcggtgctcgcaagcgaggcagccatg (Seq ID No: 703)
Homo sapiens zinc finger protein 706 (ZNF706) :
ccttcctttccctccggcgtcctctcccggccctctcgcgctgcactgtctctccgacgcaagact gtcccggcccggatatg (Seq ID No: 704)
Homo sapiens androgen-induced 1 (AIG1) :
cgccctccttgccgcccagccggtccaggcctctggcgaacatg (Seq ID No: 705)
Homo sapiens interleukin-1 receptor-associated kinase 4 (IRAK4) : cgccccttcgcggcgcttcctagttcggctggttcttctgtcgccggcttcagcagcccgcgcccg ggcaggaatagaagatg (Seq ID No: 706)
Homo sapiens transmembrane protein 66 (TMEM66) :
cgttccttcgccgccgccaggggtagcggtgtagctgcgcagcgtcgcgcgcgctaccgcacccag gttcggcccgtaggcgtctggcagcccggcgccatcttcatcgagcgccatg
(Seq ID No: 707)
Homo sapiens carboxypeptidase Q (CPQ) :
ccgcctctcggccccgcggcctggccggcaagcagggctgcagtcacggggcggcgcggagggccc cagcccagtcaggggtgtggccgccgccaccgtaaggctaggccgcgagcttagtcctgggagccg cctccgtcgccgccgtcagagccgccctatcagattatcttaacaagaaaaccaactggaaaaaaa aatg (Seq ID No: 708)
Homo sapiens hydroxysteroid (17-beta) dehydrogenase 12 (HSD17B12) : cgctcttttcattcacgaaggtagtgaggcctagtggaaagccatg (Seq ID No: 709)
Homo sapiens protein phosphatase methylesterase 1 (PPME1) :
cctcccctcgatg (Seq ID No: 710)
Homo sapiens HemK methyltransferase family member 1 (HEMK1) :
ccccctttccggcaggctactgggctccgcccacacacctcccggcctggttcctaaacgccagct cggagcaatccccttgggctggagccaaatccctgctgtgattttaaggaagaccggcaggtccgg gcccccaagggtcaaccccacacacatccccgcactttcctgtatgcaggcctgcgagcgtagagg gagtggaattcacagcctccccacccatccgcaggggtctcctgggaggaacccaccagcgatagg aacactgaagctgggctacggcgtccgcccgagccttttcttaaaggcgccgaccccggaagcggg gcgtccgagggagcgcgcgacgggccacgcacgtccgggcgtccagttcggggcagcttctccggc tggtgggtgggtggggcagcctttcaggcagggtggcaaccaactatatctgaggaccagagccat tttggggcaccagagcttgtgacctctccatctccacccagctgggtccaggggccactctcagca ctcacctcagcagctgacatcataaagcagacttgggaacctggaagcactctggagaacctttcc ctgagacatg (Seq ID No: 711)
Homo sapiens N (alpha) -acetyltransferase 38, NatC auxiliary subunit (NAA38) :
cgccctttcagttctgcttgctgtcggcaccgctgcgttacccggaaccgccgggccgaacagcat g (Seq ID No: 712)
Homo sapiens cleavage and polyadenylation specific factor 3, 73kDa (CPSF3) :
ggttcttccttttttatttaccggtggctgtgcttccaatttaggaagaccccggcgacctgttcc tcacccccgcttcgccctcacactttcgggatg (Seq ID No: 713)
Homo sapiens dynactin 4 (p62) (DCTN4) : tcgcctcctccctccccaagatg (Seq ID No: 714)
Homo sapiens hydroxysteroid (17-beta) dehydrogenase 11 (HSD17B11) : gttcctccttgctctcgcccctactctttctggtgttagatcgagctaccctctaaaagcagttta gagtggtaaaaaaaaaaaaaaacacaccaaacgctcgcagccacaaaagggatg
(Seq ID No: 715)
Homo sapiens YTH domain family, member 2 (YTHDF2) :
tagtctttccaggtgttagtcgaaacctcgtggtgcgaccctggtcgtcccaaaccccctaggcct taatcctggggcggtgggggcggggaggccgtgagcacggcttccgctcctccaatccgccagagg gcgcagcggccggcctctcccttcccggggttcttcgcgccgggccccttccgcgtgggtgagtga atgtgagagtcagcgctcgcgccgcgcgcgccgcccgcctccgctgttcggcgctctgctttaggc ggtggggggcgggcgcgcgcgtaaaagcatagagacgggcattgagctcttgggctagagcgtcgc cgagtcggagccggagcctgagccgcgcgctgtgtctccgctgcgtccgccgaggcccccgagtgt cagggacaaaagcctccgcctgctcccgcagccggggctcatctgccgccgccgccgcgctgagga gagttcgccgccgtcgccgcccgtgaggatctgagagccatg (Seq ID No: 716)
Homo sapiens tubulin, epsilon 1 (TUBEl) :
agctctctagcagagcgccgttgctgggggaatgcagaagcggccgcgggctagcaagctcccgga gccggcggcgcaccaccatg (Seq ID No: 717) Homo sapiens ubiquitin interaction motif containing 1 (UIMC1) : cctccttttcttcctcagcgggtccgcggcccgctactctccgggaggggcgcttcccgacgccaa ggtaggcctctcccgacgccggggcggcccttcctgatgccggggtgtgtctctcgcgacgcgggg gtgggctccggacgccggggctggccttgccgaagtcgggggtgggtccctccggacgccgaagtg ggctcgggatgcggggctgggaccctcccgattccggggcggattccggacgccgggaccggccat tactggtgccgggttgggcttctccagatgccggggctgggtccttcccaaggttgagacaaaagg atg (Seq ID No: 718)
Homo sapiens TNF receptor-associated protein 1 (TRAP1) :
ccgccccttcccatcgtgtacggtcccgcgtggctgcgcgcggcgctctgggagtacgacatg (Seq ID No: 719)
Homo sapiens cereblon (CRBN) : cagcctcctttgcgggtaaacagacatg
(Seq ID No: 720)
Homo sapiens ribosomal L24 domain containing 1 (RSL24D1) :
cttcctctcaagcttggcgtttgtttggtggggttacacgcgggttcaacatg
(Seq ID No: 721)
Homo sapiens leucine carboxyl methyltransferase 1 (LCMT1) :
taccctcttctgttgctttctccctgtggctcgcgccgtcccccgccgcccgtcgaccccgcttcc atgtccctggcggacacagctcccaggaacctccacgcccatggccactaggcagagggaatcctc tatcacctcctgctgttccacctcgagctgcgacgcagacgacgagggcgtgcgcggcacctgcga agatg (Seq ID No: 722)
Homo sapiens RAB14, member RAS oncogene family (RAB14) :
cccccttcttttgtggtccggcccattgcgagggtgacaggaaaccctgtgcagggagcgccgcca tcttggaccagcccgaggaagatactgagggagcacaggagcagtcaccgctgccactgctactgc cgctactgctgccggcgcgtctgcacctctcggcctgccagtgtacctgccggcgcctcggtcgac cgcccccgccccctctcccgctgcgtccgcactcctgttcctggtcctgacgcccccctcccgccc ggaaagctgcccagccaccagcaaccccccagtgccaccatg (Seq ID No: 723)
Homo sapiens Enah/Vasp-like (EVL) :
cttccttttcctgtttggttttaagtaggctataaaaatcaagttgctgtcttcagagggtctgtg gtcctctgatcaacataggctggtgggagtacaggactcgcctcctcagggttccctgtgctgcca cttttcagccatg (Seq ID No: 724)
Homo sapiens LI domain and actin binding 1 (LIMA1) :
ctctcttcccctctccctctccctctgccgggtggatgctttctccatgtggcaaggctgtaactg ttcacagctgtctgaaacagcagtggaccaggagcagcttggagttttaactttcattttacaaag aacaacatgtttgaatgtttcagcaggcaagttataactggcatctacttcttgttcttctagaac accgaaaatctctcccagcactttagaaaggggaccctgactgtgttaaagaagaagtgggagaac ccagggctgggagcagagtctcacacagactctctacggaacagcagcactgagattaggcacaga gcagaccatcctcctgctgaagtgacaagccacgctgcttctggagccaaagctgaccaagaagaa caaatccaccccagatctagactcaggtcacctcctgaagccctcgttcagggtcgatatccccac atcaaggacggtgaggatcttaaagaccactcaacagaaagtaaaaaaatg
(Seq ID No: 725)
Homo sapiens ubiquitin-fold modifier conjugating enzyme 1 (UFC1) : gtttctcttgcgccctggtccaagatg (Seq ID No: 726)
Homo sapiens coatomer protein complex, subunit beta 1 (COPB1) : cacccccttccacgtcagccaaggactctggagccgccgccgccgctgctgcggttcatagccgga gtagacggagccgcagtagacggatccgcggctgcaccaaaccactgcccctcggagcctggtagt gggccacaagcccccagtcccagaggcgtggtgggtcgggcagagtcggaagaactggctttctag ctggaagatgcggaaggggagcgactaggccgcttgcgtctgggcctggcagaagggaccggattt tctggcatccttaaatcttgtgtcaaggattggttataatataaccagaaaccatg
(Seq ID No: 727)
Homo sapiens transmembrane protein 9 (T EM9) :
gggtcttttgcggctgcagcgggcttgtaggtgtccggctttgctggcccagcaagcctgataagc atg (Seq ID No: 728)
Homo sapiens shisa homolog 5 (Xenopus laevis) (SHISA5) :
ctttctttttctccaaaaggggaggaaattgaaactgagtggcccacgatgggaagaggggaagcc caggggtacaggaggcctctgggtgaaggcagaggctaacatg (Seq ID No: 729)
Homo sapiens transmembrane protein 69 (TME 69) :
gtgcctttccagtggacctgggctgttgttgcggttgttttccttctctccgtgcaacgctggcaa gtctcaaagtcgccacagaaacatgcccctgattcagtgcctctgcttagctgtaacatgttaatc agaactacctggcatcttcctgaacaagactttcaataggggccagtatg
(Seq ID No: 730)
Homo sapiens kelch repeat and BTB (POZ) domain containing 4
(KBTBD4 ) : agatcttcttccgggcggacgtggagccggaagcggaggttccgggctccgggatg (Seq ID No: 731)
Homo sapiens pipecolic acid oxidase (PIPOX) :
cgtcctttagccgggagcctgtctttgcttgcctttgcctttgaggctctgtggctgtggggctga gtggcatcatg (Seq ID No: 732)
Homo sapiens blocked early in transport 1 homolog
(S. cerevisiae) -like (BET1L) :
agctctttccccgcgactgcgccacgtctgaggcggctgtggccgcgtcggtgtccgcgtcgagga gccggggcagggcacgatg (Seq ID No: 733)
Homo sapiens zinc finger protein 581 (ZNF581) :
ttctctctttcggccggcgccgccagttcctggggcacacccagaggtccccttctcgccgccgcc tgcaactgcgagggtagcccggggccgcttggagtcgcccggacctgagaggctgctgcactgggc ctcagccagccctccggatg (Seq ID No: 734)
Homo sapiens armadillo repeat containing, X-linked 1 (ARMCX1) : cgtccttctaatcctagtcttcgtttggtccggttgcactcttcctatagcccagagggcgagagg gcctgtggcctgggggaaggaggacgaggttctgcctggatcccagcagtaggacgctgtgccatt tgggaacaaaggaatagtctgcctggaatccctgcagatcttggggccggaggccagtccaaccct tggagcaggaagaaacgcaaagttgtcaagaaccaagtcgagctgcctcagagccggcccgcagta gctgcagactccgcccgcgacgtgtgcgcgcttctctgggccagagcgagcctgttttgtgctcgg gttaagagatttgtcccagctataccatg (Seq ID No: 735)
Homo sapiens spastic paraplegia 21 (autosomal recessive, Mast syndrome) (SPG21) :
cggcctcccgcacgcaccgcgcagcctgctgtgcccgtgggtcccgagtgctccgccgcccgcccc gacccgggcccagccgcctccacggcccgcgctcgtactggagcgaagagcggcctcctgaaggag gggaagggacgtgggggcggccacggcaggattaacctccatttcagctaatcatg
(Seq ID No: 736)
Homo sapiens . staufen, RNA binding protein, homolog 1 (Drosophila) (STAU1) : tctcccttttttccttcttccttcccctcctcgccgccaccgcccaggaccgccggccgggggacg agctcggagcagcagccagagtttattaaccacttaacctctcagaactgaacaaagacaacattg ttcctggaacgccctctttttaaaaaagaaagcataacccctactgtagaactaaatgcactgtgc atg (Seq ID No: 737)
Homo sapiens adducin 2 (beta) (ADD2) :
cggccttttgtcagcgcgcagggccaggagagctctcatttcctcccagcctcgtgcgggaaatgg ctttaattctgacggcagggctgtgagggactagcgggaacccgagccttttgtcaaggaactgcg gcgtcggtggccagtcatccccgccgccgcggagccgctgcactgctgggggatctcccagcagct ctgacgagcgcgggctgcagcatgggcagaaaacgctgccctgcagattagctgggtggatttttt aagcgcaccccaccccccaaacccataaaataacaaaaccaacccgcagtggccgaccggagatag ctaagatgccgcgcaggagtttccacctggatgtttgaggttgtgtagatgtggccggcacccttg agagtggagctagggggtgcagactgagcagtgaacagaaggagccttggacagggctgggccagc ctcccgagttccaggagcgaattgcaaacccaccgggaaaatg (Seq ID No: 738)
Homo sapiens WD repeat domain 1 (WDR1) :
ccgccttccggctccagtccccgggctcggcctcggcgaggtgtaattcgcagcgcgggccggccc cggaggctctcggcgagcgcggcgcggtaacaagtgggcgaggatg (Seq ID No: 739)
Homo sapiens family with sequence similarity 20, member A
(FAM20A) :
cgacctctacttccacctctggccccaagtacagcgccagctgcggcctcgggagcgcccgcgggg gtgcccgtgcaccggccgcgcctcctccctggcgcgggactcggccgcagctgcctcggaccccgg cacgatcgtgcacaacttttcccgaaccgagccccggactgaaccggctggcggcagccacagcgg gtcgagctccaagttgcaggccctcttcgcccacccgctgtacaacgtcccggaggagccgcctct cctgggagccgaggactcgctcctggccagccaggaggcgctgcggtattaccggaggaaggtggc ccgctggaacaggcctcagttcctgcttttgaaaggaagagggggagtctgtgacccctgaggcct ccttgcaactctgttttccaagctttgcacatcttccgaatttcttcttcaaagtctaccctaatg aaatatcagacaattttccaagtgtgcttcatgaacttctgggaggtgcttcacagtttctgcaaa tgattgattgaattttcactttgaaaaaatatactttaaggcgacacaagatg
(Seq ID No: 740)
Homo sapiens kelch domain containing 4 (KLHDC4):
ttttctttcctggtgtcccgtcgcggcttgggacccggcaagatg (Seq ID No: 741)
Homo sapiens calcium channel flower domain containing 1 (CACFD1) : tgctccctctcccacaaggcagcgcgccggctcggacgcggccggctaccgagccctttgtgaggg ctgtgagctgcgcctgacggtggcaccatg (Seq ID No: 742)
Homo sapiens zinc finger, CCHC domain containing 8 (ZCCHC8) :
gaatcttttccacagcccaaaatg (Seq ID No: 743)
Homo sapiens kelch-like 24 (Drosophila) (KLHL24) :
gtttcctttgttgtgagctgcggcagagactggtggctggaggagacgccggcgctggagagtgcg ctgcgccgcccgccgctgagggaccgcggggttagccactgctggctgcttccagtgttcgccgag aggtaccgggggtgacagctccgggaccggccgaaaggcgaggaaccggtgtggaaattaaaagaa cacacatattttgactggggctttgatcaaccaaatgctaaaaagccacataaagaagatccctaa tagtcatttctcaacaattatatagtcaactgatgtaacaatg (Seq ID No: 744)
Homo sapiens FtsJ homolog 3 (E. coli) (FTSJ3) : ctccccctttccaccatg (Seq ID No: 745)
Homo sapiens dymeclin (DYM) :
gcttccctcttctctcgccgcctcctggcctccgcaccgacgcggcccgggctggagccgagccgg ggccgagctgcaggccggaccggagccggatctgtacccgctgagacgtggaaacatggaggcctg agccggtgtgcgccacctgggctgcggcggcgacagcgacttctcctgacccctctgccaccctcc catccgtccgcgggtccgtggagctggagcagatcccccagccggctgagacaggttgtcttttgg aaatgcaggtttaaggacaaattatctgcttaagctagaagatg (Seq ID No: 746) Homo sapiens zinc finger protein 280D (ZNF280D) :
cctcctctttctcctcctcctcagggctccagtcaggccgatccgctccgctcacggaaggaaaac agaaataacttgctggcttgtctggagtcacatgtacttaggtgacaatttacagaaagtcatctc tgcagcttgatg (Seq ID No: 747)
Homo sapiens ankyrin repeat domain 10 (ANKRD10) :
cgttcctttgtgctgcggcggcggcttctcgagtcctccccgacgcgtcctctaggccagcgagcc ccgcgctctccggtgacggaccatg (Seq ID No: 748)
Homo sapiens SWT1 RNA endoribonuclease homolog (S. cerevisiae) (SWT1) :
ctctcctttggcttggggctccggagttgccactgccgccggcgctggtaagcttttcaggatg (Seq ID No: 749)
Homo sapiens leucine rich repeat containing 49 (LRRC49) :
tgacctctttcgggtctctttgaatctccgctgtagcgtcacctggaaggcagatctaacagagaa cctggactgtctcctatcatg (Seq ID No: 750)
Homo sapiens F-box and leucine-rich repeat protein 12 (FBXL12) : ccgccttctggacttggtcttagttcccagtcgcggccaaatcacgcctcagccacctcccgcaag cctctcactgcctcagccacgctttccaggctggtttctggtccccatccgcggctggtccggccc tgggaccgaatcacttcccagcgagaggaaggtcaaatttctcgaccggctacgggaaggtcgcgg ccgccgccctgtcagccgcctcggcgcccccaggacccctcgggtctctttaaccggaagcggaag tgcgtgtcggcgggatcatg (Seq ID No: 751)
Homo sapiens WD repeat domain 55 (WDR55) : cagtccttctcagcatg
(Seq ID No: 752)
Homo sapiens zinc finger protein 3 (ZNF3) :
cgttctttgttctgtccccggtgtgtgggtctgtgacagggtccaacagggcctggtccgtgtccg gtcccccaaatctgtcgtccctgcccccaggcattggcatcaacaaaagtcagaattcccgggaac ttgaacagaggctgctaaattcccagtaattgctcctttggccttctagggactgacttcaaagaa ggaaggaaagaatcaggcagtgcttcctcattctcttttaaaacccgcttcccgctgagtctgcac ccaggagaccagagagcaccttgcccttccatg (Seq ID No: 753)
Homo sapiens tetratricopeptide repeat domain 27 (TTC27) :
ggttcttctcctaggcggaagccagaccagagagcgtgcgtgtttttcccagggtgccccgcgctg ctgttatggccgcctccttgaggtagtatccgcacatggaattctagggccgcaggtgtatttacg gtaactgtcgccactagatttcagcgcctttggactctcctgttttcactttcttttgttgactcc cgtgtggccctcgtgggagcctgttttggctgcagcggtgtctggggtgatg
(Seq ID No: 754)
Homo sapiens THUMP domain containing 1 (THUMPD1) :
gtttctctttcctctcagtttgcgcacaccatg (Seq ID No: 755)
Homo sapiens ankyrin repeat and KH domain containing 1 (ANKHD1) : tgctcttctcgttcccgagatcagcggcggcggtgaccgcgagtgggtcggcaccgtctccggctc cgggtgcgaacaatg (Seq ID No: 756) Homo sapiens syntabulin (syntaxin-interacting) (SYBU) : cctcctcctggacggcggcagcggcggcgcgaggagccggcgggcagcggcgcgatg
(Seq ID No: 757)
Homo sapiens coiled-coil-helix-coiled-coil-helix domain containing 3 (CHCHD3) :
gcgccttctccttgcttctgggggtcgtggccttgctcccgctgtgcgggaaaagaatccaggccc ttccacgcgcgtgtgggtgcgggggccccgaagtgctcgtggttccccgctaggtctccgctgggg caggaaccggaatcatg (Seq ID No: 758)
Homo sapiens HAUS augmin-like complex, subunit 4 (HAUS4) :
cctccttcgtcgcggcctctagtgcactttcggctccttccccttcccgggcctttcagcttggtc tttccgggcctcgcttcccccagcccctgcgcccggcccgaacgagaggttccggagccccggcgc gggcgggttctggggtgtagacgctgctggccagcccgccccagccgaggttctcggcaccgcctt gagagcttcagctgccccaggattagaatcccaagaaaatcaaatg (Seq ID No: 759)
Homo sapiens solute carrier family 41, member 3 (SLC41A3) :
ccgcctctttcccgccgccgcctgggaggggacccgggctgccaggcgcccagctgtgcccagatg (Seq ID No: 760)
Homo sapiens phosphatidylinositol glycan anchor biosynthesis, clas s V (PIGV) :
cttcctttccagcctcccgccctcgtctgcttccggccctgtggcctggtggggctctgcaggctc cctcgggagtggtccttgggccgtggcccctctgggaggcctgagggagctcaatcctggtagcaa cacccctgaattcctggtggtgaaaggatg (Seq ID No: 761)
Homo sapiens poly (ADP-ribose) polymerase family, member 16
(PARP16) :
agttcctttatccctgggcccaacctccccgccgacccgcggtccaggcctcggtctctctcttcg gcggcgagccgcggcccagaccccggcagaggacacttgtcggcacgttctcacccctgteatetc agccccctgcctagctccaccccaggcttgggaacccggcccctgacggcccattgtccgcgggcc cagcccccgcgctgaacgcacgctcgcccttgcccctaaccagcgcgtctaccccggcaacgcgca gtgacctgggatg (Seq ID No: 762)
Homo sapiens thioredoxin-like 4B (TXNL4B) :
gtttcttttctgcgcttgtgcgttttctgttcggtttccttcccgctagcggggccacgagggttg ctaggcaacagcccctgggtgacttggtcttagggtcctgtccggcttggggctgatgaaaggagc tgtccgcgcccgggctcttccgagaagtggttgctgacagccacaaagtgaaagggagtgaggcgg cgtggacgagtaaggagtgacagtgaggattcacatttgggttatttcaagatg
(Seq ID No: 763)
Homo sapiens slingshot homolog 3 (Drosophila) (SSH3) :
cgtccttcctggtcctgcgggtccaggactgtccgcggggttgagggaaggggccgtgcccggtgc cagcccaggtgctcgcggcctggctccatg (Seq ID No: 764)
Homo sapiens zinc finger protein 692 (ZNF692) :
ctccctctggggcgcgggcctcagttccgggctacagcagccgacgccgagaggcaccgtttcttc ttaaaagagaaacgctgcgcgcgcgaggtgggcccctgtcttccagcagctccgggcctgctcgct aggcccgggaggcgcaggcgcaggcgcagtgggggtgagggcgcgtgggggcgcacagcctctggt gcacatg (Seq ID No: 765)
Homo sapiens tRNA-histidine guanylyltransferase 1-like
(S. cerevisiae) (THG1L) : tggccctttcctttccgcgtgtagaatg
(Seq ID No: 766) Homo sapiens solute carrier family 25, member 38 (SLC25A38):
tctccccttctacagagttcctccggcgcttcctccaccccgggatacacagaacctcatctccta cggtgctgaagcctgcagcagggcaggatgggcaggagagcagagccgcggagtctgcggcgcggg tgaagagcggcgcgtaattcccgcagcaagattgttccgcgcccgcagcccctggactagcaggat ccgaaccccggcggctgcgtgcttataggcgcagacgtcagagagcccgcggcttaaagcgcgtcg cctggctagcgccaccccctagccttcttcaaggcctccagggctgggcccaagcgcccgtcgacg gcaccctgggcccagaggactcgcgggcctcatctccaatg (Seq ID No: 767)
Homo sapiens WD repeat domain 13 (WDR13) :
agttctttctgatagcaggcagccatcttgcctggagcctgagaaagggaggagagacagaaggaa ccggcgacagtggtctcagggccgctccggggggcctcaagaaccggaggcagccccggaggtggt ccccgatcccgggctatgctcttggatctgagaagggaaggcggagggcggcggggacaagatggg tggagaatgtcaagcaaggaatgctaggcgggggaggggcgttgctatggcgactggggaggggcg gtgtctgttctgaatcgctgtgtgtcacccgggcgctgcccaggaagggcagggctggggtgatga ccatggtaacacccgggggggagttcgtgacatctccggcgcggagggactcgatgtctatggcaa tggtcgcctggtggaagggacggaactagatcccttcgctcgggacgctcacattccaggcccttg tcctgcaggctgccgcgggcggacacgccagaggaggaggccggggaatg
(Seq ID No: 768)
Homo sapiens chromosome 1 open reading frame 123 (Clorfl23) :
ccgccttttacgacgcgccggaaagcaacggcaagggcggcagccagcaccgggcggagagggcta ccatg (Seq ID No: 769)
Homo sapiens chromosome 20 open reading frame 11 (C20orfll) :
ctgcctccttctactcgggcgccccggcggccgccacctctccccagcccaggagaggctgcggag ccgcagccgcccagaccgcgcagcgcgggaggcaggttccgcacgaaataaatcagaatg (Seq ID No: 770)
Homo sapiens zinc finger protein 446 (ZNF446) :
ttccccttttggggacagatcccgaagttcgagcatccctcggataggccgggtgtcaggcctggt ctctcaggcccgtccaggcccatcttgacgattccaagaccacccccttgagcaagaatg (Seq ID No: 771)
Homo sapiens mitofusin 1 ( FNl) :
ccgccctttgccactccccctgcctcctctccgcctttaacttctcgggaagatgaggcagtttgg catctgtggccgagttgctgttgccgggtgatagttggagcggagacttagcataatg
(Seq ID No: 772)
Homo sapiens phosphotyrosine interaction domain containing 1 (PID1) :
agtcctctcgcagctgcgccaggacagccggcgcgcggccgtgcccacaagttgccggcagctgag cgccgcgcctcctcctgctcgcagccccctacgcccacccggcggcggtggccagcgccaggacgc acatcccgcggacaccgaccccagatgtaaagcgggaccccagcccctcgccccccggcgcgatcg acagtctcgccagcgtctcctctgccaaaacccagggctggaagatgtggcagccggccacggagc gcctgcaggagagatttgcagacacagaagcggcacagagaaggccattgtgaagatcaaggcaga aaccggagttatggcatcataagccaaggaatg (Seq ID No: 773)
Homo sapiens pleckstrin homology domain interacting protein
(PHIP) :
tttcctcctcctcctcctccgcctccgccgccgttgcttgaatggtggagccgaagctcggctcgt gaacacacactgacagctatagggcaggcggcggcaccgtccccgcttcccctcggcggcggggtg tcccgtcggcggccctgaagtgacccataaacatg (Seq ID No: 774) Homo sapiens LI and senescent cell antigen-like domains 2
(LIMS2) :
tggccttttttgggcgtctccctgctccgcggcccgggctggcgggcgggcgctcggctggcggct gcagcagcagagggagacccgcggcaaccccggcaacccagggctcggcgtcgctgccaccatg (Seq ID No: 775)
Homo sapiens SCYl-like 2 (S. cerevisiae) (SCYL2) :
aggtcttttagtctttttccccctcccttactcttcgtccccggtccctcccctccccaccccttt ccttctagctccgacgtttgcggccgcgggggcggcggaggatatggagtaaagccagagtcagtg gccaggcacgaaggcagagcaggaacagccaggaggcgtttattaggggggcggggggaaagagcc ccagcaccgcccctcctggaagaaggaagaggtaagtgaccggccgccggcaccgaccgacctccc tcaccggcggctctctcgcctgggctcccggagccggcgaggagggaatggaggactcgcgcccgg gttaggcctcccagggccgctcaggctggtgggtgttgcctggtgacgggcctgccggcggccggc cgggcgatcggcggtcggcgcccgcgcaaagcggggctggacgagcagcgagctccggggagcgga tccgagagggccgagtcctcgaaagaggccttgaggcgacgggagacccgggatcgaagtcagctg ccggagggagagccccccatgccggctcgagagctcgggtttcggtggtggagaacgtagtacctt tcggggacattggacactactctaggaccgggtaactataactacccaatattgcagccatg (Seq ID No: 776)
Homo sapiens ring finger protein 31 (RNF31) :
caccctctctcctagtacttcctgttctcggctaaccctggcgctgggccgggggctggagagtga ccgtggtctgagtgacctggggcggctgcgtgggccggggtgggcctcaaagccgggcaccagacg ggaggggcggcgctcgggccgcgcgctgcccgcgccgggtcctggcgggcggcgaggctggggctg actcctgcctcaggatg (Seq ID No: 777)
Homo sapiens mediator complex subunit 9 (MED9) : cgacctctggctaacc- tacccccggagccatg (Seq ID No: 778)
Homo sapiens ATP5S-like (ATP5SL) : cggccccttccggttacgaaaccttagcaa- gatg (Seq ID No: 779)
Homo sapiens GPN-loop GTPase 2 (GPN2) :
tctccttttgcgcgacacggtctcagctgttccgcctgaggcgagtgacgctggccgccaacgagg tatacgtactgggaccctcgccctcagtctcgtctccggcgcggctacctgccccgttttccctgt gagttgacctgctccgggccgcgggccgccaatg (Seq ID No: 780)
Homo sapiens transmembrane protein 48 (TMEM48) :
cggtctcctgtacgccctagactaggggccgccatctccatg (Seq ID No: 781)
Homo sapiens ankyrin repeat and zinc finger domain containing 1 (ANKZF1) :
ttgtcctcttcgctgctccgtagtgacggggattgttgtgttgcagaaatccggcaatcgacctga ggacttgcgagccgctcagctcccgggacgtttggagctgctgctaaataatttctgctcagccat g (Seq ID No: 782)
Homo sapiens notchless homolog 1 (Drosophila) (NLE1) :
ggctctttctcctccacgtggggacgcaggatg (Seq ID No: 783)
Homo sapiens cell division cycle associated 8 (CDCA8) :
cgctctctctcactggcacagcgaggttttgctcagcccttgtctcgggaccgcagcctccgccga gcgccatg (Seq ID No: 784)
Homo sapiens polymerase (RNA) III (DNA directed) polypeptide E (80kD) (POLR3E) : cgctcccccccacgtgtccgccggagtttctccaccagcaacatggccgccgcctgagaggagagc cgggccgccgccgtctctgcagcccgcgggtaactgggccgttgccgccgtccgcgctcggccccc gcggagagatcgagctgaaggactgcgcggctggctctcctctagtatg (Seq ID No: 785)
Homo sapiens armadillo repeat containing 1 (ARMC1) :
gagcctttgcccgccagcgccttcgctctttggctccctgagttagtccggttgcttgcgatcgcc gcggccggggctgcgaaccgaagggctcgctccgcgccgcctgggtctctacctcatccgtaggtg tggccctgatggtgtggcaggctctggactcctaaagctctggagcgaatttaagattttattcat gtgcatggcatagaagatg (Seq ID No: 786)
Homo sapiens transmembrane protein 33 (TMEM33) :
ccgtctttctggaaacaccgctttgatctcggcggtgcgggacaggtacctcccggctgctgcggg tgccctggatccagtcggctgcaccaggcgagcgagacccttccctggtggaggctcagagttccg gcagggtgcatccggcctgtgtgtggcgcgaggcagggaagccggtacccgggtcctggccccagc gctgacgttttctctcccctttcttctctcttcgcggttgcggcgtcgcagacgctagtgtgagcc cccatg (Seq ID No: 787)
Homo sapiens pyridoxamine 5 '-phosphate oxidase (PNPO) :
ccttccttccccggggtagaagtccagggtgagaaattggttccgaactcaaaggaacccagtgcc gggccacagccgggtcacgtggccggcggccccccatg (Seq ID No: 788)
Homo sapiens golgi phosphoprotein 3-like (GOLPH3L) :
attccttctctgcatcgaaggatcaggaagtttgtgctctctgcgtggctaagtttttcacctact aggacgggggtggggtggggagaacaggtgtccttctaaaatacagcacaagctacagcctgcgtc cagccataacccaggagtaacatcagaaacaggtgagaatg (Seq ID No: 789)
Homo sapiens regulator of chromosome condensation (RCC1) and BTB (POZ) domain containing protein 1 (RCBTB1) :
cgctcctcctcttcgctgccggtgggcaccgccgctcgctcgcacttctgcgcccattggagcttc ggagatccctgcggtcccgcgggacggcgcggcagcagctgacctcgcagacaggatcttgctctc ttgcccagactggaatacagtggtgtgaacacggctcactgcagcctcaacctcctggactcagag atgtcggcttatttataggaattgcttgaagccagagtcatg (Seq ID No: 790)
Homo sapiens leprecan-like 1 (LEPREL1) :
cgtccctttaagagcggctggccaggcacggcctccgcctctcagtacgcggagcgccggcggtca cctggggctcgcggagcggccagatcgcggcggagtcggcgcgcttccccgagggaaggtgggaga ggggacccggacgcgaggtgccccgaagccctctcgagcgtaaccgtcccgcgcctctctgaggcg gaggatg (Seq ID No: 791)
Homo sapiens hedgehog acyltransferase (HHAT) :
ctgtctcttggctcaggcttggaggcctccgagcagcaacatcgtcccaattataccccgttggag catcttcagatcttccactcttttcacaacgcaatcaaaatcttcgtacccattttgcagtagtga tctctgtaagttgctttacaattcataaagtttattctatttgatcttcactctaatttacaaaga aaagcagggaagtctatttctgttttacagaggtgtacagggaggctcacaggggctaagttcaca cagtaagccctcgaagctgccagggctgcaaagcccaccctctttccaccgcaccgaactacctcc tttcgcctacaaaacgtaggtggggaccactggtgttggaatgacggcccacctcgagtttcaggt gacttccactctgcaattaacttgcaggcagccccagacctgcaatgaacacacgggtgggggaga gatatgcacgccagggtcagtgggaaccaacagccgaggggtgagcggggctaggggccccgggcc gccggcggggcaaacgcggttcagaaacgcaggccgcgctctggcccgccccctgcagcagcacgg cctgctcgccatcgcccggagagcgccgcgggttcccgagtccgggcgcggagggcgcgcgggcac ggcggcaggggcgtgctcggaggacgcgcgctgcgctgctcctccaaagggcagctccgggggaaa gagggtggcgtcccggggaagcccgcagccgccgccgatgtcgctgggactcggaagtgccgaaag aggggtgttgggaactcgcggcgcgcgtgaacgttgccgtcgccgccgcccgggacagcccggaga aactctcagcgtaggcatcgggaaccttcgtgccaaggagccatg (Seq ID No: 792) Homo sapiens chromosome 11 open reading frame 57 (Cllorf57) :
cctcctttttctcccaaaccacttcttcccccctaccccccgccacgcgaggctgcggcgcacggt atgggtgtgtttgtgtgtatttgtgtggggagggcgtttggagggaaggttaccgggagctccgag gccgctggggaacagggatcccggtgacaaagatggggatatttcctctgtcttccacttggaaac ctcaacccccgcttcaggctccctagataetttctggggcccaaccgaaggccgtagccatccaaa gcgttcccagcctttctggggagtgaaacttacccccggggttcgtcctagaggagcgtgagcggg gaatgcccaggtcaaccgggctgtccgaattccgccccggctcagcctccggcctcagtccgggag agagatctgcctgtcggtctgggctgggggaaacgcggcagtggcctgggccacaggtgagggcag agtaaccagtgggaaggctgcgttttcacgaaggactcgggtgaagctgcagagctgcctttgagc cctgactccttggcttcctgggtcggaggagatcttgtaatggagtggttcttcgtctcactagca agatgcctgatttcctcaggatcaagggattgaagaatg (Seq ID No: 793)
Homo sapiens high mobility group 20A (HMG20A) :
agtccttcgccgcattggggcaaaataatcccttcatttttgtgaaggtaccgtggaaaatatttc atttttcttctcaccggagcaattgtaaatgctatgcggtaagaggagttacctgtggaaaggtgg ttaagagattaggtaaagaaaaggaaaggacaccaaaataaagtgctgcggaagaatttttgtcca gctgtgagacgacgagtgcgtgaagtgaaggcgattgagaggggctgagggaattgtcctctgtgg aagggactttcttttggccctaggccccttcctgcccctgtcgtcagcagagtctctacaaggaag ataacggactgtaaaattctataaagcaaagctacacatcacttgacaccatacaccatcttggtt acataatgaagagagatg (Seq ID No: 794)
Homo sapiens checkpoint with forkhead and ring finger domains, E3 ubiquitin protein ligase (CHFR) :
atgtctcttgacagcggcggcggcgcagccggttccgggttcggcgcggggcggggatgtgaatcc cgatg (Seq ID No: 795)
Homo sapiens nucleoporin 133kDa (NUP133) :
ccatctcttcccttaggtgtttaagttccgcgcgcaggccaggctgcaacctgacggccagatccc tcgctgtcctagtcgctgctccttggagtcatg (Seq ID No: 796)
Homo sapiens CNDP dipeptidase 2 (metallopeptidase M20 family) (CNDP2) : cttccttccaagaaccttcgagatctgcggtctggggtctggttgaaagatg (Seq ID No: 797)
Homo sapiens oxoglutarate dehydrogenase-like (OGDHL) :
gcaccccttccgcgcagccccctgacctgcagcctccggacctcgctgcagcgcggacccggcccg cccgcccgaatg (Seq ID No: 798)
Homo sapiens transmembrane protein 30A (TMEM30A) :
ccgcctcttccgctctacagcggaggtggctgtggcggtggcgctggtggctgcggcggcggcggc ggcagcggcgctcgagcggttcctgtcagggtcagccggcgggccccctgggtggtccacctgcaa atcgcggagcggcgccccagggatcgatg (Seq ID No: 799)
Homo sapiens elongation protein 2 homolog (S. cerevisiae) (ELP2) : gcgtctcttgtttgtgcggctgaccagttggcgacatg (Seq ID No: 800)
Homo sapiens WD repeat domain 12 (WDR12) :
cgttcttttctttgtatttccgcctctcgcctctctctaaaagccgcagttagaggcgagatttag gaaaaacctctgccgagtgagcctctggttgggaatatgtatgagaaaaaaaaactggcaaggcgt tagtcaagcaaagctgaaggcagaggaaatttgatatctggctggagtctagaggatttaatgcaa ataagatactctgagggcagcgtggcaaaaaaagactacaattcccggtggtcacagcgtttgaga agcgatgctttctgagacttgtagtaactaggagctgtgtttgaactatccaggctcaggacagcc tcttgaaaaaaaattttttattaataaagcggatttgagtgggatctttttcctaatcgattacgg gcccacacgtatgggaagaattctaacaatgattaaagggacatgctacctttacgactatccttt tctaatcgatgactcctaaatctaggagtaggtagtcgatgtttgtggtctgggcgtctgtagaag ggcaacctcgtgctttctgcagaggagaccggagggcagaaggcagagtccaggcttagactgcag ttcctcgcttacctgtgcagtctaattttgagctgcctctttgtagtcttaaaaggcaggagcttc gtgttgtgggtctgctaacccgtacgtttccgtgggcaagtcgtgtgtactcctcgccatg (Seq ID No: 801)
Homo sapiens tetratricopeptide repeat domain 17 (TTC17) :
cgacctcttcaagatggcgggcgccggagactagcttccgcttccggtgtgagcggcccggccggg ggggcaagatg (Seq ID No: 802)
Homo sapiens proline rich 11 (PRRll) :
ttttctttatggcgtgggagaggccacagcccggactccatcgactcccccggctcttagactaaa atcatg (Seq ID No: 803)
Homo sapiens TBC1 domain family, member 23 (TBC1D23) :
ctccctctttcttcccctctggggaagctcagtgctggacttccgaagaccttttacgacattgag tctcggagttggtctcagcgccggatccacttttcggcaaagtgacgtggacgtcaacagcaatg (Seq ID No: 804)
Homo sapiens leucine rich repeat neuronal 3 (LRRN3) :
gctcctctctggggagtggagggtgttcagttattaatgaccgctgagcaggcagcaccatgtcag tgtgacaactgatcgggtgaacgatgcaccactaaccaccatggaaacaaggaaaaataaagccag ctcacaggatctctcttcactggattgagagcctcagcctgccgactgagaaaaagagttccagga aaaagaaggaatcccggctgcagcctcctgccttcctttatattttaaaatagagagataagattg cgtgcatgtgtgcatatctatagtatatattttgtacactttgttacacagacacacaaatgcacc tatttataccgggcaagaacacaaccatgtgattatctcaaccaaggaactgaggaatccagcacg caaggacatcggaggtgggctagcactgaaactgcttttcaagcatcatgctgctattcctgcaaa tactgaagaagcatgggatttaaatattttacttctaaataaatgaattactcaatctcctatgac catctatacatactccaccttcaaaaagtacatcaatattatatcattaaggaaatagtaaccttc tcttctccaatatgcatgacatttttggacaatgcaattgtggcactggcacttatttcagtgaag aaaaactttgtggttctatggcattcatcatttgacaaatgcaagcatcttccttatcaatcagct cctattgaacttactagcactgactgtggaatccttaagggcccattacatttctgaagaagaaag ctaagatg (Seq ID No: 805)
Homo sapiens MIS18 binding protein 1 (MIS18BP1) :
ggccctctctccgcgcggagccgagccggaactgcggcagtctctccctgccaggctcttcatcca aggtttctgtggatcccttctgaagttctatctgaaaattgcgcttaagtgaattttctgttagaa gaacttggttgctactttcttgtcaagatg (Seq ID No: 806)
Homo sapiens LMBR1 domain containing 1 (LMBRD1) :
ccgcccctttaacctttagggtgcgcgggtgcagtatatctcgcgctctctcccctttccccctcc cctttccccaccccgggcgctcaggttggtctggaccggaagcgaagatg
(Seq ID No: 807)
Homo sapiens ST6 (al- pha-N-acetyl-neuraminyl-2 , 3-beta-galactosyl-l , 3) -N-acetylgalactosa minide alpha-2 , 6-sialyltransferase 1 (ST6GALNAC1) : cttcctcta- gaacccgacccaccaccatg (Seq ID No: 808)
Homo sapiens spermatogenesis associated 7 (SPATA7):
gctcctcttttccagtcctccactgccggggctgggcccggccgcgggaaggaccgaaggggatac agcgtgtccctgcggcggctgcaagaggactaagcatg (Seq ID No: 809) Homo sapiens docking protein 5 (DOK5) :
cctcctccttcctcctcctcctcctccttcttctcctccttctcggccgggaggaggcagggctgg atccctcagccgccgccgctcctcctcctggcaggccggccgcggagtcagctgacgccggcgctc cagcctcgcctccccgcgccgcgctctgcgctccccgaaagtggctgcaagccggccgcccactgt cagggttggggggacagagaaagtgatgtgcgccttctaaagcctcgcccagcgccgccgaagcag cttcacctctccaactttctcccaccgactgcttgtcttgaccctgccctccaccctccccagagc cacttcgggtgcgcgctcttgggtaaagggggggtcaccggctgtctgggatg
(Seq ID No: 810)
Homo sapiens glycosyltransferase 8 domain containing 1 (GLT8D1) : tctcctccatcgcctgcagtaagggcggccgcggcgagcctttgaggggaacgacttgtcggagcc ctaaccaggggtatctctgagcctggtgggatccccggagcgtcacatcactttccgatcacttca aagtggttaaaaactaatatttatatgacagaagaaaaagatg (Seq ID No: 811)
Homo sapiens cullin-associated and neddylation-dissociated 1 (CAND1) :
tggccttttgccctagggagcgagtgcggagcgagtgggagcgagacggccctgagtggaagtgtc tggctccccgtagaggcccttctgtacgccccgccgcccatgagctcgttctcacgcgaacagcgc cgtcgttaggctggctctgtagcctcggcttaccccgggacaggcccacgcctcgccagggagggg gcagcccgtcgaggcgcctccctagtcagcgtcggcgtcgcgctgcgaccctggaagcgggagccg ccgcgagegagaggaggagctccagtggcggcggcggcggcggcagcggcagcgggcagcagctcc agcagcgccagcaggcgggatcgaggccgtcaacatg (Seq ID No: 812)
Homo sapiens BRICKl, SCAR/WAVE actin-nucleating complex subunit (BRK1) : cgctcttcctcaggcggcggccatg (Seq ID No: 813)
Homo sapiens zinc finger CCCH-type containing 15 (ZC3H15) :
cggtcttcctcctcgtcctgccgcagggccagaacccctgacggtattcagctgcgcgtaagtctg gccggtgccatctgtctccgcaatg (Seq ID No: 814)
Homo sapiens polo-like kinase 1 substrate 1 (PLK1S1) :
cggtctccttcggcaaccccggccgaacggccacccagaggctgtgctgagctggcgcagcggcag cagcatg (Seq ID No: 815)
Homo sapiens dysbindin (dystro- brevin binding protein 1) domain containing 2 (DBNDD2) :
gtttctttcctacgcagccgctcctgccgccgtggtcgctggagctttgcctctctaggccggcag cgcctctcctccatggtcctgtctgtcagcgctgttttgggagcccgccggtgaggccgggccacg ctcagacacttcgatcgtcgagtctgtcactgggcatg (Seq ID No: 816)
Homo sapiens KIAA1704 (KIAA1704) :
gattctttttggatagggttgacgttcgtggatagactcatatctgtgaccagtgtccgccaccgc ggatg (Seq ID No: 817)
Homo sapiens solute carrier family 25, member 37 (SLC25A37) :
ccccctccctgcccacctcctgcagcctcctgcgccccgccgagctggcggatg
(Seq ID No: 818)
Homo sapiens myoneurin ( YNN) :
cgtcctcccaagatggcggagacagagtgaagaaactgtgttccccccttgggttgctatcgatca agggtaaaattccattctgatatcaaaatg (Seq ID No: 819)
Homo sapiens vacuolar protein sorting 33 homolog B (yeast)
(VPS33B) : gcttctttttctggtagaaggcggggttctcctcgtacgctgcggagtctctgcggggtgtagacc ggaatcctgctgacgggcagagtggatcagggagggagggtcgagacacggtggctgcaggtctga gacaaggctgctccgaggtagtagctctcttgcctggaggtggccattcattcctggagtgctgct gaggagcgagggcccatctggggtctctggaagtcggtgcccaggcctgaaggatagccccccttg cgcttccctgggctgcggccggccttctcagaacgaagggcgtccttccaccccgcggcgcaggtg accgctgccatg (Seq ID No: 820)
Homo sapiens zinc finger, C4H2 domain containing (ZC4H2) :
aggcctctccaagcccctaccgcacaggctcatagccccaagcccggaggaggtggctacattgtg tctattgtatcccttggctggtgtatttgtacatctctcgggacgtgaaattgacagtgaaaagta tg (Seq ID No: 821)
Homo sapiens BAIl-associated protein 2-like 1 (BAIAP2L1) :
cttcctctggcggcgtccggccgcttctcctctgctcctcgaagaaggccagggcggcgctgccgc aagttttgacattttcgcagcggagacgcgcgcgggcactctcgggccgacggctgcggcggcggc cgaccctccagagccccttagtcgcgccccggccctcccgctgcccggagtccggcggccacgagg cccagccgcgtcctcccgcgcttgctcgcccggcggccgcagccatg (Seq ID No: 822)
Homo sapiens solute carrier family 25, member 40 (SLC25A40) :
cgtccttctcgcgcctcgctctggccctgcaggttgtgtttccgcctctaccccgcctccattccg ttgctctctcagtctcagacccgggctctcggtccgccgcttcaggtcttggcgcagcctcagaga gttggcgcggctctgtgttgaccaaacctagtggatgcagttagcgccggagcccggccccgcccg tcaccagggttattcccgccttctaggtttgccaggactgccggccctgcagctgccttctgcccc aggtttttggctactgatgttacaaacaataaaatattggagcatagagttgaagaacagactcaa accaggtttttatttaattagttaaaaatatg (Seq ID No: 823)
Homo sapiens protocadherin alpha subfamily C, 2 (PCDHAC2) :
tttccttttccctccccctggagctgtagcggcagcagcagcaggaagccgagccgggttgagcga ctcggaggcgagcggaggagctggaatatggggagtcagcgaggacggtggggccaggagcccttg ggagggcctacggagggagcggccccaggcgctttctagagcgtgagcggtgggggagcaggcgca gggtggcacgagcggaggcggggcccgggcgtggggcacggctggggaagctgccgcctccggccc tgcccggctgcctccgccgcggccagtggctatg (Seq ID No: 824)
Homo sapiens chondroitin polymerizing factor 2 (CHPF2) :
gttcctttttgggttagctttggcagtattgagttttacttcctcctctttttagtggaagacaga ccataatcccagtgtgagtgaaattgattgtttcatttattaccgttttggctgggggttagttcc gacaccttcacagttgaagagcaggcagaaggagttgtgaagacaggacaatcttcttggggatgc tggtcctggaagccagcgggcctcgctctgtctttggcctcattgaccccaggttctctggttaaa actgaaagcctactactggcctggtgcccatcaatccattgatccttgaggctgtgcccctggggc acccacctggcagggcctaccaccatg (Seq ID No: 825)
Homo sapiens thioredoxin-related transmembrane protein 3 (TMX3) : gcttctcttccgctccgggtcggctccgtttccctttccgggcgggcaggcggcggaccccagtgt ctttatccctcttttgcacagtcagcttctgcagctctcccgggctagcatg
(Seq ID No: 826)
Homo sapiens ras homolog family member F (in filopodia) (RHOF) : cgacctcttggctccgctagtgcccggcgcgccgccgccagtgctgcgggctccgggcaatg (Seq ID No: 827)
Homo sapiens amyloid beta
(A4) precursor protein-binding, family B, member 1 interacting pro tein (APBB1IP) :
ctttctctcaggaaactccactcccaactgacaggtgctatttccagccagtcctatgctgttgca aatagtgagtccatgaatgccctctgccgtgtgcattacttattttcatcagcagatcttcgtaac acactcctggaagtgggatgacggggtcaaaaggcgaatccatacataagttaaatagatattgct caattctcttccacggggttcagaccattttggatttctacgagcaatgaagacagtgctattcct ctacaccctggccggccaactgagcgtggttaaacgtggggagggaggagggtgaggttaccaacc tgatggttgagaaagggcctccgcccagcgcgcccttcctccacccccacccgagagacagctgaa ctccggccgggacgcgcgtgttgccagtccagccctgcaccgcgtcccctgagggcgggctgcagg cggccgggaagccttgcacaaccggcccaaaagaggaagcccagaaagtgctgaagtaaacacttt gggagaccgttgcaacataaagcggcctctcagtctttggtggaaccatcactaggccccaatccc ttagtccctcttgcgtcgaggctgcaaaatggttccattcgccaggagacgctcctgagagaaggg cgcgcgcggcacaggggccttccttgcacctcggagcaaagcagctcggatagcgccacacgtctg cgcgctgcgtgggaagggcagggctgacagcacttcctccccggggcagcgacctggagcccgggt gcggcagtctgcaccgcgcgtcgctttcccggccggagtctcgccgccttcccgcgccccgcagcg ccccgcagagcagtcgagatg (Seq ID No: 828)
Homo sapiens roundabout, axon guidance receptor, homolog 4 (Droso- phila) (ROB04) :
ccttccctcttcactgtgagctcagagcagcaggacaaagtgctcgggacaaggacatagggctga gagtagccatg (Seq ID No: 829)
Homo sapiens translocase of outer mitochondrial membrane 7 homolog (yeast) (TOM 7) :
acctcctttccctttcggattcccgacgctgtggttgctgtaaggggtcctccctgcgccacacgg ccgtcgccatg (Seq ID No: 830)
Homo sapiens major histocompatibility complex, class II, DR alpha (HLA-DRA) :
ttttcttttattcttgtctgttctgcctcactcccgagctctactgactcccaacagagcgcccaa gaagaaaatg (Seq ID No: 831)
Homo sapiens protein arginine methyltransferase 8 (PRMT8) :
cctcctctactatctcggtatcaccaaacccttgccggctcttatg (Seq ID No: 832)
Homo sapiens adducin 3 (gamma) (ADD3) :
ctgcctcttatgaagcaatactagagaggaaaaacaaaacccattcctttaagaaagattccgcct cctctcataagcaagcgcctaatggtaattgtagagtttactaagtcaaacacttactactcagca ttgagagaagctgctgctgctaatgctgctgctgctgctgccgccgccgccgctgctgctgctgct gttggtctgaggctgcagtaggtttctgtgcagcattgcagaatccacacctagagaacagaagac acagacacgtacgtctactacccttgttagaaggaagctttggatcttcggtggataacaagagta atccacagacttaaaacatg (Seq ID No: 833)
Homo sapiens BarH-like homeobox 1 (BARHLl) :
agcccttttggatctaatgcgcagaggaggttggcccagagctcccgggctcccccaaggctgaac tccgtccaaggtgcccgcaggctccctgcccgccttccccatgccagcccgcagctaggggcaggg gcagcggcggctggggttgggggtgggtggggagcttttggggaggacaggtcgcagcttggctat g (Seq ID No: 834)
Homo sapiens intraflagellar transport 46 homolog (Chlamydomonas) (IFT46) :
ttatctttttgcctagcgactgacaacaggctggttgcttggcgtggaatcctaaagtggcctggc tttgagactggagtgagaccccagccctaggctggggttctttccattatagaggagacggattca gaagggctacagaccaaggttgttgaaaaccagacatatgatgagcgtctagagattaacgactcc gaagaggttgcaagtatttatactccaaccccaagacaccaaggacttcctcgttctgcccatctt cctaacaaggctatg (Seq ID No: 835) Homo sapiens carbonic anhydrase X (CA10) :
cccccttttcgggaggagggaggcagggacttgcaggcaagagttgcacctggtctaggaacctgc agagaaaagaactctggggtaagtagtgttctggcactggcacggaaaggggtaaagggtgggggg catgagagggacgaaatggagagggcagggaatgaattatgcaaaaaaatctccaatatttcgcag cggagggagagcacagcacagcactcccaggatgagtcctgcctgggtctcccgcgccgaacccgc agcacgaagttctttttaagaagagaaactcgaaaatcctggagggtaacagaggcagccagggcg gggcggagtgcggaggcggctgccagggactggggccgaggcggcggccaaggtggcctgaagctg tgacacccagcctcctcctcctcctcctcatggccgcgctcagcctcacctccccgcccgggcctc ctgcctccgcccccgggtgccgggctgcggagctgacgctgggacgcccggcggcggcgaggacgc tcacctggccaagcctccttctcctcctccccctcccgcccccacctgtcctcctcctctctgagt tgggaagcgtagggatccgtaggcgaggaaataacgacccctgcagttgtattgcggaaaatctcg acagcggcgctagttgcgggcgatggaagccaggcaactgggggttctggggagttcaggaaaata gcagaggagcaggaagggcgcgcgcgacctggagagtctgtgtgcccccaccgcgccccagtcccc ggggcccagcccttcccctcggcgccctggacgcactgccggaacccggctgagaggctgcaggct gcgcgcggacctggggagcagggagggtcggcggaggctgccggcggctggcggtttcgggcaata atccctgcctctctttctctgtgtgtctgctgtgtctgctccttccccgccccccggaagcaggag aagaactgccccggagcgcagcagccaccctccgaccatgccccggtgaggggggcggacttcgag ggcaacttgccgcggactgcctgggcttagccagcgagctacgcgctcccgggagcccggaattgc acggcgcagcccggcggggggctatcgtctatgtcttcttggggcgccagacgaatcggggtctcg tttttgctggaagagcccagtgttggtggcttcaggtggctgctgccgccgccgccgccgccgccg ctgctagtgcggtttccgccgctggtgcgaagagaagagacacgcgagcggggagacctccaaggc agcgaggcatcggacatgtgtcagcacatctggggcgcacatccgtcgagcccgaggggagatttg ccggaacaattcaaactgcgatattgatcttgggggtgactgtccctggccggctgtcgggtggga gtgcgagtgtgcactcgctcggaagtgtgtgcgagtgtgtatgtgtgtgtgccgtgtcgggctccc cccttccccccgttttcccgtcgagtgatgcacttggaatgagaatcagaggatg
(Seq ID No: 836)
Homo sapiens dual specificity phosphatase 22 (DUSP22) :
cctcctccctgtaacatgccatagtgcgcctgcgaccacacggccggggcgctagcgttcgccttc agccaccatg (Seq ID No: 837)
Homo sapiens olfactomedin-like 3 (OLFML3) : gttccttctactctggcac- cactctccaggctgccatg (Seq ID No: 838)
Homo sapiens phosphoribosyl transferase domain containing 1
(PRTFDC1) : ccgtcttcccttcccgcgttccccgggagaaacatg (Seq ID No: 839)
Homo sapiens translocase of outer mitochondrial membrane 22 homolo g (yeast) (TOMM22) : cctcctttccgcttccggtgtcccctacagtcatg
(Seq ID No: 840)
Homo sapiens arrestin, beta 1 (ARRBl) :
gctcctcctgctggctggggattttccagcctgggcgctgacgccgcggacctccctgcgaccgtc gcggaccatg (Seq ID No: 841)
Homo sapiens cytokine induced apoptosis inhibitor 1 (CIAPINl) : cctcctctcgcgagaggcgcaaggcgtggagtcgacggctggagagaagccgggagcgagcccagg cggcagtcttgattcccttttggccagcagtttttaggtctgtcagtactgcactgcaagaatg (Seq ID No: 842)
Homo sapiens leucine zipper transcription factor-like 1 (LZTFL1) : taccctccttccccattttctgtggtccaactaccctcggcgatcccaggcttggcggggcaccgc ctggcctctcccgttcctttaggctgccgccgctgcctgccgccatg (Seq ID No: 843) Homo sapiens phospholipid scramblase 4 (PLSCR4) :
agccctcccttccgcgcgcttactttgtttataacttgaaaaatcctctccgtctcccttccctgc ctcctttcctttccctttcctctgccagtacaactagacccggcgtctggcgtccccggtgcccag cattctgcggggcaggcggattaattggaattcttcaaaatg (Seq ID No: 844)
Homo sapiens ectonucleoside triphosphate diphosphohydrolase 7 (ENTPD7) :
cctccttccggctgggcaaggggccgcggggagcagctcgggactgaaccgagaggtgccgaagga accggcgggccgcttgatcccgctgcagacgtaggagatgcctgggacaaggaggccaccttctca gggcaaaagaaaaagaaggtgacaggcgttgagaccaccgaagggaacccatg
(Seq ID No: 845)
Homo sapiens fascin homolog 3, actin-bundling protein, testicular (Strongylocentrotus purpuratus) (FSCN3) :
agttctctctgggaacatctggtgggtactacaggccctattccaggccctatggcctgtggaacc tcaccacgggggggagggctgggccagacggagacatcacctgtggtgtcagccccatg
(Seq ID No: 846)
Homo sapiens X-prolyl aminopeptidase (aminopeptidase P) 1, soluble (XPNPEP1) :
cctccttcgcgccggcccttccgcgggtgatcagctggtctgcgctcccctgacgtgggctggggc acgtcaccgccgaatg (Seq ID No: 847)
Homo sapiens REX4, RNA exonuclease 4 homolog (S. cerevisiae) (REX04) :
gggtctcttccggagtcttttcctggacggggtccctgcggtgggtgtgtttcggcctggcctggg caggcgcttgtgctgccagggcgccgggcccggggaggccggggtctcgggtggccgccggcccag gcgctggacggcagcaggatg (Seq ID No: 848)
Homo sapiens LYR motif containing 4 (LYRM4) : ttttctttccaaaatg (Seq ID No: 849)
Homo sapiens DEAD (Asp-Glu-Ala-Asp) box polypeptide 24 (DDX24) : ggttcttcactcgcgactgacggagctgcggtggcgtctccacacgcaaccatg
(Seq ID No: 850)
Homo sapiens transmembrane protein 159 (TMEM159) :
ccttcttcctcttgttcctcctcctgcctctcttcgcttcgcctgcaaacgcggtgggggctgctc ggcggtcaggagcaggttaccctccgtctgcatgcccaccatcaaggtatgaggatggtagaagct ctcgtcgaaccagatggatgaagaccactaacggcttttgtttcctctggtaacagcaagagacag agcgacatgagagattggaccgcgggctgcactggagaatttactggtaggataattcatccctaa agagattgaagtgagcttcagaatg (Seq ID No: 851)
Homo sapiens NDRG family member 4 (NDRG4) :
cggcctccgcccctgcagccgcgggcacgcggaggggctcctggctgcccgcacctgcacccgcgc gtcggcggcgccgaagccccgctccccgcctgcgcgtctgtctcgtccgcatctccgcggcctcct gctccacgacgtgaccatg (Seq ID No: 852)
Homo sapiens pre-B-cell leukemia homeobox interacting protein 1 (PBXIP1) :
ttttcttctcgggctgcaaacaaagggaagcctgcaacaagttaagctgaagaccgaagcaagagc tggttcaggtggcagccacagcagcctcagggacctcagcaactatg (Seq ID No: 853) Homo sapiens twisted gastrulation homolog 1 (Drosophila) (TWSG1) : ctgtctctttaaggtgcccgaggctcgcgggcgctgcgctgaggggacggcgggaggcgcggcctg gcctcgcactcaaagccgccgcagcgcgccccgggctcggccgacccggcggggatctaggggtgg gcgacttcgcgggaccgtggcgcatgtttcctgggagttactgatcatcttctttgaagaaacatg (Seq ID No: 854)
Homo sapiens zinc finger protein 286Ά (ZNF286A) :
gtcccctttgtgaggcccgggatgggaggtgcccggttcccccagggacagcttcaagcggtaggg acagacatctgaggacccagcctcagggatgctgtccccgggcttccaggctccagcgccgtagga ctgaggcagactccacggtgagaaagagacccgatctaacccaggcctttcatcagagcccaggag ggaaggcaggaagtgggaccacgaggcccggggggcttctaactcgtctggccagggagatctgaa ttggggtgaagagcagaatctccagaacaaggaggaggtggtgatcatg (Seq ID No: 855)
Homo sapiens S100 calcium binding protein A14 (S100A14) :
gctcctcctgtcttgtctcagcggctgccaacagatcatgagccatcagctcctctggggccagct ataggacaacagaactctcaccaaaggaccagacacagtgggcaccatg (Seq ID No: 856) Homo sapiens ANKHD1-EIF4EBP3 readthrough (ANKHD1-EIF4EBP3 ) :
tgctcttctcgttcccgagatcagcggcggcggtgaccgcgagtgggtcggcaccgtctccggctc cgggtgcgaacaatg (Seq ID No: 857)
Homo sapiens KIAA1143 (KIAA1143) : ctgtctttacccagagctaccatg
(Seq ID No: 858)
Homo sapiens neuroligin 4, X-linked (NLGN4X) :
ctctctttttcttgcagaaccgtctctctcccttctctgtctcttagcacagagctcttattcage cactagcttggcccttcctgcttcaattgtaatgcttgttctgcccgtccacagactattggcggc agaaacaacgaatttcctccaaactaggcggtgttggtggctcttgcattcctctggatgaggaaa tctagttggggggttccagaaggggaaggctcctgggctttcaatacatcctcctgaatcatacct cgtttcgggttccctagaaaaatctggacgtgtaaaaagaactcttaacggccgatgcagctcttc caaagctaaggctgccttggagttttcataagaaattgtccctggaggtgttggatgatcacagct tccttggagcattgcagttgctggaatccagtttcaggattaagggagggctgcctccttgcaatg ggctgccaagaaaacggctgtgcttgttcttaacctcaggctctgtctgtgatcagtctgagagtc tctcccaggtctactgctccctggaaagccctatctctctgcaggctcgcctctgggctttgtctc cttggagccacatcactgggacagctgtggatgtggatgcagatttgaaccatg
(Seq ID No: 859)
Homo sapiens mitochondrial antiviral signaling protein (MAVS) : ccgcctcctcgctgcgggaagggtcctgggccccgggcggcggtcgccaggtctcagggccggggg tacccgagtctcgtttcctctcagtccatccacccttcatggggccagagccctctctccagaatc tgagcagcaatg (Seq ID No: 860)
Homo sapiens serine incorporator 1 (SERINC1) :
ctgtctccatcttgtctgtatccgctgctcttgtgacgttgtggagatg (Seq ID No: 861) Homo sapiens KIAA1324 (KIAA1324) :
cctcccctttttttccgccttctgccagcagaagcagcagccgcagcacctgagccgctactgccg ctcactcaggacaacgctatg (Seq ID No: 862)
Homo sapiens synaptotagmin IV (SYT4) :
ggacctccctctttgcctcctccctgttccaggagctggtgccctgggctctgcgctgttgttttc agcgctccgaaagccggcgcttgagatccaggcaagtgaatccagccaggcagttttcccttcagc acctcggacagaacacgcagtaaaaaatg (Seq ID No: 863) Homo sapiens pyruvate dehyrogenase phosphatase catalytic subunit 2 (PDP2) :
cttccttctggagctgggtcctgactagggaccgcctgggtgaggtgaggacctggtggccgcagt tgtggcactgtgcgcaggcgctgaactgaccggacggagcgggcggctgtggcctcgccagctggt ttaaaaatatccttttttgctgaaggaacacatttgctggtatagtttcagaatg
(Seq ID No: 864)
Homo sapiens gephyrin (GPHN) :
ctatcctttcctctcagtcctgccatctagctgccttgggtctcgcgctccgcagagcgttccgac actctccggcctcgttctgccgcctccgcgcgctctccccgtgcggccaccgcgccccccaagctt gcctccttcttgccggacttggggccgcgcgccctgactccttcccctcccgcggacccgcgcact cccggcgcggcctctcccccacgcaggccaccgtgcactctgtggcctccccctccttccccgctc tcctcgcgcttctctggctccctagctgtcgcgctctcctcggcgagcgcgctcccggcccgcgcg ctccgggctccggtttctcccggctcctgtcagtgcggtgactgcgctgggaaacatg
(Seq ID No: 865)
Homo sapiens deltex homolog 2 (Drosophila) (DTX2) :
ccttctcctgagagtcggagccacagccagagccctgcccaggccgagccggagctgcagcccgag cgcggtggtgccctcagccccgtcctcttgtcctcctcagcctcggtgccttggaatttgtgtcgc tgagtcagcaagcctttcagatttgcccggtttttgttgtttgtggtttgtatcaagatgggaact caaacaagtcattcctcctaaggagctggtgtcttcatccagaagggacagtttgtgccagctctc cagagagaaaaggatctggtactgttctggagtggcctgtagcagacactgaaccaccagccagct gcatttgttgtcctggaagtcattgccaactctgccagtcacactggggtccccagagaagtcaag atctgccggaggcgctgggcaatgaccccgggactccaggccagaggggtctgaagctgtttggga aagcagcgggactccttgggaagatg (Seq ID No: 866)
Homo sapiens melanoma antigen family E, 1 (MAGEE1) :
ctgcctttttcaccacctctaatttcagcttcagcagttgcttggaactttggttctggcagcagc agcaacatcattaccgctagcggcagttttgtgccgaggcacctacacacctcccgtcctctctgc cagatcgcgggcctgtcggtgtctgctcctacacgccaacgccggtgggcaggaccatg
(Seq ID No: 867)
Homo sapiens G protein-coupled receptor 107 (GPR107) :
cgccctttcaccccggacgtgggcgggagaggaagcggctggtgatgctggaacaaacatg (Seq ID No: 868)
Homo sapiens PDZ and LIM domain 1 (PDLIM1) :
cgctctttctccgacagctgccgggggtgccctgcaagctgttccgcgcgtcctgcccgtctgtcc ccgcgggtcgtcgcccgccacagccgcgccatg (Seq ID No: 869)
Homo sapiens thymosin beta 10 (TMSB10) :
cgctcttttgtttcttgctgcagcaacgcgagtgggagcaccaggatctcgggctcggaacgagac tgcacggattgttttaagaaaatg (Seq ID No: 870)
Homo sapiens phospholipid scramblase 1 (PLSCR1) :
agacccttttcagacccttttccggctgacttctgagaaggttgcgcagcagctgtgcccggcagt ctagaggcgcagaagaggaagccatcgcctggccccggctctctggaccttgtctcgctcgggagc ggaaacagcggcagccagagaactgttttaatcatg (Seq ID No: 871)
Homo sapiens eukaryotic translation elongation factor 1 beta 2 (EEF1B2) :
gggtcctttttcctctcttcagcgtggggcgcccacaatttgcgcgctctctttctgctgctcccc agctctcggatacagccgacaccatg (Seq ID No: 872) Homo sapiens pyrophosphatase (inorganic) 1 (ΡΡΔ1) :
ggctctctccttgtcagtcggcgccgcgtgcgggctggtggctctgtggcagcggcggcggcagga ctccggcactatg (Seq ID No: 873)
Homo sapiens X-ray repair complementing defective repair in Chines e hamster cells 5 (double-strand-break rejoining) (XRCC5) :
ggctctttccgctatctgccgcttgtccaccggaagcgagttgcgacacggcaggttcccgcccgg aagaagcgaccaaagcgcctgaggaccggcaacatg (Seq ID No: 874)
Homo sapiens GATA zinc finger domain containing 1 (GATAD1) :
gatccctttcccagtcctgcttcccagtgcctcgggccagggaatcctggcctccgcctgcggagc cggcggaacccgcttcccgcctccacggggcagcgccagcggcctggtcctttcaccggcagctcc gtgccgacgctctcaccgctcttcctatcgccgggagtggcgggccgaccagggggcggccgggct accgtccgccattcccgtgtctctgcgcccgcgggggccgcccgagccggccaccatg
(Seq ID No: 875)
Homo sapiens enolase-phosphatase 1 (ENOPH1) :
ccgccttttccagttccaggtgtgcagaagtgtcctctccccacgcgcggcgggctgcacttggtc gctggctccgagatcgcgcggggccgccggaagcccaagacggtaccgggggccgcagccgcagcc ggcgccgccctccgccctccccaacagcaggccgagtcccgtagcatccggtagggaaatg (Seq ID No: 876)
Homo sapiens regulation of nuclear pre-mRNA domain containing IB (RPRD1B) :
agctctttccgggggcccggggaactactctccttgcctcgctctgtctccttcgaagtgctctgc gcgaggttcagagcggccgccgcctccaaagggacggttttctagagctccgacgcctctcggtgc ccctctgctccggcccttgccctttgacctcgctctcgcggcagggtgagaggtcgggtggccatc ttgtggcggcggcgcgggcggctgttactgcggagacccatcccctcccccttctcgcacccctgg cagtctgtcagtcggtaaaaagtcccgcagcctgtcaggtgaggccccggcctcgtgccgtcgctc ttcccgccgcactgggcggcccaggccgctccctgccgggcctcactgccgccaccatg
(Seq ID No: 877)
Homo sapiens family with sequence similarity 60, member A
(FAM60A) :
ctatctttctagacaaggcagttgaggaggagggagcgcttgagggggactggcctggcgtgcact ccgcacctcggggacattattgcgcgtggaacggctgcttttggaaggcacaacttcctgaatgga ccatgactcccaccaaagatccctgtctctgattcaccaaacagcttcaaccctgaaaccaggacg agaagttgacaacatctgagtggacagctaattgacctaagacttcagaccagactattgcccaga agaaaagatg (Seq ID No: 878)
Homo sapiens MIDI interacting protein 1 (MID1IP1) :
gggccttttatctcggtgctgccgggggaggcgggaggaggagacaccaggggtggccctgagcgc cggcgacacctttcctggactataaattgagcacctgggatgggtagggggccaacgcagtcaccg ccgtccgcagtcacagtccagccactgaccgcagcagcgcccttgcgtagcagccgcttgcagcga gaacactgaattgccaacgagcaggagagtctcaaggcgcaagaggaggccagggctcgacccaca gagcaccctcagccatcgcgagtttccgggcgccaaagccaggagaagccgcccatcccgcagggc cggtctgccagcgagacgagagttggcgagggcggaggagtgccgggaatcccgccacaccggcta tagccaggcccccagcgcgggccttggagagcgcgtgaaggcgggcatccccttgacccggccgac catccccgtgcccctgcgtccctgcgctccaacgtccgcgcggccaccatg
(Seq ID No: 879)
Homo sapiens transmembrane protein 35 (TMEM35) :
ctctccctttgtcattctagctgcctgctgcctccgcagcgtccccccagctctccctgtgctaac tgcctgcaccttggacagagcgggtgcgcaaatcagaaggattagttgggacctgccttggcgacc ccatg (Seq ID No: 880)
Homo sapiens Fc fragment of IgG, low affinity Ila, receptor (CD32) (FCGR2A) : cttcctcttttctaagcttgtctcttaaaacccactggacgttggcacagtgctg- ggatg (Seq ID No: 881)
Homo sapiens tribbles homolog 2 (Drosophila) (TRIB2) :
ctttctctttttgtttggcttctaacgcgttgggactgagtcgccgccgtgagctccccgaagact gcacaaactaccgcgggctcctccgccccgtctgcgattcggaagccggcctgggggtcgcgtcgg gagccctggcgctgcagctccgcaccttagcagcccgggtactcatccagatccacgccggggaca cacacacagagtaactaaaagtgcggcgattctgcacatcgccgactgctttggggtaacaaaaag acccgagttgcctgccgaccgaggacccccgggagccgggctcggagcagacgaggtatccggcgg cgcccatttgggggcttctaactctttctccacgcagcccctcttctgtcccctcccctctcgctc ccttttaaaatcagtggcaccgaggcgcctgcagccgcactcgccagcgactcatctctccagcgg gtttttttttgtttgtcgtgtgcgatcctcacactcatg (Seq ID No: 882)
Homo sapiens family with sequence similarity 3, member A (FA 3A) : cgtcctctccgggggcggagcgggtcggcgggcctgacagggaacetccctgaccgagcccacgtc tccccacggccagagaaatctccggcccggcccgcatcgccagcccccaggcccggaggaacggcc cgagcccaggagaaccacatcttcgtcccagccccggaggctcctgtgggcaagatcgtgagccaa cgggttcctgaggcccctcctggccaggcagggtttccccgcgcgtttccgaggagccctgcctgg ccgggcggctggacaaacaggtcgtagcaccgatcgcgcccgcccccagcaggggtcccgcacagg cttgcccctgacccccacccaaacctgtccttccgctttgcccccaaacagtgcacttgccggcgg tcccaacccagcaggagaagtggacatg (Seq ID No: 883)
Homo sapiens exocyst complex component 4 (EXOC4) :
ggctctccccgcgtccaagatg (Seq ID No: 884)
Homo sapiens ELOVL fatty acid elongase 5 (ELOVL5) :
gcgccttcctcttcccatcgcgcgggtcctagccaccggtgtctccttctacatccgcctctgcgc cggctgccacccgcgctccctccgccgccgccgccttgctgctgctcaaagctgctgccgcccctt gggctaaaaggttttcaaatg (Seq ID No: 885)
Homo sapiens apolipoprotein B mRNA editing enzyme, catalytic polyp eptide-like 3G (APOBEC3G) :
ctttctctttccctttgcaattgccttgggtcctgccgcacagagcggcctgtctttatcagaggt ccctctgccagggggagggccccagagaaaaccagaaagagggtgagagactgaggaagataaagc gtcccagggcctcctacaccagcgcctgagcaggaagcgggaggggccatgactacgaggccctgg gaggtcactttagggagggctgtcctaaaaccagaagcttggagcagaaagtgaaaccctggtgct ccagacaaagatcttagtcgggactagccggccaaggatg (Seq ID No: 886)
Homo sapiens gamma-aminobutyric acid (GABA) B receptor, 1
(GABBR1) :
gctcctcctcctcccctccgtcggtcagtcagtccgcgaggagagtccgcggtggcggcgacggtg gcgagagccgcgggggccgtaggaagccaaccttccctgcttctccggggccctcgccccctcctc cccacaaaatcagggatggaggcgcctccccggcaccctcttagcagccctccccaggaaaagtgt cccccctgagctcctaacgctccccaacagctacccctgccccccacgccatg
(Seq ID No: 887)
Homo sapiens cofilin 2 (muscle) (CFL2) :
cctccttctcctcccagtgccacagagccgaagcccgagctgccgccgcagccacagccgagggca ctatg (Seq ID No: 888) Homo sapiens DEAH (Asp-Glu-Ala-His ) box polypeptide 35 (DHX35) : tgaccttttaccccaacatg (Seq ID No: 889)
Homo sapiens resistance to inhibitors of cholinesterase 8 homolog A (C. elegans) (RIC8A) : ccgccttccccggcgcgccatg (Seq ID No: 890) Homo sapiens FK506 binding protein 10, 65 kDa (FKBP10) :
agttctttgtagtgcctccctcagactctaacacactcagcctggccccctcctcctattgcaacc ccctcccccgctcctcccggccaggccagctcagtcttcccagcccccattccacgtggaccagcc agggcgggggtagggaaagaggacaggaagagggggagccagttctgggaggcggggggaaggagg ttggtggcgactccctcgctcgccctcactgccggcggtcccaactccaggcaccatg
(Seq ID No: 891)
Homo sapiens small ArfGAP 1 (SMAPl) :
cctcctcccgttccagctgccgctgccgcttcctgggctgagtccgcccgcggtcccggcggcgcc aggtgcgttcactctgcccggctccagccagcgtccgccgccgccgtagctgccccaggctccccg ccccgctgccgagatg (Seq ID No: 892)
Homo sapiens chromosome 14 open reading frame 93 (C14orf93) :
cctcctttttgcacacacacgaatacaaagagccatacgaccttcggatgccggaaggtccttctg aatcccttccctgttccttaggttgcactagtcgggggttccatgctggggggcagaaggaatgct ctctaccgtctgaaaccgttcatcaggaaggccttgatttgtgatgtgctaggagagcacaggatc tgcaaatagaaggcacctgtctcccttctgcaggccgaggagaggccgccatggactgtgtgcttc ttcatggcttgtttactcttctttcacagaccctacagcttggggcctgggctcctctgaccatec tcattgagaaaggaaagtgagtccagagaagttgatgcttcctacctgttggagcggcccagcagt gtaagcgtggttgttactgccccatccgccatg (Seq ID No: 893)
Homo sapiens brevican (BCAN) :
cgccctcttccgaatgtcctgcggccccagcctctcctcacgctcgcgcagtctccgccgcagtct cagctgcagctgcaggactgagccgtgcacccggaggagacccccggaggaggcgacaaacttcgc agtgccgcgacccaaccccagccctgggtagcctgcagcatg (Seq ID No: 894)
Homo sapiens H2.0-like homeobox (HLX) :
cggcctctcttcctcagtgcgggcggagaagcgaaagcggatcgtcctcggctgccgccgccttct ccgggactcgcgcgcccctccccgcgcgcccacccacccagtccggctggactgcggcagccgcgc ggctcaccccggcaggatg (Seq ID No: 895)
Homo sapiens v-rel reticuloendotheliosis viral oncogene homolog A (avian) (RELA) :
ccgcctctggcgaatggctcgtctgtagtgcacgccgcgggcccagctgcgaccccggccccgccc ccgggaccccggccatg (Seq ID No: 896)
Homo sapiens zinc finger protein 277 (ZNF277) :
cctcccttttcttttctgccgggtaatg (Seq ID No: 897)
Homo sapiens globoside alpha-1 , 3-N-acetylgalactosaminyltransferase 1 (GBGT1) :
cttcctcttttctgtctggcccgcggccccgctgcctgccctgctccaggctccacctgcgccgcc gatcgcccgggtatcgcgggggcccaggccagctgagtccgttttccgcgccggggtggcgcccct ccaaccgtcctaacgccgggccggcagcaaggagtgttcctgggacctcagagaccaggctcagag cctgacatccctgcgaggggacagcctcatccgcccaggccagtgggggtctctacaagtgcccag gctcaggtgcagcccccagcaatg (Seq ID No: 898) Homo sapiens FXYD domain containing ion transport regulator 6 (FXYD6) : ggtcctcctgggagtctcggaggggaccggctgtgcagacgccatg
(Seq ID No: 899)
Homo sapiens nuclear RNA export factor 3 (NXF3) :
tcctctctatgcttggggaaggaacttcctgtaagcaaggcttgaggcttgctctcgccttcgtca gcagccctcctcaatcttctccaaactcccgtccccaggccacacagattctcctcaagagagccc tataaggacattggtaaaatg (Seq ID No: 900)
Homo sapiens chromosome 14 open reading frame 133 (C14orfl33) : attcccttccgcccccttctctaagctgcacagcctgaatagaagggctggtccagcggcggcgga ggctggcgctgtcctgagagggagggctctgtgcggaagagtcagggcgacccttgggcgctggag tacgcttgggactggggctgcgagtgagcaccagcgattggttcggaagcggacatttggttcaga acgagcatttaactctgccagggatccgctgggctctgacgactgcggtagatccatggcttcctg gacgttcacccgtagagtcatcctagcttaactcttgttccctggtctcagttcacaagcctcacc tgtatcttcctggctcggaagataattgaaaccaagtctgacttctcaatg
(Seq ID No: 901)
Homo sapiens X-prolyl aminopeptidase (aminopepti- dase P) 3, putative (XPNPEP3 ) : ctttctcttcccgacgcgtgagttaggccgtaatg (Seq ID No: 902)
Homo sapiens death inducer-obliterator 1 (DIDOl) :
ggccctctggcaagatggctgctgcggaggcgttggagcgcggaaatctggaaccgggatggcgac gtctacactgagtcggaggcgaaggagcttactccacgggaacagcctctagataatctgagttgt tgaaaatacgaagcctgttactcgtgaacagtggctgacaacagtgttgttgtgagcctggctgtc tgcttggacccagaggtttcgtctgccagggtttttggttgtatttaggatttcagggaaaagtgt ccaagctttcagtgttggagcaggtatg (Seq ID No: 903)
Homo sapiens PERP, TP53 apoptosis effector (PERP) :
cggcctcttcgcttttgtggcggcgcccgcgctcgcaggccactctctgctgtcgcccgtcccgcg cgctcctccgacccgctccgctccgctccgctcggccccgcgccgcccgtcaacatg
(Seq ID No: 904)
Homo sapiens tubulointerstitial nephritis antigen-like 1
(TINAGL1) :
tcctctcttgactttgagcgtccggcggtcgcagagccaggaggcggaggcgcgcgggccagcctg ggccccagcccacaccttcaccagggcccaggagccaccatg (Seq ID No: 905)
Homo sapiens eukaryotic translation initiation factor 4H (EIF4H) : ggttcctctcggagcggagacggcaaatg (Seq ID No: 906)
Homo sapiens non-SMC condensin I complex, subunit G (NCAPG) :
ccccctctcgcgggaattatttgaacgttcgagcggtaaatactccctggggctgtcatagaagac tactcggagagcgctgcctctgggttggcgggctggcaggctgtagccgagcgcgggcaggactcg tcccggcagggttccagagccatg (Seq ID No: 907)
Homo sapiens MS19 nucleotide excision repair homolog
(S. cerevisiae) (MMS19) : tatcccctcccacggtctctagttcgcgttatg
(Seq ID No: 908)
Homo sapiens DnaJ (Hsp40) homolog, subfamily C, member 1 (DNAJC1) : ctgcctctacagctgtgtgtaggcctgggggcgagggtcttcggaacgtagcgctggctgcggccc cgcccgcctacccacccgcccgtccggcagccggctcccgccgcctccgcgctctgtctggggcca gccacctggcgggccgctccggtgcgcctgcccgcgcttttcactgacaggcgctgttccccacag ccagcgccgcccgccacgtcccagctctcggccaacggagctgcgcggcgggtgacctttccgagc ccagcgcgatg (Seq ID No: 909)
Homo sapiens stimulated by retinoic acid gene 6 homolog (mouse) (STRA6) :
ctaccctttcatctctgcaactccttcctccctgggcctcccttctggtgtgtctgtgggtctgtc taggtgggcttgggaaaggggaaggaaggggcgtctctttaggcagctcagactggacaagccttc tttgaaaatggtcctttgaacacacgcctgctggtggttggtcagacagatgcgccagcgggagcc ccggggccccaaggggacagctatctctgcaggaccagtgcgatg (Seq ID No: 910) Homo sapiens 5-azacytidine induced 2 (AZI2) :
cagccccttttccggctgagagctcatccacacttccaatcactttccggagtgcttcccctccct ccggcccgtgctggtcccgacggcgggcctgggtctcgcgcgcgtattgctgggtaacgggccttc tctcgcgtcggcccggcccctcctgcctcggctcgtccctccttccagaacgtcccgggctcctgc cgagtcagaagaaatgggactccctccgcgacgtgcccggagcagctcccttcgctgtggaagcgg cggtgtcttcgaagaaaccggaagcccgtggtgacccctggcgacccggtttgttttcggtccgtt tccaaacactaaggaatcgaaactcggcggccttgggggcggccctacgtagcctggcttctggtt gtcatg (Seq ID No: 911)
Homo sapiens polymerase (RNA) I polypeptide E, 53kDa (POLR1E) : acgccttttccggcccgcagcgcggcctgggctcccgcgtgtttaaaagtgcgcttgtggctgctg ctgtcttaactcctgtgcttggcggacagacaggcgagatg (Seq ID No: 912)
Homo sapiens mitochondrial ribosomal protein S25 (MRPS25) :
agtcctttctcgtcgctgctcggctcgcggcccgtggggtcggccccgccaccgttgccgccatg (Seq ID No: 913)
Homo sapiens TRM2 tRNA methyltransferase 2 homolog A
(S. cerevisiae) (TRMT2A) :
cggcctccgccgcacgcgctggcggactaagagtggctggcgaagcgagcggccggcgcgggcccc tggcgggcgggcggtacagccccaagcctgagacccggacctgagcatcgcaggttcgagtcccgc cccgcctggggcgaagccgggggtggcggcgacctcgcggcgttgcaccggctctgtgagcacctc ccctctgagcacttcccttgtgacaggccacttcccttgtgacaggcccaggacgaggtggccagg cggcccccatggcgtccctggtctaggcggagaaccgcctgggcgatg (Seq ID No: 914)
Homo sapiens lipid phosphate phosphatase-related protein type 2 (LPPR2) :
ccctccctccacctcggagtctgcgcggcgcggccaggcccggccgaccgcgtctcggtcttcgcg tctgccagcctggctggcagtccgtctgtccatcccgccgcgccggggcagtctaggcggagcggg ggctcaggcggcggcggcctcgacgcgagtgagtgtcgtggttggggtgctggacccagagtgcct accctcgcctgcctgggcctcagtttccacatctgcacaatgggggtgaccatccctgccctgctg gctgccaggagcggctgtgagtcttcaggcgtggatgcagcctgggggaagccatagggcgctttc acaggcctggccttcaccatg (Seq ID No: 915)
Homo sapiens chromosome 11 open reading frame 1 (Cllorfl) :
gaaccttttttcacctcgtctgaaatg (Seq ID No: 916)
Homo sapiens microtubule associated monoxygenase, calponin and LIM domain containing 1 (MICALl) :
cgccctcccacccgctcagacctggttgccagcccaacaggaagcggcccctcccggcttcggagc cgccgccactcatctctgcccagctgctgccctccccaggaggcctccatg
(Seq ID No: 917) Homo sapiens kinesin light chain 2 (KLC2) :
gctcctttaaggcagcgaacgggccaagagaagcgtgtttcgccccctccgacgccaccgaggtag cggcttcacctttaaggcggcgcgggggctgctgggaaggccggcgggatggaggcggcgggaccg gctcgcgggtgcgggtccgggtgaagcgggaggcagccagagtcggagccgggcccgagcaccagg cgcaggcccggcgcccgcctgcccgcaccctcgtcctcacagacgccacagccatg
(Seq ID No: 918)
Homo sapiens DNA cross-link repair IB (DCLRE1B) :
acttcctttttctgcccactctggtaacttattgctctgctgggctctttcccttagggtctctgg ccctgttcttgccccagcatgacttttatcgggacgccgttgtggaagcctcacgcaggagccctg cccccgtggagaagatcccactggtgactccaaccctaccaccatg (Seq ID No: 919)
Homo sapiens armadillo repeat containing, X-linked 5 (ARMCX5) : gctcctcccactgccgttgtgggtaacgcggacgtggaagaacctcgtctgcggaggaaaaggtag atgttaaatggtaactacgcgcgaggttctgaggagccctgggaacaggaaggagaaaagaatacc aaaagtgacaacagtttgccaatcgcagtctttaatctgataaagcggttatctcgtcttgagtcc caggtgccgagtcaatccccatacacagccgccgccattgcctcgagtccttgtgtctgactgtct gttcctgctgctgtatgacacagcacctcgaggcaaggaaataagaaaactgcctctgatccaagc agagaaggtctgcctgtagatctgctgtagggcttgtcaecattggaagcaaggtcctacttcagt ggcagatctggtggccttggagtggctgaagaccaccaccctccacagggctgggcccatgcacag ccatccttccctaccttgagtgagcttcctctgcatgttttctatatcactggcagagcctgtagt tggaaaggggacagagtgactactggactttgtgtgaaaacaccaaccgggacaaaacttcagtca aggctgagacgggtgggggtatataacttgtccttacgttaaacttggaacatg
(Seq ID No: 920)
Homo sapiens chromosome 12 open reading frame 43 (C12orf43) :
aatcctttgcggtggttcaagatg (Seq ID No: 921)
Homo sapiens vacuolar protein sorting 33 homolog A (S. cerevisiae) (VPS33A) :
ggtcctcccgtaggaaccggcggactcggttggcgttgtggggcagggggtggtggagcaagatg (Seq ID No: 922)
Homo sapiens arginine/serine-rich coiled-coil 2 (RSRC2) :
gggcctcctcgcctttgtgccatccgggtctctcgcgcgagcgatttagtctgaggcgaagcttcg gagcggccggtactgttgaaagcgacaagtggaggcgccgctctagcggccgggactctgaactat ggcggctagtgatacagagcgagatggactagccccagaaaagacatcaccagatagagataagaa aaaagagcagtcagaagtatctgtttctcctagagcttcaaaacatcattattcaagatcacgatc aaggtcaagagaaagaaaacgaaagtcagataatgaaggaagaaaacacaggagccggagcagaag caaagagcgtgcttatgcgcgaagagactgaactgaagacgctgcagactcagatagcaaaataat aagcctacttcatgataagggaagaagacatgaatccaaagataaatcctctaagaaacataagtc tgaggaacataatgacaaagaacattcttctgataaaggaagagagcgactaaattcatctgaaaa tggtgaggacaggcacaaacgcaaagaaagaaagtcatcaagaggcagaagtcactcaagatctag gtctcgtgaaagacgccatcgtagtagaagcagggagcggaagaagtctcgatccaggagtaggga gcggaagaaatcgagatccagaagcagagagaggaagaaatcgagatccagaagcagggaaagaaa acggcggatcaggtctcgttcccgctcaagatcaagacacaggcataggactagaagcaggagtag gacaaggagtaggagtcgagatagaaagaagagaattgaaaagccgagaagatttagcagaagttt aagccggactccaagtccacctcccttcagaggcagaaacacagcaatg (Seq ID No: 923)
Homo sapiens integrator complex subunit 3 (INTS3) :
ccgccttcccaccccccgcccttccactatggccgcttctgtgtggtgtggggagacgctggtcct ccccgtcctcccatagcgcttattgcctcaccctcaccccctaggggccggatccaaaggcgctgc actccccaagccttggggcatcagccaggaaggtttcctacctcctaattcaggggcaggactcct cttttccccccacggggaaaagaggcagaaacttaggggtttccctcctttcttagggtcagacgc tcttagggtccacttcttcaggggcggaagcctctcctacccttcccataggggcacaggccttta ccccactgtacttcggagccaacgcctttccctcagcactgccaccccagagtcaggacccagagg actgtgccttcgcccccaacgcaggcgcggccttttggagaggagggaggagtggagaggacaggg gcccttgctctcccctccccaacttgttcctcttgccccccagtccctggcaatccagagatcccg atatctaggactgtccatccatccactccctgaccttttcccggctcctggctgcagccatg (Seq ID No: 924)
Homo sapiens spermatogenesis associated, serine-rich 2 (SPATS2) : tctcctttcctcttctcagacccgggagcgtccgggacgcggagcccggagctggggcgacgaggc gattgcgggggcctgggctagctgctggctaccaatattctactttctgtctctatgaatgtgact accctggttacctcatataatctccctggaaaaggagacatgaatgtctgcaatgatacttcctga caagaagttgatacaagaaaaggaaaggagattaacagctagtgagcagaatttcgaacagcagga tttcgtattttttgcttccaactgcacacttccgttgcccacttttaaatcagagatacctacact caaaacccagacaaggcaaaaggatacttttcttgtatattttttgagatcgaagaaacgacaatg (Seq ID No: 925)
Homo sapiens fibroblast growth factor receptor 1 (FGFR1) :
ccgcccctttcacctcctggctccctcccgggcgatccgcgccccttgggtctcccctcccttccc tccgtccgcgtctcctgcgccccctccctgcgctcgtcccgccgctcttcccgccgcccaactttt cctccaactcgcgctcgggagctggcgaggcggcggcggctcctcaggtcagtttgaaaaggagga tcgagctcactgtggagtatccatggagatgtggagccttgtcaccaacctctaactgcagaactg ggatg (Seq ID No: 926)
Homo sapiens FUN14 domain containing 2 (FUNDC2) :
ctccctcttccgctgccgccgtgggaatg (Seq ID No: 927)
Homo sapiens ganglioside induced differentiation associated protei n l-like 1 (GDAP1L1) : cctccttctttcctgcctctgattccgggctgtcatg
(Seq ID No: 928)
Homo sapiens chromosome 19 open reading frame 43 (C19orf43) :
agtcctttgcgcggcacctggcgacaaaatg (Seq ID No: 929)
Homo sapiens MIS12, MIND kinetochore complex component, homolog (S. pombe) (MIS12) :
ccctctcttctccaccagccaacgtccgggaaaaacgagtaagtacaggttccttctgccaatccc cgccggccacagctaactttcccgcccggcccctttctgtcataattgaggtgtccacaaccagcc aatcaggaacgcgagagtatcccgcgtttgctttcgctcgccgaggcgcgtatcagtcggaatttt ggggagccaaccgcgccgtctgtccctggcaagccagcggcggtttaaaggaggtggcgggaagcc tgtgtgtgcttcaaatcgtcaccctcatggtcgctccggtaagtgctgcggggcagcattttctct gaggaggagcggggacgggcgagactggcataagcgtcttcgcgagggagcaaggcggcctgtggg tcggcctcaccccggcctccgacctgaagatcccagcatgcagcgcgggcgcggggcccgacggaa gccgggagccggccggaagcagttcctgcgctctggcttctgggtcctgtcctgcgcgatcgcggg gtcttagacagctcaactcgccgagatgacctgggcacctctgcgttgaatcggcaaatactgatc aagccgcatttattctgctctcaggaactctaagtctagcagagaagatgaggcggtagaagttca tcaatggcttggctggaggacaagcaaattgaggacattggcaacggagtgatcaaaatgatagat catgaggcctaaaatgaataaggaaagaagagaagtggcagaggctgagaacagaaagagagggtg gaggggctgtaaatcttgaagattagggtataatatgagtatatgggtaagaattggaagaattgt gtaggaggcagtagtcaaaaagtagaagcagtttggaagagtagttacaaatatcaagagccaggt ggctaaaaggtggagctataggtcattgaagctcaagaaactgagtctctagggcattggttaagt catctgtctagacttcaaagttgtctaggatgataattcagaagactgatctgtgccaaagtcaca ggtttttcacgactgaaaacaacatagcaaaataagccaagatg (Seq ID No: 930) Homo sapiens DEAD (Asp-Glu-Ala-Asp) box polypeptide 50 (DDX50) : cttcctttcacgctgtcgctgcccgtaggtggttgtggccactgtgcccggagggaggcggcggtg gccagtaatg (Seq ID No: 931)
Homo sapiens chromosome 7 open reading frame 25 (C7orf25) :
cggcctctgcgtgcacgcgcctgcgtgctcgcgctcgcggttctggcgctgccggaataatgctga cagcatg (Seq ID No: 932)
Homo sapiens KxDL motif containing 1 (KXD1) :
ccgccctttcctgtcgtgacttaacgcacgcaagcggctccagggtacgtccccgccacgcgcgct cgcaggatcggtgcgtggtgacgtttcgccggcgcgggcgccatcccggaagcgcgagcaaggccg ccagatgtgcaggcagcggaggaggagaaagagatg (Seq ID No: 933)
Homo sapiens defective in sister chromatid cohesion 1 homolog (S. cerevisiae) (DSCC1) :
acttctttcttgcccgccaagcccgcagccacccgggcgcggcgggactcctagacccggcgctgc gatg (Seq ID No: 934)
Homo sapiens zinc finger protein 426 (ZNF426) :
cgttccttttgtgacgccggctgtgagcgcctgagagtctttttgcctttcagagttaaggcctca ctggcctgggaaaataattgctgccttttgcatccgcgttggctccgtccccaggatcttcccggt tcagggacctggcgatttctgagtgttccggaatcccaataaccctgtttaaagaggaatggagat tgccactgtccatttagattaatgaggtgtcctgaagtgatggtgacatcaatgaaaggagggttc tgacacgttctcacctcgcgggatg (Seq ID No: 935)
Homo sapiens TATA box binding protein
(TBP) -associated factor, RNA polymerase I, D, 41kDa (TAF1D) :
caacccttttcttccgcacggttggaggaggtcggctggttatcgggagttggagggctgaggtcg ggagggtggtgtgtacagagctctaggacaccaggccagtcgcgggttttgggccgaggcctgggt tacaagcagcaagtgcgcggttggggccactgcgaggccgttttagaaaactgtttaaaacaaaga gcaattgatg (Seq ID No: 936)
Homo sapiens PHD finger protein 1 (PHF1) :
ccgcctcctcctcctgccgctgccgctgctttggctgctgcgtcatacgccccagagccgccggga cggaggggctgggcctggggaccccccggcctccgcctgcacgcccccccacgcccggacgtgccc tctccgcgcgggggactcgcctaggtctcctacgtctgcccctgcccggctcccggcggccccagc tgtcaccggcccccccaggatgcaatg (Seq ID No: 937)
Homo sapiens family with sequence similarity 134, member A
(FAM134A) :
cccccttccgcctgacgcgcccccggcggcggccgcgcagccctggctcctcgcgggctcgggcgg cggctgcggcggggctatg (Seq ID No: 938)
Homo sapiens membrane bound O-acyltransferase domain containing 7 (MBOAT7) :
ccgcctcctttccggagcccgtctgttccccttcgggtccaaagcttttggctcctccttgttccg agcccgaaggcccgccccttcacgtactcggagctcggatcccagtgtggacctggactcgaatcc cgttgccgactcgcgctctcggcttctgctccggggcttcttccctgcccgcccggggccctgacc gtggcttcttccccggcctgatctgcgcagcccggcgggcgcccagaaggagcaggcggcgcgggg gcgcgctgggcgggggaggcgtggccggagctgcggcggcaagcgggctgggactgctcggccgcc tcctgcccggcgagcagctcagaccatg (Seq ID No: 939)
Homo sapiens major facilitator superfamily domain containing 11 (MFSD11) : acgccccttttttgctcagccgtcagccccgtctccgtctgaagagtgcttctgccctcatttgcc tctccctgtgaccccggccccctcagactccgctgcgtcgtctctcggccccgtccagccgttcct gactgctcttcgccggagtccgcttcccaaccccctttcgccagagcccgagagctccgtcggctc tgcgtcctggcggattgtcagtggcttcgccccgaggagagctgactgccctgggctgctgcctcc ggcagagctgagccaaaatg (Seq ID No: 940)
Homo sapiens thiamine triphosphatase (THTPA) :
ctcccttccccctctgtgggtcccgcgaggagactctcgggctttgaggtgagacctgaagttccg ctggccggtagtgtagcaggaaagggcaggtcctcccgggtcgtgagccagtagcctcctggggtg gcaaggtgtagagaggggggcgttgaaaggacacccgctacccggcctgctttctaggggtctctt tggattgaggacatcagcagcagtggaagggattttactggagacctgtcactgtcagagccttaa aatatcaccgacggggccttaatgtcaccgaggtagagagaaaagggcagtagccctagagactat tgcgacacagtgtgcccctcataagtttttccagggaggggttctgtactgagttgacgccccagg agctgagcaccaggctttgcatccttgggaactcagcaaacgtttgttcagccaattgcaggtagc atg (Seq ID No: 941)
Homo sapiens acyl-CoA synthetase short-chain family member 3 (ACSS3) :
tactcccttccctcaggccccaggaagttgcaagagtaccatttgtcgcacactcggggaccgcgg gtggccggaggagatg (Seq ID No: 942)
Homo sapiens chromosome 6 open reading frame 211 (C6orf211) :
gctcctccttcgcggcggtaccgcctctgtttctgcggcgattgaacagccgagctttgcggccgg gatcgcggaaagtgatg (Seq ID No: 943)
Homo sapiens transmembrane protein 204 ( EM20 ) :
atttcctctctgctgagagccagggaaggcgagctctgcgcacacgggcgtccctgcagcagccac tctgctttccaggaccggccaactgccctggaggcatccacacaggggcccaggcagcacagagga gctgtgaacccgctccacaccggccaccctgcccggagcctggcactcacagcaggccggtgctaa ggagtgtggcgcgggctcgactcccactgctgccggcctcccgagtgactctgttttccactgctg caggcgagaagaggcacgcgcggcacaggccggcctccgcttcccgggaagacggcgcactcctgg ccctgggttcttgctgctgcccaccctctgctccctgggatgggccccgaggcgagcagcttcagc acaggcctggccctgctccaggtgcaggaaggaggataaggccgggccgagaggcggcacacctgg accatcccatgggcctccgcccgcgccgccccgaggatgagtggtgatgtcctctagccaccccta gcagcgtcggctctccctggacgtgcggccgcggactgggacttggctttctccggataagcggcg gcaccggcgtcagcgatg (Seq ID No: 944)
Homo sapiens DEAH (Asp-Glu-Ala-His) box polypeptide 40 (DHX40) : tcgtctttcccctcccatctcctcagatcggtggacgtgctcgcctccactcggggccaggtctat g (Seq ID No: 945)
Homo sapiens importin 4 (IP04) : cctccccttttcggcccagtagcggcggctcag- ttgctgccatg (Seq ID No: 946)
Homo sapiens N-acetyltransferase 10 (GCN5-related) (NAT10) :
ccttctctttcggagttgttccgtgctcccacgtgcttccccttctccactggctgggatcccccg ggctcggggcgcagtaataatttttcaccatg (Seq ID No: 947)
Homo sapiens lin-28 homolog A (C. elegans) (LIN28A) :
aaccctttgccttcggacttctccggggccagcagccgcccgaccaggggcccggggccacgggct cagccgacgaccatg (Seq ID No: 948)
Homo sapiens CAP-GLY domain containing linker protein family, memb er 4 (CLIP4) : cggcctttcctccgcgcccccgcgtccccagccggccgctccgagaggacccggaggaggcaggtg gctttctagaagatg (Seq ID No: 949)
Homo sapiens zinc finger, ANl-type domain 1 (ZFAND1) :
ccgccccttacggcgccggagagatg (Seq ID No: 950)
Homo sapiens GTPase, IMAP family member 6 (GIMAP6) :
cctccctttttctacttccgaggctgcaaagtgcaacagcagactcttctgactcaggaaggccgg tgctcctacccacttcctgttcctccatctccagcggacactgctctttcaagggcaggtctccag cccagctctctgaaaacattttgctgaaaatataagcaaacatcggccttgtcctccttgtgttca tacactgtggaagcttttctctgcctcctccgtgagagtgcgtggccgggagaccagaaacgtggt cctttctcttgcctgtgagctggtgcagagatg (Seq ID No: 951)
Homo sapiens thioredoxin domain containing 15 (TXNDC15) :
cttcctccggctggcagcacgactcgcgtagccgtgcgccgattgcctctcggcctgggcaatg (Seq ID No: 952)
Homo sapiens asparagine-linked glycosylation 9, alpha-1, 2-mannosyl transferase homolog (S. cerevisiae) (ALG9) :
aattcttttttccccaggcttgccatg (Seq ID No: 953)
Homo sapiens glutathione S-transferase, C-terminal domain containi ng (GSTCD) :
acttccctttttccggtccgccggattatgaatgacggccggcgcgagtattttccacataaggtg gctgtcgtttttctcctggcgtctgtggaggcgagtggtctgcgggcagcagctcccagaggcagc cttggaattccagctcggactgggcgggaaggcgcaggcggcccaggtcgccgacacgctcacgca ccctccctgcctggccgcgcctctgcgaccaggtgacccaatgaaagaagaaaatg
(Seq ID No: 954)
Homo sapiens CXADR-like membrane protein (CLMP) :
actcctttttctttccaaacagggaaaagtgttccacgaagcggtagcgcctttccgcctcgcgtt ttcctccctgaccctggtcccggctcccgtccgggcgccagctggtggggcgagcgccgggagccc atctgcccccaggggcacggggcgcggggccggctcccgcccggcacatggctgcagccacctcgc gcgcaccccgaggcgccgcgcccagctcgcccgaggtccgtcggaggcgcccggccgccccggagc caagcagcagctgagcggggaagcgcccgcgtccggggatcgggatg (Seq ID No: 955) Homo sapiens nonhomologous end-joining factor 1 (NHEJ1) :
cctcctcttgcggtggggggaaagcggcctcttactctaggcctttcggtttgcgcgagcgggcag gaaagcgtgcgtgcggctaagagagtgggcgctctcgcggccgctgacgatg
(Seq ID No: 956)
Homo sapiens gametogenetin binding protein 2 (GGNBP2) :
cctccttcttccactccccgcggcgcgagcggctgactgcccgtagaggaaacgacattcggagct gcgctcccgcccaggccggccctgacgcgggcctcgtcagccagtaacagggagcagaggtgggag ttagcgaggcgaccacgaaaacggtgaaggtcggaaccgacagcctcctccgagaagggcaggagc tgggaggaggcggcagcggcggcggcagaaacagcagcggcggcggcggcggcagctgggaggagg tggtgacggtggcaacggcagcgtcggggacgatg (Seq ID No: 957)
Homo sapiens zinc finger protein 672 (ZNF672) :
ctttctcttttagccccgcctgcttcccggctccagctggggccggagaggctgagtggttggtac gctgctcgctggcctcccagtcttcccagcaaccggtgacactgcccgcgccagactgaccactag ccgacgcgggcgagagggacaggagcgtgacctccccatcccgaggggccggacgctcgggcgcct ccccgctccccccactcggaggccgcgcgcgccgttagccccttcctcgctcccccgccccagtcc cgcagtccgggaggcgggggtcggcagccggctgagtgggaaccgcgcggtgtctgaggaggcagt cggcgaccggtttccacttcaagcgtgacccttttgcctgtgggatgagctccagcatggggtgag gtacagaagagagacttgaagagcgtgccttgggactcaagcgccaaacctgtaccctagcgagtg tcctactccgcatccgtaatggaaggaaatgcacatcttactccagaggcacaagaggaggacatc ccatgcggctactcctgcccagcgtggtggggcagcagaagctccagagcccagacttgcaggctc acggtgcagggtgaacctggccacagctcaccctggaacagccacaatgtctgccccttagagaag aaccctgaaatcagaccagtttttgcggcctccccctttcctctctgttacagtgccctttccagg ccttaagagaagtaaaacttagctgcagcgccaggaggtggaccccagagtgtgagtggcacgctt ccctgtgaacccgtcctcaccatg (Seq ID No: 958)
Homo sapiens N (alpha) -acetyltransferase 60, NatF catalytic subunit (NAA60) :
ccgcctccgtcccggctgcggcccctgccggttacataactcgttgcgggctccgcgcggtcccac ttcccggctcccttcgcctccaggatgcgctgagccctacaacacccccagcggccgccggctccc ccacgaggtgtgaatg (Seq ID No: 959)
Homo sapiens transcription elongation factor A (Sll)-like 4
(TCEAL4) :
tgccctctgtccccgcggctgggtctcgtctgctccggttcctgggctcctaattcttggtccagc ttcttccaggtcagtgtgcgggccttccacgctgccagcggaacactggaatggcggaaggggaac gggtctgcgcgtctgttgttcccagcgctctgcgaagcctgaaaaggaggagcaacctgtccagaa tccccgcaggacaggaaaaggaggggaaatctcgacatg (Seq ID No: 960)
Homo sapiens progestin and adipoQ receptor family member VI
(PAQR6) :
tcccctttgtctccccactccccgcccaggcctggcccgcctgcctggccactcttcctccatcag cctggctggcagcagccttggactccgcccgtggagccctgggcctgttgacccaccagcttagga gcacccaccaagctctgggtaaggaagctcaccttctggggctcttctgggaaaatagaggtcaac gtggaggtaccaggccaccatgctcagtctcaagctgccccaacttcttcaagtccaccaggtccc ccgggtgttctgggaagatggcatcatgtctggctaccgccgccccaccagctcggctttggactg tgtcctcagctccttccagatgaccaacgagacggtcaacatctggactcacttcctgcccacctg gtgaggggaggctctgccccaggccgcggccttgagctcagagggggtacccaggcgggcagggac cgtccaggcccacgggctgcagcggcagtcgcgggggtccgcggcggcctgagcacgcgcccgccg caggtacttcctgtggcggctcctggcgctggcgggcggccccggcttccgtgcggagccgtacca ctggccgctgctggtcttcctgctgcccgcctgcctctaccccttcgcgtcgtgctgcgcgcacac cttcagctccatg (Seq ID No: 961)
Homo sapiens DENN/MADD domain containing 2D (DENND2D) :
catccttcttgctcaaccactgggtgcacaggatggaaacttctattccctctctggaagacagcg cgtggcttggcttcacagagttgtggctggagaccgaagcagcccctttctcaggcttactgtcac cagtctgtctgtgttaggggagaggggagtccgctctgtcctgaaggcccagagatg
(Seq ID No: 962)
Homo sapiens family with sequence similarity 188, member A
(FAM188A) :
ccttcttctttcctgcctcaccttccaattcgtttgccgccgccgtcccgcagctgctgtttccgg agttgccccttccccatgttccggggcaggagtccgcaaagcgaagatccgcccgccggttcctca tcatg (Seq ID No: 963)
Homo sapiens neurensin 2 (NRSN2) :
ccgcctttgctcggcggagacagcaggcagagagatgaggaaactgagacccagaaaggtggaagc acttgtctaaggtcacgcctccaggaagcagtgtgtccacgactccagtccaagtggtcaggctcc agagcccacagtcccaggggtccatg (Seq ID No: 964) Homo sapiens tripartite motif containing 46 (TRIM46) : agccctcctcacacccccactgggctcctgcattaagcccggggttcgcagccgcagccgggatcg ggcacccaggggcgggcgggcacggtagggccatg (Seq ID No: 965)
Homo sapiens target of EGR1, member 1 (nuclear) (T0E1) :
catcctctctgggaatttaccgatgcccagaacgcccttctttcccccacacgaccctctcctagt ctaactcctgggcgtgctttaagctcagctcaggcagcgtcaccttctctggaaagcccaaaccca gccaccccactacccgctacccgcggcccacgctgatgaagacagcagaacacggaggccccgcgt tcccgccgcgagagcaggagagaaagattacctcccgcgagctctagcgcgcccggctttccggcg cactccagggggcgtggctcgggtccacccgggctgcgagccggcagcacaggccaataggcaatt agcgcgcgccaggctgccttccccgcgccggacccgggacgtctgaacggaagttcgacccatcgg cgacccgacggcgagaccccgccccatccccgactgcctgaaccgcgccaggagacggaccgcaag tccagcgtacccacagacgactcaggcgggagacgagcggtgtcatg (Seq ID No: 966)
Homo sapiens DBF4 homolog B (S. cerevisiae) (DBF4B) :
cgttcttttaggggtggagccggcaggaaatttaaactgaagccgcggccgaaaacgccaagagat tgatgctgtagctgccctgagataaccaggactgtggaatcgggaagagctcatggagctcgcgaa tgtaatacggaggcctctgaggaaggagtacggaggccgagaaggagccggcatttgatg (Seq ID No: 967)
Homo sapiens myc target 1 (MYCTl) : atttccttttatg (Seq ID No: 968)
Homo sapiens myosin XIX (MY019) :
ggttcctttcctcactgcacgctcttgcccctcctcttttctctcctgcccgtgttcttcccgccg cctgacctggcccgcccgcctttccagtctggccgggcgggggcctgaagcacggcggctcgggcc gtgggaccgtgttcacaccctttccagaaattcttggctggtaaccgcgaaaccgactggagcagg agctgggagaactggagaaaactgctctaatctcacttgactccagctaggagctgatgctgcatc gtaataacatttgcagagcgctttcacaggcgctggagtgacttgtctgagattcctccagaactg agccctttgttggaaccataccccagcccatggtcccatgactaggtggatagtactccttgtacc tcctgcaacccagaaccctggctgaccactttgaaggaggatg (Seq ID No: 969)
Homo sapiens KIAA0226-like (KIAA0226L) :
cctcccctttctgctgttaccgggagcgcggtggccacggaacgctgcccggagccgcgcgaggga ggacccgacgcgcggcgtttacccagcgcagcgttccaccgctcgggtttggctggataaaataaa aaatggggatattgacctcctgtcactactgcatggactttgatggtttccaatcattactttctc ctctgtgtcaatctgcctcttcgagaaatteatactcctgaatagctctccagacccccagctggc catgtggtgagttcagggcccaaatcaagtagtaccagcaatcagggaactcctatctgttttgaa tggattcacaccagccacaagcctggaaagatg (Seq ID No: 970)
Homo sapiens US81 endonuclease homolog (S. cerevisiae) (MUS81) : ctccctcttcccccgccccgccctgggccaggtgttcgaatcccgactccagaactggcggcgtcc cagtcccgcgggcgtggagcgccggaggacccgccctcgggctcatg (Seq ID No: 971)
Homo sapiens zinc finger protein 430 (ZNF430) :
gggcctttgtccctcgctgtggcctgagctccaggtctcgtcttcagcgctctgtgtcctctgctc ctagaggtccaggctctgtggccctgtgacccgcaggtattgggagatctacagctaagacgccag gaacccctggaagcctagaaatg (Seq ID No: 972)
Homo sapiens mutS homolog 5 (E. coli) (MSH5) :
gctccttttgcaggctcgtggcggtcggtcagcggggcgttctcccacctgtagcgactcaggtta ctgaaaaggcgggaaaacgctgcgatggcggcagctgggggaggaggaagataagcgcgtgaggct ggggtcctggcgcgtggttggcagaggcagagacataagacgtgcacgactcgccccacagggccc tcagaccccttccttccaaaggagcctccaagctcatg (Seq ID No: 973) Homo sapiens proline rich 3 (PRR3) : gccccttcctcac- taccctccaaatcccgctgcagccattgccgcagacacgatg (Seq ID No: 974)
Homo sapiens sirtuin 2 (SIRT2) :
cgccctttaccaacatggctgctgacgccacgccttctgggactcgtagtccggtcctcgcgcgct ttcttacctaactggggcgctctgggtgttgtacgaaagcgcgtctgcggccgcaatgtctgctga gagttgtagttctgtgccctatcacggccactcccatttctggtgccgtcacgggacagagcagtc ggtgacaggacagagcagtcggtgacgggacacagtggttggtgacgggacagagcggtcggtgac agcctcaagggcttcagcaccgcgcccatggcagagccagaccgactcagattcagactctgaggg aggagccgctggtggagaagcagacatg (Seq ID No: 975)
Homo sapiens KIAA1715 (KIAA1715) :
ttgtctctctgtcagtggcggctgctgcctgctctggaggcaggctgggcggtggcggccgagact ggcgggggtggacgcccgggccgggctgcgcccgcttcttgcagctgtgaattcctttggacaatt gatgatatttatcattgtgcccagtttctacaaataaaagatg (Seq ID No: 976)
Homo sapiens proline-rich transmembrane protein 1 (PRRT1) :
ctgccttcatctctccatctctgcgctgctgccggctgcgccatccagcacccagactccagcacc ggccgaggacccccactccggctgcagggaccctgtcccagcgagaccgcaggcatg
(Seq ID No: 977)
Homo sapiens t-complex 1 (TCP1) :
ccgccccttccccggagcctcacttccgtcacagtcctgtttctctccctgttgtccctgcctctt tttccttcccgccgtgccccgcggccgggccggggcagccgggaagcgggtggggtggtgtgttac ccagtagctcctgggacatcgctcgggtacgctccacgccgtcgcagccactgctgtggtcgccgg tcggccgaggggccgcgatactggttgcccgcggtgtaagcagaattcgacgtgtatcgctgccgt caagatg (Seq ID No: 978)
Homo sapiens Yipl domain family, member 5 (YIPF5) :
cgttctttggccctgtgacacgtagcaacggggctggttcagggtctgaaacagagtttgggggtt gtttgggattagtgaagctactgcctttgccgccagcgcagcctcagagtttgattatttgcaatg (Seq ID No: 979)
Homo sapiens glucose-fructose oxidoreductase domain containing 2 (GFOD2) :
cctccctttccagagcccccagttccttagaaaccaggcggcgcgttcccggtggcggcgccctgg actcccgggcccgcgcatccccgccagccttccttaaggcggatgggtggcccccgagaccccgtc ggacccatggtttccagtgcagcgcggagtgggcgatgccagcgtgccaggagccatgtctgacca ggacgtttggaagatcatatccatgccagaggctcttgtgaggagatgagttggtaaagagagagg ctgggatg (Seq ID No: 980)
Homo sapiens apolipoprotein L, 2 (APOL2) :
ttccctttcgaattccagggtatatctgggaggccggaggacgtgtctggttattacacagatgca cagctggacgtgggatccacacagctcagaacagttggatcttgctcagtctctgtcagaggaaga tcccttggacaagaggaccctgccttggtgtgagagtgagggaagaggaagctggaacgagggtta aggaaaaccttccagtctggacagtgactggagagctccaaggaaagcccctcggtaacccagccg ctggcaccatg (Seq ID No: 981)
Homo sapiens microtubule-associated protein 4 (MAP4) :
ccgcctccctgcgccccgcccctccggctagctcgctggctcccggctcctcccgacgtctcctac ctcctcacggctcttcccggcgctctcctggctcccttctgccccagctccgtctcggcggcggcg ggcagttgcagtggtgcagaatg (Seq ID No: 982) Homo sapiens exonuclease NEF-sp (LOC81691) : cttccttctttgccaggca- gacgcccgttgtagccgttggggaaccgttgagaatccgccatg (Seq ID No: 983)
Homo sapiens ST6 (al- pha-N-acetyl-neuraminyl-2 , 3-beta-galactosyl-l, 3) -N-acetylgalactosa minide alpha-2, 6-sialyltransferase 5 (ST6GALNAC5) :
ctgtctctaatctctgcaacagccgcgcttcccgggtcccgcggctcccgcgcgcgatctgccgcg gccggctgctgggcaaaaatcagagccgcctccgccccattacccatcatggaaaccctccaggaa aaagtggccccggacgcgcgagcctgaggattctgcacaaaagaggtgcccaaaatg
(Seq ID No: 984)
Homo sapiens heterogeneous nuclear ribonucleoprotein Al (HNRNPA1) : tgctcctttctgcccgtggacgccgccgaagaagcatcgttaaagtctctcttcaccctgccgtca tg (Seq ID No: 985)
Homo sapiens zinc finger protein 93 (ZNF93) :
gggtcctttgtctctcggtgcagccggagctccaggtctcctcttcactactctgtgtcctgtgct cctacaggcccagcctctgtggccctgtgacctgcaggtattgggagatccacagctaagacacca ggacccctggaagcctagaaatg (Seq ID No: 986)
Homo sapiens N-terminal EF-hand calcium binding protein 3 (NE- CAB3) :
cggcctctagccacaccgagtccgccgcggcgtccagggtcggcagcaaccgcagccgagcccgag cgggtggcggcgccatg (Seq ID No: 987)
Homo sapiens splicing factor 3b, subunit 5, lOkDa (SF3B5) :
cattcttctgcgacggcgcggacctggagcttccgcgcggtggcttcactctcctgtaaaacgcta gagcggcgagttgttacctgcgtcctctgacctgagagcgaaggggaaagcggcgagatg (Seq ID No: 988)
Homo sapiens INO80 complex subunit B (INO80B) : gtcccctttcctcgcag- gacctcatg (Seq ID No: 989)
Homo sapiens polyamine modulated factor 1 binding protein 1
(PMFBP1) :
ctttcttcctcttggcttatattagggataggggatgtggtttgttacaaaggatgagtattttga tagcttctcattccttgaactattctgcaggtttataacaaagctcagaaaatactaaaggttaaa ggagaattgagagctgccaaggaaatg (Seq ID No: 990)
Homo sapiens pseudouridylate synthase 3 (PUS3) :
cttcctttctcggaaacgcggcgcggccggctgccggaaaacagggcagacctgtatggttcgttt attcctggggttgtcatatcatg (Seq ID No: 991)
Homo sapiens heterogeneous nuclear ribonucleoprotein D
(AU-rich element RNA binding protein 1, 37kDa) (HNRNPD) :
tattcttttttagtgcagcgggagagagcgggagtgtgcgccgcgcgagagtgggaggcgaagggg gcaggccagggagaggcgcaggagcctttgcagccacgcgcgcgccttccctgtcttgtgtgcttc gcgaggtagagcgggcgcgcggcagcggcggggattactttgetgetagtttcggttcgcggcagc ggcgggtgtagtctcggcggcagcggcggagacactagcactatg (Seq ID No: 992)
Homo sapiens GABA(A) receptor-associated protein like 1
(GABARAPL1) :
atttctccatctggctctcctctacctccaggcaggctcacccgagatccccgccccgaacccccc ctgcacactcggcccagcgctgttgcccccggagcggacgtttctgcagctattctgagcacacct tgacgtcggctgagggagcgggacagggtcagcggcgaaggaggcaggccccgcgcggggatctcg gaagccctgcggtgcatcatg (Seq ID No: 993)
Homo sapiens chromosome 22 open reading frame 13 (C22orfl3) :
ccttcctttccccagtgttgagcgcggtctcgcctccgcttcctcctcactccgcctgccggctgg gaaactagggcaccagtacgatagttccggcaccggaaaagagggctgatgactgggcccgggggc cgccgcaacgacccttggggccggcaaagagccagagagggtgctcacacttccaagcaccccaca ccaaggacaggctggacggcaaggcggagacgcggggcttgggccctcagaccggggacagcagga ggttgggccaagggccaggacttcccgtcacaatttcatttgttgatcccggcaccgccaggtaag gggggccctgagtgaggctaggtatctggtacggataaagttaggtatagagtagagcggctgccc gctcagggttatccctaaagacagttggaggagagttgcttggggcctcggggatgcactgggcgg gatcagggcttacacctaggactggcaaaagagcgggacccggcagaggcggggcttgccgaaggg acgagcctctattcaggaaatgcacgagctttggggcggggctcaaagaaaggggcggggcttccg gggcccgcgtcctggtgagctgcgcgtctgcgcgaggattgggcgagagggtggggccactcaacg ctgaggcggcgaatggccggagcagacttaaatcaagaggctggggacctctaagatcaaagtttg gggcggggcctaaggagggggcggggcctccagattcgagacctggaagggctggggcggcgcttg gggcggccctgccgccgcctcccgttctcccctccgcagcggcggcggtggcggagaaggaactcg acacgcaccgaccgccctcccgccccagccgaagcggaagctgtagcccgctctgggccggggcca tgggcgccccgcgccg.cccgggtcatg (Seq ID No: 994)
Homo sapiens Ion peptidase 2, peroxisomal (LONP2) :
ggctctttttgacagcccccagtgcgaaaggctgccagcatg (Seq ID No: 995)
Homo sapiens RNA binding motif protein 4B (RBM4B) :
ggttctctctgacgtgggagccgccgtcgctgccgccacccggaggctcttgtcaggatg (Seq ID No: 996)
Homo sapiens protocadherin alpha 3 (PCDHA3) :
aggtctttctccacaaaagaaataacagcgtgcattacgtattcagatactgctttgcttcatcct ctctaaaatttaacaccgaggagtttaagaaatgaagataaggaactcgaattatttttaaacttt ggatcaatgtaaaggcaatctaatatttggaaaatacttgcaatg (Seq ID No: 997)
Homo sapiens RAB34, member RAS oncogene family (RAB34) :
gcctctccttgggccccttctctccccctttcccctccctgctggttcctggcatcgccagatgct gcgcagcagtctccgattccccatcaccaattcggctggcgtctccgagaccgcggactcccgtag ggtccccgtggccccgagttgtagtcgggacaccccggccgcgggtgatcgtcgggtctccacgcg cccgggtcgctgacgcggatccggcctcggcgccttctcagggcgccctgcaaggccgcaggcagg atg (Seq ID No: 998)
Homo sapiens cell division cycle associated 7 (CDCA7) :
gctcctcctgctgtgggaccgctgaccgcgcggctgctccgctctccccgctccaagcgccgatct gggcacccgccaccagcatg (Seq ID No: 999)
Homo sapiens ArfGAP with GTPase domain, ankyrin repeat and PH doma in 3 (AGAP3) :
gggtcttttaggagagcactgctgcagccggcagtggagagcctgggcagggagacagggagaaaa ctccggcagcagggtggtctctagggctgacctcggagcctggggacaggggagcctatgccgcac tgaaggcgggacgctgtaagcgaggagcagctgggcctgggcggactcctcggccaatcagcctcg gtcagcagcaccctcaggcgcagggcactgtttgggcattgcctagagatccgacaccccgcccag atcagcgcagggaggcgaaagcgacagccgggcgcgggaggagaccagggcagctgtcccctccgc gagggtggccctcgaggcaatgcgggtgggggctggtgaggaggcggaagggccgaggctgagtgg gaggggccggggcgccagggctggagcgcgcggctcgggggtggaggctgcagagccagcgagcga gcgaggggcgggggcgcccgggccggcgcgcaggaggggcgggggcggcggggaggggggctcggg ctgcgtgtgccggagccggcgggggcggcggtgcgtgcgcatgacgcggggggagggcctgggccg cgcgctcccggtcccgttgttgttgccgctggaggctgctccgaggcagcgggatcacggcgctgg gaagcgctcggcagcggcggccacagcgtgcgcggcggcgcctcctggcctcggcctccggccccc ggcccccggctccatgcgctagccccgcgccgccagcccagtagtcccggccccgccagccccgcg ctcccgctcgccgctgccgccgccgccgccgccgccgcctccgccgcgccgccccgggcccgcctc gggccccacggctccgaagccatg (Seq ID No: 1000)
Homo sapiens potassium channel tetramerisation domain containing 1 0 (KCTD10) : ctgcctctctcagtccgggtttggagactcctgcgtcctccgacttttcatg (Seq ID No: 1001)
Homo sapiens cyclin Bl (CCNB1) :
cattctctgcgaccggcagccgccaatgggaagggagtgagtgccacgaacaggccaataaggagg gagcagtgcggggtttaaatctgaggctaggctggctcttctcggcgtgctgcggcggaacggctg ttggtttctgctgggtgtaggtccttggctggtcgggcctccggtgttctgcttctccccgctgag ctgctgcctggtgaagaggaagccatg (Seq ID No: 1002)
Homo sapiens eukaryotic translation initiation factor 2A, 65kDa (EIF2A) : gtttctctttccgggacaacatg (Seq ID No: 1003)
Homo sapiens protocadherin gamma subfamily B, 7 (PCDHGB7) :
cagcctctagcctgggattccctgcgcagccaacaacagaaaagaaaaccagctcccacacagagg ctcccggctgcgcagaccttgcccagcacaccagattgccagctccgagacccgggactcctcctg tcctgggccgaatgctcttttagcgcggtagagtgcactttctccaactggaaaagcggggaccca gcgagaacccgagcgaacgatg (Seq ID No: 1004)
Homo sapiens acyl-CoA dehydrogenase family, member 11 (ACAD11) : ggctctttcggcttccttcctcgctgggccggctaaacccggccgcagcagcaccggggtgataag tgtccagggcaggaggccagcgatgttgccttgctaaccgggtatctaagagaaacagggtctttt tattcttaggctcgacagtctgacggccctttttctgaacgggaccctgcaggtcttccgcctgct gttgcattaaatttgggggtggaagaggcttctgcgttgttccttacccgcaacgatgaccatggc tttgccttctttaaaattgaggcctccaactctgacgctgactggagaattgaaacccgaacacac attgggctcttttggcacttgactagagctaaaacctcgggattcagcgggcaagcgttgctcagc aacggcgcgtaggctgtgtgcggttggctggagccagaccccaccccggcctcggcccatgctcta gaggggacgttgccccaatcctgaaggacttcggcactcgagacctgtggatgccgcgttgctgtg gcctgcgggggtgatcatg (Seq ID No: 1005)
Homo sapiens zinc finger, CCHC domain containing 7 (ZCCHC7) :
ccgtccctctacgcgttttggttcccggttggtgcttcctgttcgcagctgcggcacttcaaggtt actgactttttatg (Seq ID No: 1006)
Homo sapiens zinc finger, YND-type containing 12 (ZMYND12) :
gggcctttctggacttggactccttgggagtcgtttctcggccatttgacccgtgggacttgtggg ttttgtgctgctttttctttctttcttccccttttccaacttcagcaatacacccagatgttagtc gagtcacgtcccgccgccctctgcccttgaaatgctggcaagtacgcagccccgcgatcgtcacgt gacgccggggttcagcgtatccttgctgggcaaccgtcttagagaccagcactgctggctgcacca tg (Seq ID No: 1007)
Homo sapiens forty-two-three domain containing 1 (FYTTD1) :
cgctccctcggtgcggcgggctgcgtgcgcgagtgggaggtggcaggcctgcgactccggccttgt ccgcgcccgctctcggcgcgacgtctccagccatg (Seq ID No: 1008)
Homo sapiens SH3-domain GRB2-like (endo- philin) interacting protein 1 (SGIPl) :
ctccctttctctcagcatcttcttggtagcctgcctgtaggtgaagaagcaccagcagcatccatg gcctgtcttttggcttaacacttatctcctttggctttgacagcggacggaatagacctcagcagc ggcgtggtgaggacttagctgggacctggaatcgtatcctcctgtgttttttcagactccttggaa attaaggaatgcaattctgccaccatg (Seq ID No: 1009)
Homo sapiens GTPase activating Rap/RanGAP domain-like 3 (GARNL3) : cagccctttttgcaaatg (Seq ID No: 1010)
Homo sapiens DCNl, defective in cullin neddylation 1, domain conta ining 5 (S. cerevisiae) (DCUN1D5) :
gagcctcttgcttgctgtgactggtggagctgccgcgctgtccgcgttatctcctcccggtgagaa cgaaccgcagtgtccaccggcgaggagccagccctgtcccggtcagagaaagacgacgaggatacc tgggagcgggcggcggccgggctgggccgcgccggtgcgggctggcgactctgctcctccgcttgc tgctgtctctgggaactgggtgccagcgctgaggggcttccagcggacagggacccccttccccgg ctcccctgcccaccctgccggggagggcggaagatg (Seq ID No: 1011)
Homo sapiens alkB, alkylation repair homolog 7 (E. coli) (ALKBH7) : tgccctctctcatgaccccgctccgggattatg (Seq ID No: 1012)
Homo sapiens nitric oxide associated 1 (NOA1) :
ccgcccctttggagctacttcctcatg (Seq ID No: 1013)
Homo sapiens BTB (POZ) domain containing 10 (BTBD10) :
tcgcctcttcgcattgtgagctctcgcggtaagaggctgaggagccggcctgcaacctgccggggc ggctccgctacgcgcagccgcctcagtggcttcctccacagccacctccggagggatctggctgag gaggaagtggaggtgtcactggccccggcctttgccccaatcttgtgtgggcactgaagggggact acaggttcgagagttatgggtgctacatgtgtgctttcagagcagtagtgtgaggaagcttggagt gggatg (Seq ID No: 1014)
Homo sapiens zinc finger protein 397 (ZNF397) :
cggtctttgtggcttgcagctcggggtgggtggctcatttcctggccgctcctgggcttcgcggaa agaagagattactcacactccttcgcaagcacagaaccagttgtactgagctttttgctaagctgt ttcagccaagaatg (Seq ID No: 1015)
Homo sapiens mitochondrial ribosomal protein L45 (MRPL45) :
gctcccttcccggcggcctttgcgggaacaagatg (Seq ID No: 1016)
Homo sapiens AKT1 substrate 1 (proline-rich) (AKT1S1) :
cttccttctccatattgtatactggaattgaagccaaggaggtaccattttgctcgagggcatggc ctaagccggtcagctaaggccatgttaatacggggctgtcccatctctctgcggggcgcgacagct ggaagagccgaacggataagagaagaggaggtgagaggagctgtacaccacaagaggcactgaggg actcaggataacgggatgaagccgtcagtgcccccagaaacgaagcggccccggacgaatttctga gtcaccgtcgcgagaaagcgggctgagccgccattttgaagcctggcaaaccgaagcaagaaatgc tgccgtgttggatctttgccagccttcgtgccgaatgggagcaggttggagggagggagagccaat atacactatgggctgattaagcccggttggctgccatgttgttaacgagcaccgatttcctctact tttgtcgaagaagtttattgtgggtcagggacgtcaggtcgcttgccttcgtttactgtggtcatg attgagcatatgaggacggccattattgttgggggcaaatggaaatgctctaggcggggccatttt tcttaggggcaagctgtcgtcacccttgtcaactggttcggatgaagcccctgtggccgccatctt gatctcgggcggccccgataagggaggcggagtgtgcggagaggaggcggggcaactgcgcggacg tgacgcaaggcgccgccatgtcttttgagggcggtgacggcgccgggccggccatgctggctacgg gcacggcgcggatg (Seq ID No: 1017)
Homo sapiens transmembrane protein 101 (TMEM101) : ctgccctttcccaa- gatg (Seq ID No: 1018) Homo sapiens eukaryotic translation elongation factor 1 delta (guanine nucleotide exchange protein) (EEF1D) :
ggccctccctttcatcagtcttcccgcgtccgccgattcctcctccttggtcgccgcgtccttggc tggcgttagagacagggtttcaacgtgttagccaggatggtctcagtctccagaccctgtgatccg cccgcctcggcctcccaaagtgttgggattacaggtgtgagccaccgtgcctggccgaggctcctt cttttatg (Seq ID No: 1019)
Homo sapiens ADP-ribosylation factor GTPase activating protein 2 (ARFGAP2) :
cgccctccccgccgtggattggcccgcggcgggacccgtcagccgcggttgtgtctgggaaggaga gaaaatg (Seq ID No: 1020)
Homo sapiens junctophilin 4 (JPH4) :
atttctctcctccctgggggtctcagtgcatctccttctcctctctgcctgcctcctccctcaccg aagggttagcggacacccatccttttctgcttggggaccccaccaccacccgcaacactgccgctg tctcttcttcaccgtatccttctctacccaccctcttctctcttctcttctccctgcccctttaaa tctgcctggcccagcctcccccgtgatgctgggatggagcaaacattgatttgtgctgggatggaa tcggaattttgatttatttttcctctcccaaccataagaagaaaaaaataataaaaacaccccctc ttgagagccccctccccctttgcatccagctcccagctcttcttccctatctccatccaaggcaga ttttttcccctacactattctcatcttcccccacccttgccactacctcgcccccccacccagcct gctcctccagctggggagagaggggactctccggactcccccacctttcctctctgggttggagca gtctctccggaaggggagggggcttggcttgtccgggcgaggtgggagtggaggtatcctgccatg gatgctgtgccggggaggcagcctgagccccagcccacatgagacgccgaagaaccggggcagagg ggtcctgacagcagccagggaaacgggtgccctacgattctgcccagccccctctcaggaccccca aactgccatccacactcgacacttcggggttctagccactcaggatgagggtccggccctgcctgc cctcgctggggcccccccgcccggccccggtctaactgcccccgccccgaggcctcgcccggctcc aaggcccccagcaggctctccagtcccaggatgcgctgagccgccggggggctgaggccgcgccaa ctacatgcatg (Seq ID No: 1021)
Homo sapiens embryonal Fyn-associated substrate (EFS) :
ttttctttctcctcctccaaccttggcggaggccacgactcaggcgccacagctgggggctagagg ccgcggaccatggtgcggggcagccaccgctgaagtcagcaaaaccgagcctggcctgaggcaggc tgcgcgggaggccaaagccatg (Seq ID No: 1022)
Homo sapiens GH3 domain containing (GHDC) :
cgctccttctttctggccggatgtgtgctgagacccagagtcacccaggggtctccgtcacgtgcc aggagtaggcagaagtgggctgtgacagatcaggaaacagagctcagtgcagcccactaaattgct cagggccctacagctaacaagcggcagaggcaggatctgcactcaggagctgcttggagatg (Seq ID No: 1023)
Homo sapiens acrosin binding protein (ACRBP) :
ggctctctctgcggcttggcccgttagaggcggcttgtgtccacgggacgcgggcggatcttctcc ggccatg (Seq ID No: 1024)
Homo sapiens jagunal homolog 1 (Drosophila) (JAGN1) :
agttctcttcacggagccgcgcggctgcgggggcgcaaatagggtcagtgggccgcttggcggtgt cgttgcggtaccaggtccgcgtgaggggttcgggggttctgggcaggcacaatg
(Seq ID No: 1025)
Homo sapiens ligand of numb-protein X 1, E3 ubiquitin protein liga se (LNX1) :
gttcctttcctgggcatcagcttgcctgctctcagcctaagctctctcgccaaccgtggtggctcc ttgcgttcctacatcctctcatctgagaatcagagagcataatcttcttacgggcccgtgatttat taacgtggcttaatctgaaggttctcagtcaaattctttgtgatctactgattgtgggggcatggc aaggtttgcttaaaggagcttggctggtttgggcccttgtagctgacagaaggtggccagggagaa ggcagcacactgctcggagaatg (Seq ID No: 1026)
Homo sapiens cyclin-dependent kinase 2 interacting protein (CINP) : tctccttctacggatatctgtggaccttatg (Seq ID No: 1027)
Homo sapiens splA/ryanodine receptor domain and SOCS box containin g 2 (SPSB2) :
gcttctttccgcccggctccttcagaggcccggcgacctccagggctgggaagtcaaccgagctcc cttccaggtcaatccaaactggagctcaactttcagaagagaaagacgccccagcaagcctctttc ggggagtcctctagctcctcacctccatg (Seq ID No: 1028)
Homo sapiens Berardinelli-Seip congenital lipodystrophy 2 (seipin) (BSCL2) :
cctcctcctttcctccctctactctgacacagcacttagcacctgaatcttcgtttctctcccagg gaccctccattttccatatccaggaaaatgtgatgcgccacaggtatcagcgtctggatcgccact tcacgttttagccacaagtgactcagtggaagatccagagtcaacagaggctcgtcaggaagatg (Seq ID No: 1029)
Homo sapiens tubulin, alpha lc (TUBA1C) :
caccctttcactacttctcccccggactccttggtagtctgttagtgggagatccttgttgccgtc ccttcgcctccttcaccgccgcagaccccttcaagttctagtcatg (Seq ID No: 1030)
Homo sapiens l-acylglycerol-3-phosphate O-acyltransferase 9 (AG- PA 9 ) :
tttccttcctctcttcccttcgcagaggtgagtgccgggctcggcgctctgctcctggagctcccg cgggactgcctggggacagggactgctgtggcgctcggccctccactgcggacctctcctgagtgg gtgcgccgagtcatg (Seq ID No: 1031)
Homo sapiens l-acylglycerol-3-phosphate O-acyltransferase 1 (lyso- phosphatidic acid acyltransferase, alpha) (AGPAT1) :
gcccctttctttccttcgcttcctcttttagagaatgtccggattgctattggactttggagcgta tggctccaaatcaactcattggctaaaacttgacggaaaatggtggttaggtggccagaatg (Seq ID No: 1032)
Homo sapiens abhydrolase domain containing 14B (ABHD14B) :
cggcctcttcccagcgttcctcctccggccccaggtcaccgccagcacgcgcctgcttcccgtctg cgcgagtccacgcagctccccagatcaagaagctgaggccccaggttacacactaaagtaaatggc agaggcagaaataacacctatgtcctcctgaccccaaggcatgttcttaaagttctggaaacctcc tggaggcttccttgctgctcctctgggactgccaccctgggcagggtgttctgtggcccctcatca tcgtggttttgaaccacaggcccttcaccagcacagcagcagcaggcatg
(Seq ID No: 1033)
Homo sapiens protein tyrosine phosphatase, non-receptor type 5 (striatum-enriched) (PTPN5) :
catcctcccgccagcctgcccgcctgctcgccggcgcccggagcccgctctggccgcttgcttttt gctgagaaagcttcctgccctggaagatggcacccttccccatccagacaccttgggaatg (Seq ID No: 1034)
Homo sapiens carbonyl reductase 4 (CBR4) :
cttcctccttttcacggcgtcttgcattactattgtgcggctgcaggaggtgtcgagcggcgttat ttttttttgcggtttgcctttttttttcttttttttttttttggaaccgcggttgtttaaaagcct gagggaacctggagaggggctcccactccctaccctctttcctccgagtttgtgactccgagatg (Seq ID No: 1035) Homo sapiens zinc finger CCCH-type containing 10 (ZC3H10) :
ggctctttgtcgaagctagaggaccggcaggcggcagcagcaactacggcggcggcggcagaaccc agcagcgatgtggaggtggagacccacaggagccccggacttcacctgagctacctcagtggtcac caagagtggcaagataaagaaaaccctgagttgggcgggaccaggatg (Seq ID No: 1036) Homo sapiens poly (ADP-ribose) polymerase family, member 10
(PARP10) :
ccgtctttcagtttcacttttgttttcctgctcccagcagggttaggcttgctgaggggcaggcac aggagtcctggctgagctcatggcctgaggctgcctagcggccacggggaatg
(Seq ID No: 1037)
Homo sapiens RNA pseudouridylate synthase domain containing 4 (RPUSD4) : ccgcccttccttgtaagatg (Seq ID No: 1038)
Homo sapiens family with sequence similarity 73, member B
(FAM73B) :
ctgcccttccgcagcgatggcatcccgggtgagtatcggccccggccgagcccccaaggcgggcgg gcagcgcggcagggccgggacttgagcggaggaccgagtaggcgcaggtgtccgggcccaacagga ccaggaaggtgtcggggttggaatgagtgggtacccgggccggggacggtgcgagagggtgccttg cttgggagcggaacgagaaggtacttgggtcagggaggtgatgcccgggcctggaacgtggcgggg attggagcaggcgcgcaggtacccgatccgaggcggggagagcacccgggatggaaggagcaggcg tgcgggccgtgagcggcgccagagggtacctggctctgtggaggggccctctggtatgtgtgtccc tgtccttctggggcgtggatggtgcctgggacccagctggcaaccagttgaagacgttctccttgg aagctcttggccctgaggactttgcctggggcattggccctgccatg (Seq ID No: 1039)
Homo sapiens protein phosphatase 1, regulatory subunit 15B
(PPP1R15B) :
gcgtctcttccggcgtctaggggggtgtcctgccggcgcgcgggccctgcggccattttgggcttc gcttccaccgcaccagccggcctacccagtccttccggtatcgcgttgctcaggggcttttcaacc ctctgtcagtcggaaaaccatcgccgaggccgtggggggactcctatccatggtgttgaagcgtcg agccgactagggaacctccttccccgccaggatggaagtcgcatcagtcgccgcctattgcgcggg ctgttcttccctgtgttctgccgcccgctgccgcattcgctgccctctgtggcttttctgctggct cgaagatcggcctggagcagcgacgccaccgctgggcaaggccgagactctgtaggcttcctccga atcccgtcgacctccagccgctgagcgccgcggccctacctgagagactgtcaagaaaaaggagat g (Seq ID No: 1040)
Homo sapiens family with sequence similarity 104, member A
(FA 104A) : ccctctcttcgcggagcggcgccgcgtagcttccatccgccagctgccatg (Seq ID No: 1041)
Homo sapiens PRP38 pre-mRNA processing factor 38
(yeast) domain containing A (PRPF38A) :
agccctttacactacggtgtttccggcttcaagatggtcgcctaagctgtttagtgaaacttcttc cacctttctccattcctctaggtgctttttctgaacctggatgtgaggcattaaaggatccgacgg aaatagaattgaaggcattctaaaatg (Seq ID No: 1042)
Homo sapiens synaptotagmin-like 1 (SYTL1) :
cctcctccgtgtggggcagctgctggctgggctgcctgttgagtcagccttcttccctcacggctc ttctcccggtccctgaaactcggctgccaggggagctggagccacctgcgaaggtgtcctcccata ctggacccctacaggaagctccgtgtgcccagctggggcacagccccagctgatg
(Seq ID No: 1043)
Homo sapiens ubiquitin associated and SH3 domain containing B (UB- ASH3B) : getccttttcctttttgatccattcaaaaattactcattgcaaattcccggactgetaggcgagga gagggaagggggcggaggagacagggctactgcaggcgcagagctgggggcagccgggggcccgag tggctgaggctggtcccgcagcggccgcttgccggcgttctggctcctgtggcctcaccaggaagc gtcagagtcccgacactggggaagctcggagcgccgcctccgctgccgccgcctcctgcctggctc tgggtccccgagccccctcccctggcccagcccgactccctcctccttcccgaaccatccggctcg ggctccttccctggcgatggctggccgctgagccatg (Seq ID No: 1044)
Homo sapiens transmembrane protein 241 (TMEM241) :
ccgtctctgggcggctgctgccgctgccgctgctgctgctgcgggggtcgggcggcggccagggga tttgggcaggcaccgtggatccccgagaaggggacgagttgacagatg (Seq ID No: 1045) Homo sapiens ataxia, cerebellar, Cayman type (ATCAY) :
gagcctctgccagccctgagctgggaagaagcagctacctcggaggcagggcgcgcaggcgggcgg cgatgagagggggcgcagccgcagccccgcgctggggagcccaccgctaaccctgcaccccaccca cccctgcacaaaagagctggcgggcgctggccacgtcgccctgggtgaccttcctcggatgcagaa tccgcccctgcgagcatcctcttcctcctaggctctgaaggcccggggagcgtgagcgatgcccag ctgcacccgggcagggctcgcctttgtttgccagtaaggaggagaggctgtctcagctgcagaggg gtcatccctgcttcaagccagtgcctcttcccagctcccatg (Seq ID No: 1046)
Homo sapiens ELL associated factor 1 (EAF1) :
attcctctctcacccccacgcagaggagagaacttgcttctggacccgggtgggtgccggctcggc tctccttgtcttccagagcggtggcccggaagcacagtcctcccagacgccagcgccagaagctcg gatcgcggctgcaccgggagagcgccgatctgggtgcgaggcaggtgcggggccatg
(Seq ID No: 1047)
Homo sapiens tripartite motif containing 5 (TRIM5) :
gttcctctaggaaaattcctttgtgcagatcaggcccgtggattggtgagtgaatcctaaccacgt cttccctggcctgtcttcactcttctccccagaatcaccacttctgcactggtgtctgaaggtgta ttgagtgattttgtggagggcagaagtaggaagtctttgggacaaaactgtatttaccttgggatc tgtgaacaagaggaacctcagcagccaggacaggcaggagcagtggaatagctactatg
(Seq ID No: 1048)
Homo sapiens wingless-type MMTV integration site family, member 3A (WNT3A) : cgccctctcgcgcggcgatg (Seq ID No: 1049)
Homo sapiens chromosome 16 open reading frame 45 (C16orf45) :
ctccctccctgcagcccgcaacgggaatggagtaaagggagacccgtcgacctggccacggggatc agegatg (Seq ID No: 1050)
Homo sapiens zinc finger protein 502 (ZNF502) :
cattcttccggtttcagaagttaaggctggtgtcctggccccagtccacctctgggagcgcctgcg ccgctccgcggagagtccgtggatctcacagtgaaaaatgtttgctgacccttgacattgacaaac tgctgacagctcagatgatccatgattggaaggatgtggtcatcaccaagatgtctttctttctcc ggttcccagttttccagacctgaagtgttttccaatcaaagcgaagagacgatctgtggatg (Seq ID No: 1051)
Homo sapiens armadillo repeat containing 6 (ARMC6) :
ggctctcttgcgcaagcgcgctgtccgcttcttctgggcggacgctctggaggcaaaacatttccc tgctgggggcggcgaccaccgtgagcgtcccggaaggggcggcaaagacgcctccgtcgcgcacga ggtggcctcgttggctttaccttggttcgcggtcgtccttggttatcgtgagcgtccgcgagtctc tgggaggccaagcctaggggcgccacagcgcctgcgcgcgtacggcggccggaaggggctagaggc ggctccctgggtgacaaccgcgcgccccacctttccccacgtggccgcgaagaccggctcaggagc atctatcggctgcacgccaacatcaacacaggcgaagatg (Seq ID No: 1052) Homo sapiens post-GPI attachment to proteins 3 (PGAP3) :
gctcctcccccggcggcgagccagggagaaaggatg (Seq ID No: 1053)
Homo sapiens histone cluster 3, H2a (HIST3H2A) :
tgccctcttgtttttagtctcgcttttcggttgccgttgtcttttttccttgactcggaaatg (Seq ID No: 1054)
Homo sapiens ethanolaminephosphotransferase 1
(CDP-ethanolamine-specific) (EPT1) :
ggctctcctaccttctcgggcagcccagtctttgccatccttgcccagccggtgtggtgcttgtgt gtcacagccttgtagccgggagtcgctgccgagtgggcgctcagttttcgggtcgtcatg (Seq ID No: 1055)
Homo sapiens F-box and leucine-rich repeat protein 5 (FBXL5) :
ccgcctctgccccgcggcgagggtgtctatggagaggcggcggccgcggctgctgaggcggaggct gaggcagtggcgatggcgccctttcctgaagaagtggacgtcttcaccgccccacactggcggatg aagcagctggtggggctctactgcgacaagctttctaaaaccaatttttccaacaacaacgatttc cgtgctcttctgcagtctttgtatgctactttcaaggagttcaaaatgcatgagcagattgaaaat gaatacattattggtttgcttcaacaacgcagccagaccatttataatgtacattctgacaataaa ctctccgagatgcttagcctctttgaaaagggactgaagaatgttaagcctactactgttgactgg aagccttaccaataacataaaacaatcgaataacaattatttcatgtattatatgtaaaatatata tactggattcttacagtaagaatgaatatgaacagttaaattatgcaaaacaactgaaagagagat tggaggcttttacaagagattttcttcctcacatg (Seq ID No: 1056)
Homo sapiens major histocompatibility complex, class II, DP alpha 1 (HLA-DPA1 ) :
ctgcctccactcggcctcagttcctcatcactgttcctgtgctcacagtcatcaattatagacccc acaacatg (Seq ID No: 1057)
Homo sapiens secretory carrier membrane protein 1 (SCAMPI) :
tcgtctctctctctgcgcctgggtcgggtgggtgacgccgagagccagagagatg
(Seq ID No: 1058)
Homo sapiens chromosome 15 open reading frame 57 (C15orf57) :
ccgcccctcccgatttcctccgggctacaggcgacagagctgagccaagcgtttactgggcagctg ttacggtaagtgaggaggggctggggtgcccagcgttttggatctcccactctggcccggccccgg aataccacatagaggccttgggacctgattcatcccgtccagacagccctagagacctgagcgact gaggcctgggatctggacgccggaatttcctgcgtggttctggacgccctgccctgggctcagatt ccaaatg (Seq ID No: 1059)
Homo sapiens WD repeat and FYVE domain containing 2 (WDFY2) :
cctcctcttgtagtggcgccggcttgcatcccaggtcgtggcggttttggtgcctgaagcagggag cgcggagtcgttcccgagagaggcggccaggctatgctcgccggtttccggcgttccgctccggcc agccagagtctctgtctcaacctgtgtccgtgctccagcagtctcctcagcccggccccgcggcgc ggttggcggcggcgccccaggcgcgccccctcctccgatg (Seq ID No: 1060)
Homo sapiens topoisomerase (DNA) I, mitochondrial (TOPlMT) :
cgctctttcccggaggctggcagatg (Seq ID No: 1061)
Homo sapiens intraflagellar transport 122 homolog (Chlamydomonas) (IFT122) :
ctttccctttcggacatgcgcgctcggagcaaggcgccctcgcactcagcttaccgcgcatgtacg ttgccaggggtaacgcaggtagccaaagtggcttgtggagtggcgaccgttagtgaggcggttgct gagacagacgctgaggcgggtaggaggagcccgagccgtaagggaagccgtgatg (Seq ID No: 1062)
Homo sapiens mitochondrial ribosomal protein L53 (MRPL53) :
agttcttccggggcggaggtcaccatg (Seq ID No: 1063)
Homo sapiens T-cell activation RhoGTPase activating protein (TA- GAP) :
ccgccccttcgcttataatgcagagcatgtgaagggagaccggctcggtctctctctctcccagtg gactagaaggagcagagagttatgctgtttctcccattctttacagctcaccggatgtaaaagaac tctggctagagaccctccaaggacagaggcacagccacacgggagtgaaatccacccctggacagt cagccgcaatactgatgaagctgagaagcagccacaatgcttcaaaaacactaaacgccaataata tggagacactaatcgaatgtcaatcagagggtgatatcaaggaacatcccctgttggcatcatgtg agagtgaagacagtatttgccagctcattggacattctcactattctatgccttaaaggcccttca acggaagggatattcaggagagcagccaacgagaaagcccgtaaggagctgaaggaggagctcaac tctggggatgcggtggatctggagaggctccccgtgcacctcctcgctgtggtctttaaggacttc ctcagaagtatcccccggaagctactttcaagcgacctctttgaggagtggatg
(Seq ID No: 1064)
Homo sapiens phosphoserine aminotransferase 1 (PSAT1) :
ggtcctccttggctgactcaccgccctggccgccgcaccatg (Seq ID No: 1065)
Homo sapiens CD97 molecule (CD97) :
ccccctccttcataaagtcctggcctcgggacagcctgcacagctgcctagcctgtggagacggga cagccctgtcccactcactctttcccctgccgctcctgccggcagctccaaccatg
(Seq ID No: 1066)
Homo sapiens protein tyrosine phosphatase, non-receptor type 2 (PTPN2) :
cgctctccccggatcgtgcggggcctgagcctctccgccggcgcaggctctgctcgcgccagctcg ctcccgcagccatg (Seq ID No: 1067)
Homo sapiens chromosome 20 open reading frame 112 (C20orfll2) : gcccctctccccgggcagccgcggcggcagcagcagcagcagcagctggagctgtggggctgtcac cgccgcccgccccgctcactcgcggatcccgaccgcccatctccgcctcgcttccagcccaggatg agacttctgtgagcagcgaggattttgatatg (Seq ID No: 1068)
Homo sapiens APEX nuclease (multifunctional DNA repair enzyme) 1 (APEX1) :
cacccttctttgtgctcgggttaggaggagctaggctgccatcgggccggtgcagatacggggttg ctcttttgctcataagaggggcttcgctggcagtctgaacggcaagcttgagtcaggacccttaat taagatcctcaattggctggagggcagatctcgcgagtagggcaacgcggtaaaaatattgcttcg gtgggtgacgcggtacagctgcccaagggcgttcgtaacgggaatg (Seq ID No: 1069)
Homo sapiens intermediate filament family orphan 1 (IFFOl) :
tttcctcttgagccatcatgcacatctgactgcagccccagcgagcccttccttccttgtctgact gctcttcttctcgatttcttcttgttctgccttctcggtttgcagccctgacccccgctgtgtgtc tggcccttggtgactgtccgtgtttctgttcctgtcattgtaactgtgacttttctctctgtctgc ccccccttcctactggttcatgcttctcccccattcccaccctctctgcccggcctcccgctcccg ccctttctcctcatgcacccggcctcgtctctgtagtctctgcacttgtctcccattaaggtccca tccatg (Seq ID No: 1070)
Homo sapiens neuralized homolog 2 (Drosophila) (NEURL2) :
cagtcttcctcccgccccttctttggtccctacggacctggggggcggtggcggtcaatgccgggt caaggtccgcgggcctcgcagatcgtagcccgggcgcacgcgatcagatgatcctgttgtggacgg ctaagttgtaggcgggatggctgagaaagcggcgctaggacccccgggcagaggctcggggaaggg agtcaggggggaaatgccttacaaggtcgccttgcggtcaccatcattgcccgccgcccaaaatag cccccggcgccagctggcctgccctatggccgagagatg (Seq ID No: 1071)
Homo sapiens drebrin 1 (DBN1) :
ctccctctttccctccctcctcctccgtccgcccgtccgtccgcgcgtctgtccgttcggcccggt ccggcccgaagcatg (Seq ID No: 1072)
Homo sapiens WW domain containing adaptor with coiled-coil (WAC) : cagcctcccttatttagtccgcgatggcttccctcgcgccccaccgtcctcttccggaaggcggct ccctccctgcgcagcccggagcccctgagatcagcctcgagcaggcgcccgagcgagactatccct aaacgggaacggcggtggccgactcgcgagtgaggaaaagaaggaaagggcagactggtcgcgaag agaagatccaggcctcagaggaggagaaaggccggagccagccgaggtttgccgagggcggtgttc cggacccgcgcggtgcggggaggaaggccgagggtgggagaggaggggcccggcggaaactgccga ggtttcccgaaggcggcagcgtccgagttgcccggatgtagttggtggagcggcagcggcggcacc agcggcggcggcggcggcgggaggaggaggaggagaagaaggaccaggcggcggcagcagcggcgg cggcggggggaggaggggaggaggcggcggagcaggaggaggagaaggcggaggaggcagtcgctc tccgcggggctgagccggacgcgtcgtcttgcccccctccccccggttcgcggtgccgccgtgtag ttggcgccgctgccccggctgagagtgagcgtggtgtcgacggagggagatggcccgggagcgccg gcgccagtaactgggagctgatgagagtcgccgagggcgcgccgggcccaggtgccggggctgccc gccgcccgccgccgccgccgcctgcgcgcccgcccgcctttcgcggccgctctcccccctccccga cacacactcacaggccgggcattgatg (Seq ID No: 1073)
Homo sapiens kelch-like 6 (Drosophila) (KLHL6) :
cgctccttcagtctcgatg (Seq ID No: 1074)
Homo sapiens GTPase, IMAP family member 1 (GIMAPl) :
cagccttctgcactcacagccgaagggaaagcagcaggttggggcttcttgtggccaacttcagag cctgtcaccaggaaaggtaagcatg (Seq ID No: 1075)
Homo sapiens RAB24, member RAS oncogene family (RAB24) :
cgccctctagccccctcccgcgggagtcgcggcgctgcgggtaggagccgggttgcgggagacccc aggttcggttgggattcccagccagaacggagcttaagccgggcaggcgagcgaatgacggagtag cgagctgcacggcggcgtgctgcgctgttgaggacgctgtcccgcgcgctcccaggccgccccgag gcttggggtcttcgaaggataatcggcgcccggggccgaacagcgggggcacacggggcgctgccg aagtgcaaggccacggccagagctcgagcccgacgcgctgtctggagtcgtaggaccctgacgtgg ctgaagcggccccgggagcatg (Seq ID No: 1076)
Homo sapiens adaptor-related protein complex 2, alpha 1 subunit (AP2A1) :
agccctccccgcggccggctcggctccttggcgctgcctggggtcctttccgcccggtccccgctt gccagcccccgctgctctgtgccctgtccggccaggcctggagccgacaccaccgccatcatg (Seq ID No: 1077)
Homo sapiens copine IV (CPNE4) :
ctccctcttttctcagtaccctcctctttactctccgagttaactgagagccgacctgacatctcc aacattttcaccctcttcccccacccccatcaccgagaatggagtcagggtttccggagagaccga actctgctctcagcacctttcccagccgctgttgctaaactgacctcggaggacgagaggggaagg aggtgcgacgccccttacatcagtacataactaccacaccaaccacctccacttcaaagccggatt ttgcatcctgggggcgggacagacctcgtcccgggctgaattctctctccactcttcgagattggc acacccagaatg (Seq ID No: 1078) Homo sapiens synaptosomal-associated protein, 25kDa (SNAP25) :
ctgtctttccttccctccctgctcggcggctccaccacagttgcaacctgcagaggcccggagaac acaaccctcccgagaagcccaggtccagagccaaacccgtcactgaccccccagcccaggcgccca gccactccccaccgctaccatg (Seq ID No: 1079)
Homo sapiens cAMP responsive element binding protein 3-like 4 (CREB3L4) :
aggtctcttgactctttccgcctttgtttacaaccctgccatgatctccctcttgcaaaagcgagg gctacagaacaggcattcaggagtcctgtgctccagtcacagccttttctgttcttcagctaggag acaccaaaccctcaggaagatttactatagctaagagaaaactgcagcagaaagggcgcggctacc tacttcttaaattccgtttgtggaccctcagactcttagtcccctactcccagatacagcggccct accgtggctcctggcaaggtggcatccacttttgtagtaagcatg (Seq ID No: 1080)
Homo sapiens leucine-rich pentatricopeptide repeat containing (LRPPRC) : ctgtccttctggcggagcgtgcttcccgctgcggggacgttcgagcaatg (Seq ID No: 1081)
Homo sapiens zinc finger protein 418 (ZNF418) :
cgttctctggtagcgaccattttggttaatgttgggtgtgtttctgcggtttgtgaggtgagaggc gctggagctatgggtccgaaccgcggtgtctgaacccagaaggtgaagagtccttcttgctgcaca gaggcagatcttaggccccgtaacggcgcccgccgctcccggcagtgctttccccgcgtactcggg atggcggcggccgcgctgaggctcccggctcaggcatcatctggctgcaaagaagagaacacactg tgtttgagggaggaggaaggaggatcagagtttaaactcctgccataatg
(Seq ID No: 1082)
Homo sapiens tetratricopeptide repeat domain 14 (TTC14) :
gtttcttccgcttcctgtaccacccggctcaagtagcggacacggaacagggaactatcagcccgt cggcctccgggccctgcattctctagccatg (Seq ID No: 1083)
Homo sapiens BMP binding endothelial regulator (BMPER) :
agcccttttcgactgtgagctgcggcagctgagcagaggcggcggcgcgggacctgcagtcgccag ggattccctccaggtgacgatg (Seq ID No: 1084)
Homo sapiens zinc finger protein 384 (ZNF384) :
cccccttttcgtttccggcgctcccgccttctctccgcagagctcttctctgagcctgttgggggg agggaggggggcgtggaggaactggggttcgcgggagcacgagctgcagcaccacttccgggtgag tgcaaggggagggcagcaaggagggggggccacccactacctcgcgcccccgccctgcgggtgtct cgcgcgcgttccgtgcgtgtgagtgtgtgggtctgtctcgctccagaagtgcgtgcccgcgcgctg cgccttgcgctttttcccctccctcgccccttcctggtcctcccaccctcctcggctccctccttt cccagcaaacgccgcccctcccgcgccctggctcaggctctggcgccgccgcagccgtcgccgccc gaaagttcaggagccctggaaaggagaaggaataagacggcaggaggaagagagagagagggtaga atg (Seq ID No: 1085)
Homo sapiens RAD51-like 3 (S. cerevisiae) (RAD51L3) :
ctctcctttctcctccggcagccagcgcgcctgtgtcctctctaggaaggggtaggggaggggcgt ctggagaggaccccccgcgaatgcccacgtgacgtgcagtccccctggggctgttccggcctgcgg ggaacatg (Seq ID No: 1086)
Homo sapiens CD99 molecule-like 2 (CD99L2) :
gctcctcctcccgctcctcctcggcctccccttcgggcgctctcgcgctaactgtgctcctccggg gccctccgcctgctcccagccatg (Seq ID No: 1087)
Homo sapiens glucosamine-6-phosphate deaminase 2 (GNPDA2) :
gcgcctttatctgcatccgggtccgtgggattcgcgctccactggtcagctggggtcgctctcggg tggttgggtgttgcttgttcccgctgttccagcgtcgaagaaccattgggtctgccggtttgaact tgttctggaagctgtgcgtcaccgtaatg (Seq ID No: 1088)
Homo sapiens methionyl-tRNA synthetase 2, mitochondrial (MARS2) : ccgcctcctccgcttgcggccggtctgcaccatg (Seq ID No: 1089)
Homo sapiens chromosome 12 open reading frame 57 (C12orf57) :
tttcctttccgctcccaggggcgttgggaacggttgtaggacgtggctctttattcgtgagttttc catttacctccgctgaacctagagcttcagacgccctatg (Seq ID No: 1090)
Homo sapiens tRNA-yW synthesizing protein 3 homolog
(S. cerevisiae) (TYW3) :
ggaccttttcggccaccgctcgcttcaatatggctgcccccagggagagacgaggctaccatgaag gagccgagcgcagaccctgagtccgtcacccatg (Seq ID No: 1091)
Homo sapiens Spl transcription factor (SPl) :
ctccctcctccttacccccccctccctgtccggtccgggttcgcttgcctcgtcagcgtccgcgtt tttcccggccccccccaacccccccggacaggacccccttgagcttgtccctcagctgccaccatg (Seq ID No: 1092)
Homo sapiens histidine triad nucleotide binding protein 3 (HINT3) : cgccctctagtggcagccggttttgaggccggcctccggctttgaagttcctcaccgcgtctcctt ccctctccccaaagcctggatcaccgcccagcgtcaggcgaggggcgacgtctcgaggtaaaacgg aggaggtgcgggacgcggagactgcgcgggcccggtagccctggagaggccgaggctctaggccgc gaggggcgggtgcaatg (Seq ID No: 1093)
Homo sapiens M-phase specific PLKl interacting protein (MPLKIP) : agttctctgcggagggccggttgatacagttccggtgggagaacgcggctgcgaggttttcggctt tggctcctgatatg (Seq ID No: 1094)
Homo sapiens palmitoyl-protein thioesterase 2 (PPT2) :
cacccttccccccgccaccgtgggttccagacttgggataagtaaacagcgggtggagcgaggcct acggacccaggccaggtgggagtctgcactcttcaaggggcctgggctgctgctcacgggtattaa agaactccgcgttgttcatggctgaggcgatgcattaggaagatcctggacctagagaacaagtcc cccgaacgctgagttggaggcgggacttcgggtgcgcgttggcgggagcatg
(Seq ID No: 1095)
Homo sapiens BCL2-like 14 (apoptosis facilitator) (BCL2L14) :
aagcctcttttcaggctgagtcctaaacctgaagaaagtttagagcctggggctctaaactacctg agtctttccaaacgacaagccaagaagacctgttgaaagtttcctcttaagtttcgtggagagaga ctcaggtatagaaatatccttactgccacctgacctgaagcagaagaaatcacagacagcttccag accaggcccaacatg (Seq ID No: 1096)
Homo sapiens galactose mutarotase (aldose 1-epimerase) (GALM) : acgccccttctcctgtaaacttgggtcgcctctagcttagcgagcgctggagtttgaagagcgggc agtggctgcacacgccaaactttccctatg (Seq ID No: 1097)
Homo sapiens carboxymethylenebutenolidase homolog (Pseudomonas) (CMBL) :
cttccttcccttccccgactttgcagatttctcttcccccaggcctccctcctccacctctccgcc ccctccgggcttggctctcccaggaggctacgactggagccactggtcccgcaggatccccgcgtc ctcggtcgccgcgtccacgtccctctcgcgtccccgcccggcgccacgccgcctcctctgggttcg gcctccgcgcggtgcagcgcagtctcaggccgcgggacaagcccgacttaaatctctgcaatg (Seq ID No: 1098) Homo sapiens chromosome 7 open reading frame 31 (C7orf31) :
cgtccttctcccgcccccgcccctgcctgccagctccaccgggccgtaggtgcggacgacctcaaa attcctcggcccgcgaaggccgccagctgcggggaggggaggggaggcgcggtcccgcagcgcccc caggctcatgtcccaggtatgtccagacccccgaggcaccgcttgcagggcagtgacagcccgtga ggctcggcctcgacccctggcacccttggtcccagctacgccggctcctggccttcccccaagtcc gagagagaggtgggattctccccgacgcagttggaaaccgggaatcccctttagggtcccgttcgt gctgcactactgactccaccatctgcaaagggattcttgtccagaatccccgaaggctttaggaca gcgcttattttgttgaatgaagagtctctaattttcggaaagaccacaggctaaaagtcaagttgt gcctttttagccaagaagcatg (Seq ID No: 1099)
Homo sapiens secretory carrier membrane protein 5 (SCAMP5) :
cggcctttcggcagccgaacggccgcggcagttcaggacaaagaggtgtgggcaggccactgggcc agctggtaacatcatg (Seq ID No: 1100)
Homo sapiens mitogen-activated protein kinase 10 ( APK10) :
tgctcctttcggttgccatagcaaccccattccccaagccctctgtccgtctcctctggtaggttc cacaatggtacaggcagcatcacgctgcacaatggtttccaggcagtgaaagagggtgattcagca agccactcttcttctattttctttaacctccccttcactttttatttttatgggggtgggtggtgc ttgctatatgcttacctttttcttttcttttttcatttttacaaatttccttttttgtcctcaccc ctcaattcctaggggcttgagtgagtttaagattgggttttcttggaaatcacctgtccatcgtta attttaaacaatctccatatctccaaagaatctcttccatgttagtctggaatgtggttaatgaaa aacaagtagggaggatttctggggcaaacactgccggatcaggatcgtagttctcaggcacggaat ggctagtgtgagaaacaccaacagcaggcccatctcagatcttcactatggcaacttatgcaagaa actgttgaattagacccgtttcctatagatgagaaaccatacaagctgtggtatttatgagcctcc atttcttatactactgcagtgaaccaacattggatgtgaaaattgccttttgtcaggtgtgtgttc cttacaggtaaaacaagggattcgataaacaagtggatgtgtcatatattgccaaacattacaaca tg (Seq ID No: 1101)
Homo sapiens beta-site APP-cleaving enzyme 2 (BACE2) :
cgtcctccccgccgccgccggtcccggtgcgcgcccatccctgcccgcagccccgcgcgccggccg agtcgctgagccgcggctgccggacgggacgggaccggctaggctgggcgcgccccccgggccccg ccgtgggcatg (Seq ID No: 1102)
Homo sapiens SWI/SNF related, matrix associated, actin dependent r egulator of chromatin, subfamily d, member 1 (SMARCD1) :
acgccttttccgctagtcgccccgctctatcccatagtctcgctgccctgagcctcccgtgccggc cggccggccgggggaacaggcgggcgctcggggggcgctcggggggcggggggagttccggttccg gttctttgtgcggctgcatcggcggctccgggaagatg (Seq ID No: 1103)
Homo sapiens family with sequence similarity 175, member A
(FAM175A) : cgtcctcttgtgtagcctgaggcggcggtagcatg (Seq ID No: 1104)
Homo sapiens adenosine deaminase domain containing 1 (tes- tis-specific) (ADAD1) :
aggcctcttttgaaagatgcggccctgaccctgtgaacctcgcgcagagcggcctgaagcgagagg ttgaggctgggaggtgagaaaatg (Seq ID No: 1105)
Homo sapiens acyl-CoA synthetase short-chain family member 2 (ACSS2) :
gcccctctacggaggccccgcctctagttcggcctgttttctcagtcccggcacccgccgcgaccg caaaggcggccgcggttctaggaacttgacgtgatg (Seq ID No: 1106) Homo sapiens multiple coagulation factor deficiency 2 (MCFD2) : cttcccttactcaccggtgtccggaaaggtgaacgctgcgctcgggctgcctcgcctgttacctcc gccgccgggcatg (Seq ID No: 1107)
Homo sapiens SPOC domain containing 1 (SPOCD1) :
gctccttttcagctagtgggtggaaccccaggagggaaaactcagggaagcccagggcccgtgttg tgcttttggcccaggtaggtggacagacatg (Seq ID No: 1108)
Homo sapiens LY6/PLAUR domain containing 1 (LYPD1) :
agttccttcagtctcagccgccaactccggaggcgcggtgctcggcccgggagcgcgagcgggagg agcagagacccgcagccgggagcccgagcgcgggcgatgcaggctccgcgagcggcacctgcggct cctctaagctacgaccgtcgtctccgcggcagcagcgcgggccccagcagcctcggcagccacagc cgctgcagccggggcagcctccgctgctgtcgcctcctctgatgcgcttgccctctcccggccccg ggactccgggagaatg (Seq ID No: 1109)
Homo sapiens cytochrome b5 domain containing 1 (CYB5D1) :
cattctttcatactgcctcctcccttgtttttctgtctcagagagatagtctgtcctaaatatccc atgtagcccaggccactgaattaaaacggagcgtattcgttctctgccccaccccgcaactcctga aagcggcgcaactcaattacttgatccttatatgccccacgcgggactcatactacgtttcccgtg aacacgtgcagtccaaaccccgcccctgatatttatctcagtggacggtggccggaaaaggacaat ggtttccatgtcagcggataaacgctctcccctcggctcccggacgcgacggaggtcgtagtagta gtgagtacgtgctgaggagcaaaggagtaaccaagagatccagtgaccgacagagcaagagccatg (Seq ID No: 1110)
Homo sapiens synaptoporin (SYNPR) :
tctcctcctttgcttcataaaaagagggacaagtggctggtgctgtggacagagaagctttatttt tagtatgagacaacctctattttctttcaggagagggaagttggattatcaattcttttgtaaatg (Seq ID No: 1111)
Homo sapiens heterogeneous nuclear ribonucleoprotein U-like 1 (HNRPUL1) :
ccccccctttcccccttcgcctcctgacaggaaaggtttaagggggacagagccctgggaggccgg gccgggctcgggggccaccccgggggcccgggccatg (Seq ID No: 1112)
Homo sapiens schlafen family member 5 (SLFN5) :
ggttctctgctctggacttgggaggctccgttgcctgctcccggagggagacgcgctgccgaggag aacccagcgggagaacatttcaggataggaataggccaagtgctgagaagatg
(Seq ID No: 1113)
Homo sapiens MAS-related GPR, member F (MRGPRF) :
ccatctcttccagcaggagagggctctactctgagctcctattttccaaggctccgggccgcgctc ggcgctggcctgctgccccggcgggtccgccggccggaggcgggagtcacaggaagagccctccac aaaaggaggcctcggcggatcaggacagctgcaggtgggtgtgcagactggtgagctgccagcagg ggcccagacgcgccaggcctggagatg (Seq ID No: 1114)
Homo sapiens ubiquitin-like domain containing CTD phosphatase 1 (UBLCP1) :
cggtctctcagcggccggtttctgcgtccgctgccgcaggttccaccgcgctccaggtattttttt ttctgaaggaaagctgcttcctcatatgtttcaagaatg (Seq ID No: 1115)
Homo sapiens Rab interacting lysosomal protein-like 2 (RILPL2) : cctccttttccgttgtcccttcgcgccccaaaccacatcctggagcgcactctccagcgtggctgg cagcggggacggtgcgccggggcgcaggcccaagagtcgcgtgcgcggccccttgcaccatccccc cgggcccacccccgggccgcgctgattgggcaggtagggactctgcccagcggaaagttttgggtg ccgggaggaagtctaacctttgggagactccaagacagcagctccgaggtcggcgggggtctgggt ggccatg (Seq ID No: 1116)
Homo sapiens zinc finger with UF 1-specific peptidase domain (ZUFSP) :
acttcttttccgtgggagtaaggaagtgcttttgaatgaggtactgagggccaaggtgttggaagt tcctaattctttcctcggttaactgtgaaactctgcgtattgggaaggcctggcctcagtcatcag gccaggagaggtactggacgccgcgcacgcactcgtctgccagcgaggcccaaaggggaagcctag cggagctcagtgtggcagctgctggcctctgggccgctacttgtcaataccatg
(Seq ID No: 1117)
Homo sapiens mitogen-activated protein kinase kinase 5 (MAP2K5) : ccgccttcctcctcctcctctcgccgctaccgccgtcgccgccgccgcagccgccgccggtccgcg cggcctcgggtggccggagctcagcctgcgcgcgccgcgccctgtgtctccgggtggggcagaaga ctcgccccttgaacctcccgcggggactctccgtggtgtggcggccctggggctctttcttaatag ccccggactgagtcccctccagtcgaggaccctctcctagtccactgacgagcggtggacacctgc cgctgtatctcccccaaaccgagtccttgccctgctgcctcctcatacccacacggcggcagagac cttcaccatagcgttcgctcaactccagaaccttccgacctccgctagttcctgcgggcctttgcc cgcttcccggtgcaccctccccgggagacacctcagacccccgacagcctgggcaggctcggtgcc tgcgggtgcgttcctgatcacccctcccctcttccctccccctcatcctccattcccttgttttca ccctctgtcctctgcccgtcactccccttgtcacctcttggagccccctcctaaccagcggccagt gggtttcccataccccaggatgtgagcctctttaacctgtaatg (Seq ID No: 1118)
Homo sapiens solute carrier family 2 (facilitated glucose transporter) , member 12 (SLC2A12) :
cactcttctttagcatgctattatggggaaagtgaccactcctgggagcgggggtggtcggggcgg tttggtggcggggaagcggctgtaacttctacgtgaccatg (Seq ID No: 1119)
Homo sapiens mitochondrial ribosomal protein L30 (MRPL30) :
cttcctctgctctgcttcccttcggaggaaaatttcaggctgaaggtttagcgggtgccgcctcta aagagagcaatcactacacttatg (Seq ID No: 1120)
Homo sapiens tripartite motif containing 11 (TRIM11) :
gctcctcttcctgccggcatccgggatccctacgtcccgcgtcccccgagcgctcggagcctacgc gcccagcgctaccgaaacccagagtcctgcgccctggagtccccgcgccccggagcccgagcaccc gggagtcccgagcctcgcgccccggagtgcccgagcctgcgccgccgcacccggataccccgcgtc cccgcgagctgccgaggccgcccgccgccgccccgcggacagtaccgccttcctcccctctgtccg cgccatg (Seq ID No: 1121)
Homo sapiens proline-rich transmembrane protein 2 (PRRT2) :
ctccctccctagctgacttgctccctcccgggctgcggctgctgcaaaagccagcagcggcagcgg gagctgtccggaggccggcgtcgagggtttgccgctgtctctgctattccatcctccccatagggg ctctctcccctctcccatctcaagatg (Seq ID No: 1122)
Homo sapiens zinc finger protein 626 (ZNF626) :
cggcctttgtctctcgctgcagtcagagctccaggtctggttcttctcctaaaggcccaggctgtg tggccccgtgtcctgcaggtattgggagatccacagctaagacaccgggacctcctggaagccaaa aatg (Seq ID No: 1123)
Homo sapiens solute carrier family 25, member 43 (SLC25A43) :
cggtcttccgggcccgggtcggggctcgatg (Seq ID No: 1124) Homo sapiens crystallin, zeta (quinone reductase) -like 1 (CRYZL1) : ggctctctgacgaaggactggaaggtggcggtggtgaaggtgcaggccgttggggcggctcagagg caggtgactatg (Seq ID No: 1125)
Homo sapiens mitogen-activated protein kinase kinase kinase 7 (MAP3 7) :
ctgcctctacccccgccacggatcgccgggtagtaggactgcgcggctccaggctgagggtcggtc cggaggcgggtgggcgcgggtctcacccggattgtccgggtggcaccgttcccggccccaccgggc gccgcgagggatcatg (Seq ID No: 1126)
Homo sapiens septin 6 (SEPT6) :
ctttctctttgtcggaggagctcctctgtttcctgtgcagtagctcccgttgcggcggcacccgtg gcagccctggcggacgcaggagcgatg (Seq ID No: 1127)
Homo sapiens myotrophin (MTPN) :
ctgcctctcctcggccaggcggaacctctctgctgggcccggtggccgcaaaagaactttctttct cccgcccgaacggtcgccgcggccaactgcctcgcccgcctggcagcctaaccctccttctcttct tctcctctccggcttcgcgcggccctgcctccctctcgcccggcggcatccgcttgctgctgccac cgcctcctcatcttctgcccggccaaccggcctgccccgctgcagtgatg
(Seq ID No: 1128)
Homo sapiens annexin All (ANXAll) :
ccctcccttgcactgcctctggcacctggggcagccgcgcccgcggagttttccgcccggcgctga cggctgctgcgcccgcggctccccagtgccccgagtgccccgcgggccccgcgagcgggagtggga cccagcccctaggcagaacccaggcgccgcgcccgggacgcccgcggagagagccactcccgccca cgtcccatttcgcccctcgcgtccggagtccccgtggccagggattattggacctgcctggtttaa actattgtcttagttaattttgtgctgctctaacaaaatatcacagactgagtaatttataagcaa tagtagcttatttggctcacagttctggaggctgagaagatcgtgaggctgcatctggcaagggcc ttcttgctgcttcataacatggcagaagacatcatgcgggtgtgtgtctggggaagagacttacag aagtggagttgctgagtcaaagatctaaccatg (Seq ID No: 1129)
Homo sapiens RNA binding protein, fox-1 homolog (C. elegans) 1 (RBFOX1) :
ttttctttctttcctctcccggcgttgatgagtgcttggctcctgacagaagggatttggctccca gctttgtagttcggaagaagttgggtctatagatttccccctaactctccattgatgtgttgagct tcagagggaataataactctacgtaaagcatg (Seq ID No: 1130)
Homo sapiens prefoldin subunit 5 (PFDN5) :
cttcctcttcgttaagtcggccttcccaacatg (Seq ID No: 1131)
Homo sapiens high mobility group AT-hook 1 (HMGAl) :
cgctctttttaagctcccctgagccggtgctgcgctcctctaattgggactccgagccggggctat ttctggcgctggcgcggctccaagaaggcatccgcatttgctaccagcggcggccgcggcggagcc aggccggtcctcagcgcccagcaccgccgctcccggcaacccggagcgcgcaccgcaggccggcgg ccgagctcgcgcatcccagccatcactcttccacctgctccttagagaagggaagatg
(Seq ID No: 1132)
Homo sapiens zinc finger protein 323 (ZNF323) :
cggcctttgcggttgatcggtcattggggtgctgcagccccgccacctgttccgtagcttgccggt gccccgaaggtgtcttctcctaaggaagattaaatcagaaaattttaaatcacagttatcccttta cttaaagccagagtaagccttccaaattaaccccaggaatg (Seq ID No: 1133)
Homo sapiens tumor protein p53 inducible protein 3 (TP53I3) :
ctttctcttctcttagcagcacccagcttgcccacccatgctcaagatgggcgggatgccagcctg ttacataaatgtgccaaaagcctggccatgcctggaaaatggaccaatccgcccgccaagaggttg ggtctcgttccctagagagaaggaagtttcctctccttgaagtgagagctagaatcgcactttctg tcaagctgagagaaagactcttttccagaggctaaaaggacaagaaaatctgatttgcttgcttct aactttgcgttttaaagggggaaggaggaaaggaaagagggggagggtggttctgcttagccccac ccctccggctaccccaggtccagccgtccattccggtggaggcagaggcagtcctggggctctggg gctcgggctttgtcaccgggacccgcaggagccagaaccactcggcgccgcctggtgcatgggagg ggagccgggccaggaacaatatg (Seq ID No: 1134)
Homo sapiens ceramide synthase 5 (CERS5) :
ccgcctccccgcgggttccgttggctgtggcggcagctgacgcttgtggcggcggtggcttcgggg tgggcgtaagatg (Seq ID No: 1135)
Homo sapiens TRAF3 interacting protein 2 (TRAF3IP2) :
tgttcttctacttacctgggcccggagaaggtggagggagacgagaagccgccgagagccgactac cctccgggcccagtctgtctgtccgtggtggatctaagaaactagaatg
(Seq ID No: 1136)
Homo sapiens Smith-Magenis syndrome chromosome region, candidate 7 (SMCR7) :
ggtccttcacgttccattcccaggctggtctgagctccggggccgtggtcccgctgcctcctccgg tcgtcgtgcggaagctgcgacgcaggcagaccatg (Seq ID No: 1137)
Homo sapiens mitochondrial ribosomal protein L10 (MRPL10) :
cattcttccggtggagatggctgcggccgtggcggggatgctgcgagggggtctcctgccccaggc gggctagagtgcagtggcatg (Seq ID No: 1138)
Homo sapiens proteasome (pro- some, macropain) subunit, alpha type, 1 (PSMA1) :
acttctctgtagatcgctgagcgatactttcggcagcacctccttgattctcagttttgctggagg ccgcaaccaggcccgcgccgccaccatg (Seq ID No: 1139)
Homo sapiens sorting nexin 5 (SNX5) :
cggtctttctctagacgcgtcttgctgggagagtgtccgttgcttcccgtccgtgtcgcggccctg cggttggcggcctcctcgtggagcggagcaaggccaggcggcccctgctcgagtcccgcgtcgcca tg (Seq ID No: 1140)
Homo sapiens zinc finger protein 276 (ZNF276) :
gggccccctccgcgcgtactgcgggccccacgggtgttagtggcgggggcggcagagtccgggtgg gttgtcgcgacggagccgggcctcttcgccgtcttgagacggggctggcgagaagggcccctcacg gagttgccatgggcgtctaaccgcggcagccaggcccctctctacgtgagaccccggcccccctcc cctttctgcagcccgcccgccacctgcgcgccgcgtggcctccgccggcgcctgcccgccccgcgc ctccgtctcccacggagcaggccgggctctcgccatg (Seq ID No: 1141)
Homo sapiens zinc finger protein 561 (ZNF561) :
ccatcttttccggcgctggctcctctccgtcagtgcggtttcgcctttatggtggtggagtctgcc caggctgtggaccgcaaataaccctgtacaaagaggaatggagattgcctctatccacctagattc ataagctggcctgaggtgatcttggcatcaaggaagggatgcacatcatcacaccatcagcttcag agaatg (Seq ID No: 1142)
Homo sapiens mucin 7, secreted ( UC7) :
ctttctcttcttttgcttctagttaccatcctcaaaggattggctaaaagcaagcaactggattga acaccctaagaagaaagattcacactgcaccaggagacatcagaaagaatg
(Seq ID No: 1143) Homo sapiens threonyl-tRNA synthetase (TARS) :
gcgcctttcgattgcatcagctggtccagccgaggccaagtcccgggcgctagcccacctcccacc cgcctcttggctcctctcctctaggccgtcgctttcgggttctctcatcgcttcgtcgttcgccaa tg (Seq ID No: 1144)
Homo sapiens ATPase, Na+/K+ transporting, alpha 3 polypeptide (ATP1A3) :
cagcctctgtgcggtgggaccaacggacggacggacggacgcgcgcacctaccgaggcgcgggcgc tgcagaggctcccagcccaagcctgagcctgagcccgccccgaggtccccgccccgcccgcctggc tctctcgccgcggagccgccaagatg (Seq ID No: 1145)
Homo sapiens chromosome 11 open reading frame 46 (Cllorf46) :
cgtcctctcagtggtagcgcggggactggctgggaagcggtcggtcgagtgtggcctgtgtggact cgcatcttgcccgaagccgggcggaggagagctcaagctaagggtgatcagcccatgacctaaacc tccagacaaaataaaacggaaaatttgctagaatcaagaatg (Seq ID No: 1146)
Homo sapiens chromosome 17 open reading frame 45 (C17orf45) :
tgaccttttcattcccgttgttatggaggtaggctctctaggaatctgggagtagtagctgggggg caagagcaaataaagagctcgagcttctgtggtctctggggagatg (Seq ID No: 1147)
Homo sapiens AHAl, activator of heat shock 90kDa protein ATPase ho molog 2 (yeast) (AHSA2) :
gggccttctggcagtttctgggagctgcgaacgcgccgccccggggctcggcggccggaaacgctg gcttcggagccttaggcgccgcggcctttccttgttttccgcccagtccacgccgccatggccaag tggggccaggggaacccccactggatcgtggaggagcgggaggacgggaccaacgtgaacaactgg cgctggcgcggctggcggcggcctccttccgggatctggggagggccgggccgcgggagccggggc tgccctggggtctgtgcggggccgcggggccagggggtcagggggccgccccccctcagctgctgg acgcagggctcggccttcgcctctcggctcgggagagtccttgagtacggagaccggctaggaggg ttgcagctgcctctttttgaaagttgggttgggccccaagagtgacttccgacagacctttccact cccaccgtctgtggcctgagggccttcccttctcctcccgcccacccctctggatgtttcggggag ttagaagggagctggattgagagactgtgttaggggcgggggtatggaacgtagtggaaagggcag aaatttggatctcagttcgcgcccaccccgcaggcgcctcccgcgagccgggccctctgtgagtga gacaagctccccttcctttacgcgcctcacctggcgcgtggggagaggtcggcagccctccgccgc agaacctccggaagggatgtcctctgccctgcgcctctggccggggctgtggtccctccaggccgt cgaggggatgctgaggccggtccccagaggagcatgacttggctggtccggaggagctctgagggc atgggcaatcttggctcgctgcaacctcagcttccagagttcaagcgagtctcctgcttcagcctc atgagtagctgggactacagatgcgtgccactacgtccgtctgatgtttgtatttttagtagagac agggtttcaccatgttggtcaggctgctctcgaactccagatctcgtgatccgcccgcctgggcct actaaagtgctgggattacaggcgtgagctagatctgactttctagtgtcctagccttggcccgat ggacatgtcatttctctcagctcgtttctgtcccctaaagtgagaatattgcctgggaagattaca ttagacgatgtatatgcgaagacacttgatagctggtattgtcatgattctgattagttcactact gctactttccctgtggcctaggctttgcctatttccagtgggcgagctagctagatcctcctccct taaataagccagtgtttttaagacagaatactacttgcatagtggacaataatatcttaaagaact gagcaggatgaaaagaatttgatagaaagcaggtttgaggagcacattggaggttggcaggtttcg aggctgcttgagaggacttgggccgatctgggctgggcttggacgtgaccctggcacccaggcagg tggatcccagctggggcttccattcacgactttctggtccctggcaggacagagcgggatgccacc agcttgtccaaagggaagttccaggagctcctggtgggcatcgttgtggagaatgacgctggccgc ggcgagatcaacgagttgaagcaggtggaaggggaggcttcgtgcagcagccgcaaaggaaagctg attttcttctatgagtggaacatcaaactgggctggaaaggcatcgttaaagaatctggagtgaag cacaagggattgattgaaatacccaatctttctgaggaaaatgaagtagatgacactgagaattta caacgggaatg (Seq ID No: 1148) Homo sapiens GrpE-like 2, mitochondrial (E. coli) (GRPEL2) :
ctgcctctcagcccaaattggaaacatg (Seq ID No: 1149)
Homo sapiens xyloside xylosyltransferase 1 (XXYLT1) :
ccgcccctttcatggccgccgcctggcgccggggctaagtggccgccggcgtccgggtacccgagg gctctcccgcgttgctggcaccgctggcgccgcggtctcgtagcgcatg
(Seq ID No: 1150)
Homo sapiens chromosome 7 open reading frame 60 (C7orf60) :
cctcctctggctgctgcctccgcagctccctcctcctaccccacctcctccatctggggagcgtct gcgggggcctgaggggcggcggcggcggcggcggctgcgatatg (Seq ID No: 1151) Homo sapiens tetratricopeptide repeat domain 39B (TTC39B) :
ccctcctttgcgctgggctgagcccagagccgagagcaggggtcggctctgagttccctgcttggt ttttgggtggcagcagccagaggaggaatatg (Seq ID No: 1152)
Homo sapiens motile sperm domain containing 2 (MOSPD2) :
cacccttctctgtctacctctgggcgggactgccgggtgatgagatactcggtcggcgacggtaga acgggcgacggcgacaaccgcaatcacatccacgacggtgatcatg (Seq ID No: 1153)
Homo sapiens major facilitator superfamily domain containing 6-lik e (MFSD6L) :
ggcccctttcggtccaacggcaggacctgggggctgtggccgggggcggccgttgacctggtgacc gcggcgccgccccagaccgggggcgcagtcccactcgctccgagccccggtcccccaagcctccct cccgggtacctggggccgcgcccgccctgcgcccagctccgccctccgtcggcccaggcctgacag agcccggcagccatg (Seq ID No: 1154)
Homo sapiens consortin, connexin sorting protein (CNST) :
cttcctctctagccgccagtgctctatgctccgcggtcgcgggccgccagcctccagccggccagc cgcgaggggtgcgcagagggaggcggggcggaaaggcgagaggtgtctcctccaccggagccaggg gagacccgagcaagctccgtgacagcacgtcggccgccatgtcgccgagtggggctggaaacagac ccggcgcccagcggtagccctccttgcgcctccgattcccagacatggaaggtctttaatgtaact ttaaatggttcaccaaaggatgctctaatg (Seq ID No: 1155)
Homo sapiens zinc finger protein 92 (ZNF92) :
gggcctttgtctctcgctgcagccggcgctccacgtctagtcttcactgctctgcgtcctgtgctg ataaaggctcgccgctgtgaccctgttacctgcaagaacttggaggttcacagctaagacgccagg accccctggaagcctagaaatg (Seq ID No: 1156)
Homo sapiens DnaJ (Hsp40) homolog, subfamily C, member 18
(DNAJC18) :
cccccttctctttcagcctcgggcacgggggaggctcggcggacctgctgattgggaaccgatatg (Seq ID No: 1157)
Homo sapiens polymerase (RNA) I polypeptide D, 16kDa (POLR1D) : cctcctccctccttccgtcctccgcgccttccgtcggtcggtccttgcttcctgcttcgcctccgc gcctcgcgctatgggacagagcccccgatccgccagcaccacctgaggatccagaaaccgccccag cgatg (Seq ID No: 1158)
Homo sapiens ring finger protein 182 (RNF182) :
acctccctcccctcccaggcgccgccgcagccggagcggctcccgggccctgggccgccgccggcc aggaagaaatacttgtgttggctgcatttccagggatgctaccagagctcaaggctgtcacctggt cttgcccagaagagccgttcttagaggcaggacttgatgaaggctttcctgctgatggaataggtt tgctagagctggccttggaattagaacccttcatgtggcctttataaatatgcgtttgagacagag ttatatgcagaagttgaaaatgcctggaagatttctggtttctttcactacttatcctgccttttt gcatcgctgccagatttggatgatatgatattcagaggggcaccttaatcaaagccattcttcaac aagacccacctggcataagattgcacacataattcaagatg (Seq ID No: 1159)
Homo sapiens transmembrane protein 18 (TMEM18):
cctcctctgtggattctggccaggccgggttcggcggttgctgtgagagcgggcttcccaacacca tg (Seq ID No: 1160)
Homo sapiens Hermansky-Pudlak syndrome 4 (HPS4) :
aggcctctctgccgcgcgcgcaggtacggggcagaagtcgcaggtacccagctgctgcccacattt ctggtccagagtcccgaaccccgagcactgggatgcctggctactccgagccaaggcactgatgtt tgaactggaaacttcaaaacgtttaataagagtcttcaggatgggtttgaactagacaagctagaa atttctttagaacaccagctctagcatgcatctcccacttttggctttcctggagaggagcttgaa gaggtggttctgcagacagccacagtgatacttaggaaaccagaggaatggatttgacttttctgc taggattctctgttatagtttctccctgagttgtaagaggcatggaaatatacatgaaactgaaga acctgcaaggaagggaagtggaactttccatgctgagtgaaaactaaccaagtggcagttgtgact gaaaacactgaaacctaccacgtccagattcactggattgggggatagaggaacggtcacagctag ggagaaagaagtgataccggaaaagaaaacctaaatgaagagaatgaggatgactgcacagtagat g (Seq ID No: 1161)
Homo sapiens PTK7 protein tyrosine kinase 7 (PTK7) :
agctccttttcctgagcccgccgcgatg (Seq ID No: 1162)
Homo sapiens kelch repeat and BTB (POZ) domain containing 6
(KBTBD6) :
agttctcctgggcgcctagcattgtcgcccacgctgcagtagcggcttctgcggctccaagccagc gggtcctgtgaaggcgagcagacgcggagaaaggacgcgggagtgagagagggtgagtcagccact gtctaaacgataacgggaggcggctctgcggggtagggttgaattcagtaaatgggctcgtgctgc tgtctcttcggagacgctgctatcttagcgtcagcgagggaaggttgaggaggagccagagccggg tcctgcagcgtttctcgccatcagcgcccgtcgccatctccaccatg (Seq ID No: 1163)
Homo sapiens sperm antigen with calponin homology and coiled-coil domains 1 (SPECC1) :
ctttctttgactggagcggacccgccggacgcaaccgcctcgccagccggagccagcgcgagctcg gcacggtggacacccggtccgaggccggcaagccggctggtgcccgagtcggccaagcatg (Seq ID No: 1164)
Homo sapiens ST6 (al- pha-N-acetyl-neuraminyl-2 , 3-beta-galactosyl-l , 3) -N-acetylgalactosa minide alpha-2 , 6-sialyltransferase 3 (S 6GALNAC3) :
ggtccccttatttggatctgcgggaatgtgggctggagaggtcctgccgtggtaccagcctccagc ctgcccccaggactgcccctgacccaggcgcgcccgctgctcggtggcaggagggccggcggagcg ccatg (Seq ID No: 1165)
Homo sapiens transportin 1 (TNPOl) :
gattctctttgttccgcagccatttcaggccccggacaggaggcagtgccgcttcggccgaaggcc cgagcgcccgaggcgtctgggatg (Seq ID No: 1166)
Homo sapiens heat shock 70kDa protein 8 (HSPA8) :
cttccttcgttattggagccaggcctacaccccagcaaccatg (Seq ID No: 1167)
Homo sapiens hyaluronoglucosaminidase 1 (HYAL1) :
ggctccttcctccaggagtctctggtgcagctggggtggaatctggccaggccctgcttaggcccc catcctggggtcaggaaatttggaggataaggcccttcagccccaaggacatcctggctgccatac ctgctcctgacttctcagggctggcagtcatcgactgggaggcatggcgcccacgctgggccttca actgggacaccaaggacatttaccggcagcgctcacgggcactggtacaggcacagcaccctgatt ggccagctcctcaggtggaggcagtagcccaggaccagttccagggagctgcacgggcctggatg (Seq ID No: 1168)
Homo sapiens STE20-related kinase adaptor alpha (STRADA) :
agtcctcccggtcgccccactgcgcatggcacgttgcgtactcccctcccagcaaccggtctggcg gcggcgcggcagtaaaactgaggaggcggagccaagacggtcggggctgcttgctaactccaggaa caggtttaagtttttgaaactgaagtaggcctacacagtaggaactcatg
(Seq ID No: 1169)
Homo sapiens transmembrane protein 161B (TMEM161B) :
ccctctctttcgctgtttgagagtctctcggctcaaggaccgggaggtaagaggtttgggactgcc ccggcaactccagggtgtctggtccacgacctatcctaggcgccatg (Seq ID No: 1170)
Homo sapiens Usher syndrome 1C (autosomal recessive, severe) (USH1C) :
ggctctttccagctcctggcagccgggcacccgaaggaacgggtcgtgcaacgacgcagctggacc tggcccagccatg (Seq ID No: 1171)
Homo sapiens interleukin 12 receptor, beta 1 (IL12RB1) :
cagtcttttctccttgctcagcttcaatgtgttccggagtggggacggggtggctgaacctcgcag gtggcagagaggctcccctggggctgtggggctctacgtggatccgatg
(Seq ID No: 1172)
Homo sapiens eis homeobox 2 (MEIS2) :
atcccttcctctcttttctgttcgccctcttctccctgctctttttccctttccacccccctcctc tgttctccctcacctcctgcgccccctcccccttcccgggttctgacagtacgatgagctgcccca ttacggcgggatg (Seq ID No: 1173)
Homo sapiens G elongation factor, mitochondrial 2 (GF 2) :
ttttcttttcgtttagatacattgccttttgcctaggctggcgtcgagacttgaggccgttgcaga ctttggcgcggctcgcgcctcctgcttcaagagcccagcggtgagagctggcctgcggcacgcggc ctaatgccagacagtaacagtttggaggatcaagatg (Seq ID No: 1174)
Homo sapiens lamin A/C (L NA) :
gagcctttgccccggcgtcggtgactcagtgttcgcgggagcgccgcacctacaccagccaaccca gatcccgaggtccgacagcgcccggcccagatccccacgcctgccaggagcaagccgagagccagc cggccggcgcactccgactccgagcagtctctgtccttcgacccgagccccgcgccctttccggga cccctgccccgcgggcagcgctgccaacctgccggccatg (Seq ID No: 1175)
Homo sapiens calcium/calmodulin-dependent protein kinase II delta (CAMK2D) :
cgctctttctctcgccgcgccgtcttgaagccgcgcgggctcgtgagcagcgcgaggccgccaagg tgcctcgcttcgccggagccgctgccgcccgccggagggaagccggcctcgggcgcgcacgctcgt cggagccccggcgcgccccgcgcctgagcctgctgacagcggccgctgggctcaggctgtccgctc tgggctccgcggcctcggccccgctgcactccacctccgccccctcggactccctcccctctgctt ctactcctcctgctccagtgcggatcgtttcgcaactgcttgccactcgtcccgtgcctggctgtt tttccatttcccggccccctcttcttgagtactttaccccctgcatttggggacagggactggaaa aggggcgggtggagcgtccagtggagaagaaggaagcgaggcccgcaggaggaggaggatcggcgg actgtggggaggagaccccacgccaccctttctggtcatctcccctcccgccccgcccctgcgcac actccctcgcgggcgagctactttcggaccaggaaagtaagagcggccctgggtgacagcgccgcg gggccagtcccggggttagccgcgcgtctgctcgcttctggtccgtcgcgctcccagccagggcac agcccggaccgaggatg (Seq ID No: 1176) Homo sapiens calcium/calmodulin-dependent protein kinase II gamma (CAMK2G) :
ccgtctcctcctcttgctccctcggccgggcggcggtgactgtgcaccgacgtcggcgcgggctgc accgccgcgtccgcccgcccgccagcatg (Seq ID No: 1177)
Homo sapiens interleukin 15 (IL15) :
ttttcttttcgccaggggttgggaGtccgggtggcaggcgcccgggggaatcccagctgactcgct cactgccttcgaagtccggcgccccccgggagggaactgggtggccgcaccctcccggctgcggtg gctgtcgccccccaccctgcagccaggactcgatggagaatccattccaatatatggccatgtggc tctttggagcaatgttccatcatgttccatgctgctgacgtcacatggagcacagaaatcaatgtt agcagatagccagcccatacaagatcgttttcaactagtggccccactgtgtccggaattgatggg ttcttggtctcactgacttcaagaatgaagccgcggaccctcgcggtgagtgttacagctcttaag gtggcgcatctggagtttgttccttctgatgttcggatgtgttcggagtttcttccttctggtggg ttcgtggtctcgctggctcaggagtgaagctacagaccttcgcggaggcattgtggatggatggct gctggaaaccccttgccatagccagctcttcttcaatacttaaggatttaccgtggctttgagtaa tgagaatttcgaaaccacatttgagaagtatttccatccagtgctacttgtgtttacttctaaaca gtcattttctaactgaagctggcattcatgtcttcattttgggatgcagctaatatacccagttgg ccGaaagcacctaacctatagttatataatctgactctcagttcagttttactctactaatgcctt catg (Seq ID No: 1178)
Homo sapiens protein O-fucosyltransferase 1 (POFUT1) :
gtccctccttccctccccgactgtgcgccgcggctggctcgggttcccgggccgacatg
(Seq ID No: 1179)
Homo sapiens calpain 3, (p94) (CAPN3) :
cactctctttctctctccctctggcatgcatgctgctggtaggagacccccaagtcaacattgctt cagaaatcctttagcactcatttctcaggagaacttatggcttcagaatcacagctcggtttttaa gatggacataacctgtacgaccttctgatgggctttcaactttgaactggatgtggacacttttct ctcagatgacagaattactccaacttcccctttgcagttgcttcctttccttgaaggtagctgtat cttattttctttaaaaagctttttcttccaaagccacttgccatg (Seq ID No: 1180)
Homo sapiens PTK2B protein tyrosine kinase 2 beta (PTK2B) :
agcccttttactcagccacagcctccggagccgttgcacacctacctgcccggccgacttacctgt acttgccgccgtcccggctcacctggcggtgcccgaggagtagtcgctggagtccgcgcctccctg ggactgcaatgtgccgatcttagctgctgcctgagaggatg (Seq ID No: 1181)
Homo sapiens ST6 beta-galactosamide alpha-2, 6-sialyltranferase 1 (ST6GAL1) :
cttccttccttctccagtcccttccactgtgcgtcttctgtcccccgttcttccccagcggacccc tctttcgagactccctagtggggtccccagctcccgggcgatcctgcccttgccgagcgcgttttc tggagtcacctgggggaggggagtcctgggcagggccgggctggggaagacgcctggggcactgcc cggcgttaacaaagggagccgataccgaccggcgtgggcgcggagcgggcggccgccaccgagcgt gctgagcaaccgcagcctccgcggccgagagtgcagcgagcaaggggagagccagttgcgcagagc cctgcaaccagcagtccagggagaagtggtgaatgtcatggagcccagctgaaatggactggcccc cttgagcctgtcccaagccctggtgccaggtgtccatccccgtgctgagatgagttttgatcatcc tgagaaaaatgggccttggcctgcagacccaataaaccttccctcccatggataatagtgctaatt cctgaggacctgaagggcctgccgcccctgggggattagccagaagcagatgatcatgacgcagtc ctgaggtttaatggggcacccacagccaacttccaacaagatgtgggcacaaaaactaccattcgc ctgatg (Seq ID No: 1182)
Homo sapiens ubiquitin-conjugating enzyme E2Q family member 2
(UBE2Q2 ) : ctccccttccgcgcccggctccccttccgcgcccctcccgccggagatgaggg- gaagatg (Seq ID No: 1183) Homo sapiens membrane magnesium transporter 1 (MMGT1) : gcttcttttgctgggctgctgctccttcggcatcatg (Seq ID No: 1184)
Homo sapiens PAP associated domain containing 4 (PAPD4) :
cggtcttccgggtgtctttgacagggttttctacgccgctttttcggcgactttttgctcttccgc tttttgccaccgcccccaaccttctatatccttgcagcccctaccttttcttgtgttgctcctccc ctggcagccgtgaggggggttagatctcagccggagccggagctgggcctagctgtcccacgggcc accactacctcctttggttcgggagaaagctacgaccaagtacgcccagctcgggccttagaactt ctgaacgggcagtgcgggtaggccctgcttagcccttcccggaggacacctgaccaaaagaggaag atagtcttgggacccttgcatggtgtttcaaagggtggtgaagaactaaggtagaagaatacatgt tcacttccagtgaacaagagcatg (Seq ID No: 1185)
Homo sapiens chromosome 3 open reading frame 23 (C3orf23) :
ctcccttctggtgtactgggtgggaggtggaactagtcggacaaagccctcgcgtcggacccttgc cagaactcaattaatggatgcctcgaagttgacgtacatatatattcagaaatg
(Seq ID No: 1186)
Homo sapiens mucosa associated lymphoid tissue lymphoma translocat ion gene 1 (MALTl) :
cgcccctttgcgcggctggcgcggccagccggccaggctcccctcggcaaacctgtctaattgggg cggggagcggagcttcctcctctgagggccgtgccgcgctgccagatttgttcttccgcccctgcc tccgcggctcggaggcgagcggaaggtgccccggggccgaggcccgtgacggggcgggcgggagcc ccggcagtccggggtcgccggcgagggccatg (Seq ID No: 1187)
Homo sapiens UDP glycosyltransferase 3 family, polypeptide A2 (UGT3A2) :
ctacctctacccacagccagtgcctttggcgcactgaggtgcacagggtcccttagccgggcgcag ggcgcgcagcccaggctgagatccgcggcttccgtagaagtgagcatg (Seq ID No: 1188) Homo sapiens sodium channel, voltage-gated, type IV, beta subunit (SCN4B) :
cctcctctcgctctctgcccgctaactttcccgagccccgaccggcggcgcagagctccggggtag ctttgtggccgaacgccgacctcgggcggagagcgcggctgtgcccagtatcccatccccgcgacc cccgcgcgctccggagagaacaggactatg (Seq ID No: 1189)
Homo sapiens JAZF zinc finger 1 (JAZF1) :
tcccctctgcctcccggtggctcctcgctctccttccatctctctcgccccctctccctccgtccc gtcctcgccgctcccctcaccccgcctctctccccctcccccagcccctcctctcctcaccccacc cggcctccctccctccctcgcccgcccggcgctcgcagagccgacaccaggggggctctcgatgta gcaccatg (Seq ID No: 1190)
Homo sapiens chromosome 15 open reading frame 55 (C15orf55) :
ttcccttccttggatccctgtgcacctactggagccaggttactctgggtcctggacctgactgcc tcattctggaggcttccagacagccacagttagtgcccaaacctgagaggatg
(Seq ID No: 1191)
Homo sapiens ras homolog family member C (RHOC) :
cgccctctcttcctgcagcctgggaacttcagccggctggagccccaccatg
(Seq ID No: 1192)
Homo sapiens CTP synthase II (CTPS2) :
cattctctttccttttccttctctcctgagcgctcctgcagttcctggggcgtagtaggggatcca caagcgtttgtgaccagtgaagttctttacaagggtgagatctgcacgggaggacccgagcgaggg tctcggcttgccaggaagccggggttccccgggaagcgtggagttcacccgcgcactcgaagtgcc tttgcaaaattatatctgggtgttggcacccagccactattctgccaatg
(Seq ID No: 1193)
Homo sapiens PRP4 pre-mRNA processing factor 4 homolog B (yeast) (PRPF4B) :
agctcttttccttcttcctccacttcccctaccctccaccgtccgggagccgccgccaccgccgcc gaggagtcaggaagttcaagatg (Seq ID No: 1194)
Homo sapiens molybdenum cofactor synthesis 2 (MOCS2) :
gcgcctttgcggccgtgattcggtcccgctgtcctaggcgggatggtgccgctgtgccaggtaagg gtggcgggtgtgcgtgcgggcctgggtgcggagccctcctcgacgtgtctctcccgccctttccct ccacatacccagccttggtcagtcggacctccccactagcccccaacctggccggcgtcttgggtt cgggggcgcccccgcccccgcccccgggcccttcctgtctccgggctttactgcgactgccccagc agaagtcgggtcctctccgagaactcttgtcagctcacggcagcaaggacggactcgttctgaagg cgcctccaccttttatgaccacctctttcccagattattcgttttgatgaagctaaaattttaatc taaaaagaaatgcacctcatggagaattcttgtgaagaactgtgcttcatctgtggatttctacac ccttgatcatttgcaaacctgtaattatttcgtaaagagttgtttgcacggagtgacaggttgaag tattgtattttgcaaaaagtgctgaaataacaggagttcgttcagagaccatttctgtgcctcaag aaataaaagcgttgcagctgtggaaggagatagaaactcgacatcctggattggctgatgttagaa atcagataatatttgctgttcgtcaagaatatg (Seq ID No: 1195)
Homo sapiens cat eye syndrome chromosome region, candidate 1 (CECR1) : tttcctttttccggaggggagatg (Seq ID No: 1196)
Homo sapiens solute carrier family 13 (sodium-dependent citrate transporter) , member 5 (SLC13A5) :
ctgcccctcactcgtctcgcccgccagtctccctcccgcgcgatg (Seq ID No: 1197)
Homo sapiens armadillo repeat containing, X-linked 3 (ARMCX3) : agtccttcttgtcctggtcgttgttcccgtctgagtaccagctccccactgccctgagggcgggcc ggcctgcggcggagggaaaaaggaagaggagaaggaaattgtcccgaatccctgcagtgggtccaa gcctctcccgggtggccagtctttctgtaggttgcggcacaacgccaggcaaaagaagaggaagga atttaatcctaatcggtggaggtcgatttgagggtctgctgtagcaggtggctccgcttgaagcga gggaggaagtttcctccgatcagtagagattggaaagattgttgggagtggcacaccactagggaa aagaagaaggggcgaactgcttgtcttgaggaggtcaacccccagaatcagctcttgtggccttga agtggctgaagacgatcaccctccacaggcttgagcccagtcccacagccttcctcccccagcctg agtgactactctattccttggtccctgctattgtcggggacgattgcatg
(Seq ID No: 1198)
Homo sapiens armadillo repeat containing, X-linked 2 (ARMCX2) : cgtcctcctctgggtaccaactctattgcgcagctcgctgccgtgcgtttaacccaggcgaggagg aggaggagaaaattcccccagattcgggcaggcccgcaccccacattccgtcctgttttgagagga ggagggaagagaaataaacgtggcagcgcatagaaggccagcagggagactgctttccagacacct ccggcccacacagccgttcaccccccgtcttttcagtcctggaaaaggaattcggtctgtccttag gatgaagctctaactgaactgaagtaaggagaaacagccttgaatctttggagggtctgtcttcct tttgggctctgtgcaactgcagctacagtggaaaaaagcaaactgctcttgatcccaggccctgcc taagcctcagcagaacttgtaagcctaaactgaagagcctcacccggacgagcaggcatcccttaa ccttaagcaatccagttccacgccctggatcagtgaataaccccagctgcaccatg
(Seq ID No: 1199)
Homo sapiens UBA domain containing 2 (UBAC2) :
cgccctctggggctccgagcccggcgggaccatgttcaccagcaccggctccagtgggctctgtga gtaccggcctccgccatcctggctgccccctacacgccaccctaggcacctctttgaggaggctgg ggcagcggggaccctcgggtttgccggaggtggtggggccgaccctccagacccgcgtccgaaccc tgctagttcccggtcttgggggtcagcggaaaccgcccccatttcggcctggaggggcgaatgggg acaaagccccgccgcccgccccgaccccacctggtatccccaggtgctctgcccaggagtctcttg gggccgctgcaagtgggcaggtgccctggtgttctcgtgggccggccccaggccctttgcggagcg tgtgccgcgctgaaggaaggggccgtcccccttaccatgccccattcttttaggcttgggggaccg aactaactccccccgcccccacttgcaaagttcagcctccgctttagaagctgacctctcagtttc acttggatg (Seq ID No: 1200)
Homo sapiens cancer susceptibility candidate 4 (CASC4) :
cctcctccctcggccggccctggggccgtgtccgccgggcaactccagccgaggcctgggcttctg cctgcaggtgtctgcggcgaggcccctagggtacagcccgatttggccccatg
(Seq ID No: 1201)
Homo sapiens protein phosphatase, Mg2+/Mn2+ dependent, 1G (PPM1G) : cgctccctcacagctcccgtcccgttaccgcctcctggccggcctcgcgcctttcaccggcacctt gcgtcggtcgcgccgcggggcctgctcctgccgcgcgcacccccggggcttcggctccggcacggg tcgcgcccagctttcctgcacctgaggccgccggccagccgccgccatg
(Seq ID No: 1202)
Homo sapiens StAR-related lipid transfer
(START) domain containing 13 (STARD13) :
ctttctttttaaaaatcgctgggtctgttgagctgtcctgggctgggtgccttgctctttgactga gactggagacagacggcaacagccacaggcagactgaggtggcaataggaaatctgccgagatg (Seq ID No: 1203)
Homo sapiens tubulin, beta class I (TUBB) :
gattctcccgcctcccagccecggcgcacgcgcgccccgcccagcctgctttccctccgcgccctc ccctctcctttctccctctcagaaccttcctgccgtcgcgtttgcacctcgctgctccagcctctg gggcgcattccaaccttccagcctgcgacctgcggagaaaaaaaattacttattttcttgccccat acataccttgaggcgagcaaaaaaattaaattttaaccatg (Seq ID No: 1204)
Homo sapiens cytochrome P450, family 4, subfamily X, polypeptide 1 (CYP4X1) :
tttccttcttcccgcgagtcagaagcttcgcgagggcccagagaggcggtggggtgggcgacccta cgccagctccgggcgggagaaagcccaccctctcccgcgccccaggaaaccgccggcgttcggcgc tgcgcagagccatg (Seq ID No: 1205)
Homo sapiens doublecortin (DCX) :
ttttctttctctcagcatctccacccaaccagcagaaaaccggtgagtggggcttttaagtgattt tcaagaagaatgtaacagatgtcaaacgggaaaagcacaaggcaaagcctgctctctctgtctctc tgtctcctcttctccttttttgccttattctatccgattttttccctaagcttctacctgggattt tcctttggaaaagtctctgaggttccaccaaaatatg (Seq ID No: 1206)
Homo sapiens protein phosphatase 2, regulatory subunit B1, gamma (PPP2R5C) :
ttgtctttttttttttaaactaaaatggaggctggtttcttgccttaaggagcccattgcctttcc cgctgaagtctagatg (Seq ID No: 1207)
Homo sapiens solute carrier family 9, subfamily B
(cation proton antiporter 2), member 2 (SLC9B2) :
ccacctttccgggggaagccacgcgcaccaggcatcgcacgcggctctgcacccgcgccgccggac ctgaaacccggcggagggcacacggggctgccgctgcgggccccggaccaacccatgcttactccg gagcctgtaccggcgccgacgggtcggacctccctgcgcggtgtcgcccagcgggttcgtgcgaaa ggcggggccgactacacgcggtgccgcgccctgagaccgtttatctgcagtcaacgcagcctcccg gctcagcctgggaagatgcgcgaatcgggaaccccagagcgcggtggctagaccgggctccgccgc ctcccccacagcccctttcctaatcgttcagacggagcctggtcgacttcgccggagactgccaga tctcgttcctcttccctgtgtcatcttcttaattataaataatg (Seq ID No: 1208)
Homo sapiens hypoxia inducible factor 1, alpha subunit (basic helix-loop-helix transcription factor) (HIF1A) :
caccctcttcgtcgcttcggccagtgtgtcgggctgggccctgacaagccacctgaggagaggctc ggagccgggcccggaccccggcgattgccgcccgcttctctctagtctcacgaggggtttcccgcc tcgcacccccacctctggacttgcctttccttctcttctccgcgtgtggagggagccagcgcttag gccggagcgagcctgggggccgcccgccgtgaagacatcgcggggaccgattcaccatg
(Seq ID No: 1209)
Homo sapiens interleukin 21 receptor (IL21R) :
cctcctcttcctccccactctgcacatgcggctgggtggcagccagcggcctcagacagacccact ggcgtctctctgctgagtgaccgtaagctcggcgtctggccctctgcctgcctctccctgagtgtg gctgacagccacgcagctgtgtctgtctgtctgcggcccgtgcatccctgctgcggccgcctggta ccttccttgccgtctctttcctctgtctgctgctctgtgggacacctgcctggaggcccagctgcc cgtcatcagagtgacaggtcttatgacagcctgattggtgactcgggctgggtgtggattctcacc ccaggcctctgcctgctttctcagaccctcatctgtcacccccacgctgaacccagctgccacccc cagaagcccatcagactgcccccagcacacggaatggatttctgagaaagaagccgaaacagaaga tgaggcaatgaggctgcgagaggtagagtgattttccctcggtgactcaactgggacgtagcaggt cgggcagtcaagccaggtgaccccatg (Seq ID No: 1210)
Homo sapiens DDB1 and CUL4 associated factor 4 (DCAF4) :
tggtctttccgggtccttgcacgcttcgctccaactcctgcagagctgagccggaggggaatccgg aagggacacgctgaacaggtctgactcccgggcagcacagcccgctcacgattccggccacggtga tgacgagtctccgtcaacctcgtctggcacagctgggacctcctctgtgccagagctacctgggtt ttactttgaccctgaaaagaaacgctacttccgcttgctccctggacataacaactgcaaccccct gacgaaagagagcatccggcagaaggagatg (Seq ID No: 1211)
Homo sapiens oxidation resistance 1 (OXRl) :
ccgcctcttgtgaggcgcgcggagccgcctcccctgggtcaggtctgatgggccggtgggcgcgct agtggtggccgccaccgccgaaaccgtcgacctcctgggccccagttccgcgtccagccccgcggc agcatg (Seq ID No: 1212)
Homo sapiens cut-like homeobox 1 (CUX1) : ccccctctctat- cagccgctcactccgtctcaatatgtctcaagatg (Seq ID No: 1213)
Homo sapiens atlastin GTPase 1 (ATL1) :
ctcccttttcctccccactccttcccaccagcgccacagcaacatcctcagagtctgagcgaactg cgcccagcgcgggcacggagcctcccaccgccagcaacctgcggccccggagaaggcagcgagcgc agtgacagcgcctcaccgccaccagctcctggaccaccatg (Seq ID No: 1214)
Homo sapiens chemokine-like factor superfamily 5 (CKLFSF5) :
ctgccttctctcccggggccctgtgggcaagcctcctgcttcactttcaggtttctcgaagtgcct tcttgctcctgtctgtttccccatcctgccagatttctgtttctcttgctgggcttttggcagtag ggggctgtgttggtgggccctacgaagatg (Seq ID No: 1215)
Homo sapiens transmembrane emp2 protein transport domain containi ng 7 (TMED7) :
aggccttttccgcttctcttttacctccccaggtccgcccgtctgcgcccctcacaggaagccgga gggtcgctctgatcccgaatctcccacaggcgtgaacctgctctgctgtgtatctttgcggggtgg cctgcgctgaggcctgccgcgcgcggtgagtccgcgcagacctgaccctgcgtctcgcagctcggt tgaggccgccgccgccttctcgggatg (Seq ID No: 1216) Homo sapiens ubiquitin-conjugating enzyme E2D 3 (UBE2D3) :
cttcctttaccttcctcccatggtctccttccggttctcgatgcttctctgagcctaagggtttcc gccactcgttcaccctccccccagctcatgatcctcctccctcccccgccctcctggtccaatctc cgatctgtttagtaagaaggtgctgttccgagaagaaggaaaagggcttgacacgtattcactcgg ccccggacgtgggaagcaagccgtctggcttcggcctcacatcggtcttgtgctcgggacggcggc gttggcggactgatccgcggcggtgaagagaggccgggaagttaaacttgtagccaccacctccgc tcttcccgtcaccctcgcccccacttcgggccgaaagcacggtacagaggctgttggtggctttgc cacgccaccccacccaccccggatcgcggctgtcttaagggacctggattcatcaggggctcttcg gggcctgtgcgagtgctgatctgctccgtttttgcaaaaggcgcctgtgtctggcagagctggtgt gagacgagacaatcctgccccgccgccgggataatcaagagttttggccggacctttgagcataca ccgagagagtgaggagccagacgacaagcacacactatg (Seq ID No: 1217)
Homo sapiens zinc finger protein 595 (ZNF595) :
tttcctctggctcctgcgagggcttggtttagggcttcagctctctgcgttctcggctccgggagg cctcggtgattcagccacagcctctgcctcccgttgctctgtgacctgagggtattggacaatttg tagctaagactcccggataccctgaagtcgggaaatg (Seq ID No: 1218)
Homo sapiens acyl-CoA synthetase medium-chain family member 2B (ACSM2B) :
tgctctcttccaaggctgtaggagttctggagctgctggctggagaggagggtggacgaagctctc tccagaaagacatcctgagaggacttggcagcctgcagatggcctattgtgggaccttgtgatcat gcctgaacatg (Seq ID No: 1219)
Homo sapiens SRSF protein kinase 2 (SRPK2) :
tttccctttatagcaccattgaatcccagtcctaacagaagtactgcgaatcttgtggcctcattc tgaacaaaagggattagagaagaaaaatctcttgatataaggcttgaaagcaagggcaggcaatct tggttgtgaatattttctgatttttccagaaatcaagcagaagattgagctgctgatg
(Seq ID No: 1220)
Homo sapiens synaptophysin-like 1 (SYPL1) :
tgcccttcctcgccaccgggctgctctggtctcgtcggtcccctcctccgccccgtcgtcctgact ctctctccctcctttcctcagaggatg (Seq ID No: 1221)
Homo sapiens thioredoxin reductase 1 (TXNRD1) :
aaccctttcacctcagttttcttcactccggcatttgcagcagagcgaaaggtggtcgagtcctga aggagggcctgatgtctteatcattctcaaattcttgtaagctctgcgtcgggtgaaaccagacaa agccgcgagcccagggatgggagcacgcgggggacggcctgccggcggggacgacagcattgcgcc tgggtgcagcagtgtgcgtctcggggaagggaagatattttaaggcgtgtctgagcagacggggag gcttttccaaacccaggcagcttcgtggcgtgtgcggtttcgacccggtcacacaaagcttcagca tgtcatgtggcttatcaggagggcagacttcaaaagctactaaaaatg (Seq ID No: 1222)
Homo sapiens minichromosome maintenance complex component 7
(MCM7) :
tgtccttccgcgcggcggccgcggagagagctgcggcccgggggggcgtgcctgggatccggagct tcgctcgggcccgggaaaggcggcagtgggctgggatcgcggtgtctctgggtgtgatggccaatg gctggactggctcccgccctgggcggaggaatcccgagctgtgaagcggctggaatccgggcccat gtgcttctttgtttactaagagcggaagcgatggcgggagcgggggtggggtgcggtggcggggtg cggtggcggaggtcccggtgaaatcaggggctaaggggacccaaagaaggcgggggatcatagggg tggaaagaaagctgagaaccttgagaccggagtgtgaggggccaacggggaagggcgctagaattt taaactaaagtagggaccggaattcccctggggagatgttggatggccctgtgcactgccacgggc tctttattcttcgctggttagaaacagacttgtgaaaaagagttatgcccactttggggagacttc gaaaaggttaagaagttcttacaagagttctaccaggatgatgaactcgggaagaagcagttcaag tatgggaaccagttggttcggctggctcatcgggaacaggtggctctgtatgtggacctggacgac gtagccgaggatgaccccgagttggtggactcaatttgtgagaatgccaggcgctacgcgaagctc tttgctgatgccgtacaagagctgctgcctcagtacaaggagagggaagtggtaaataaagatgtc ctggacgtttacattgagcatcggctaatgatggagcagcggagtcgggaccctgggatggtccga agcccccagaaccagtaccctgctgaactcatgcgcagattgtgagtggtctctgtcgggaaagat gtagggattggttctccaggatcttgtttgtgactgttttctccccttagtgagctgtattttcaa ggccctagcagcaacaagcctcgtgtgatccgggaagtgcgggctgactctgtggggaagttggta actgtgcgtggaatcgtcactcgtgtctctgaagtcaaacccaagatg (Seq ID No: 1223)
Homo sapiens pre-B-cell colony enhancing factor 1 (PBEF1) :
tttccccctctccccctcctccgccgaccgagcagtgacttaagcaacggagcgcggtgaagctca tttttctccttcctcgcagccgcgccagggagctcgcggcgcgcggcccctgtcctccggcccgag atg (Seq ID No: 1224)
Homo sapiens cyclin Bl interacting protein 1,. E3 ubiquitin protein ligase (CCNB1IP1) :
ctttctttccctctccgttttggtgggctggttgaagatgaaatccactgaggagggaagtccagc accctgtgtgccagtccagaactggcccatctgtagaccccctgaaaatcatatgggcttggattt ggatattctcaacagaaagggttaaaggctgatggtacctaaagcctggtacttgaattttgatca agataagctgccttaagttctcttcattacacaaatgatcctagataattgatagatcctgtggtt caactggatttctagatagaagctggattcatgtgatgccagaggagtaaaatttcaagagactga aaccagatctgagtttcgctgttccagtctggacctctttggtgctgtaaatcctggatatactgt agatgagtactgcgtttttcttttatggcctctcttcagcttctggagacctcactatcctattat g (Seq ID No: 1225)
Homo sapiens STEAP family member 3, metalloreductase (STEAP3) : ccgccttcgccgcggaccttcagctgccgcggtcgctccgagcggcgggccgcagagatgacattt attcattttatgcatcctgggttctactggtcgtcccacctcagttcctgtagcaaagagacttga gtctgagccactaattatcacccgtgaggtttcctccccgagcaggaagcagcaggccagagctgc gctctctcagtgcactctccaaccaagcatcagtcaccactcccggtccagcccctgtggccaaga gctggcgtgcaggctgcgggaggcagctggctgtgcaagaccctggcagggccctcgcctcctgag aaaccgagagtcagaaccaaagccaggctgtcctggttggagactgagccagaaagggtggctcac ctcacggtgaggctgtcgagtgacctgagagcctcagaccctcacgtcagccggatg
(Seq ID No: 1226)
Homo sapiens nicotinamide nucleotide transhydrogenase (NNT) :
tgttcttccgggttggaggcgcagcgccgcggggcccaagcccgggtctgccagcgcgacgtcctc tcgcggccctcagggcacagcccaaggctgtcagcctcccggcccagtgatttgccttcaaggaaa ctggggagtcagaaaattgggaactcatatcaacatg (Seq ID No: 1227)
Homo sapiens SHC
(Src homology 2 domain containing) transforming protein 1 (SHC1) : gtccctctccctccccaggacttctgtgactcctgggccacagaggtccaaccaggctaagggcct ggggataccccctgcctggcccccttgcccaaactggcaggggggccaggctgggcagcagcccct ctttcacctcaactatg (Seq ID No: 1228)
Homo sapiens bromodomain containing 8 (BRD8): cggcccttcca- gaccgtctctcctcagggttggagacttcggggccaagatg (Seq ID No: 1229)
Homo sapiens ring finger protein 13 (RNF13) :
tcgcctctttagtaggtcgggtgagtgtagtgtgcagggaagagacgcgtcagcgccagggccagg cccgcccgggggcagcccggcagccgaatcttgggctactctgtcccaacagccggagcagatcag accgaccggccctgcccgctcggtcccgcgccctccagaccctacggtctccgtttctaggggcac atggttagcggcaggcgcccacagccaatccactttgccagcctgccccttcctctgccaagagca gcttcttcagccgcgctccagttccgcagacgcctgccccaccctgctcttcccttccagggaaga cggatcacgcggccaagaacgagactcgcaaactgggcatttctccgagccgggctagagcaagta gcgagactccgcgtgagagtgggaaagagccttaacaggcaaccatgttgcccagtgggttttctg tgcctttgggtgcggaccaatgaggcgcgtggggcgggacttccgcttcgcctaggtgttgtcgtc cctgctagtactccgggctgtgggggtcggtgcggatattcagtcatgaaatcagggtagggactt ctcccgcagcgacgcggctggcaagactgtttgtgttgcgggggccggacttcaagagagaaagag agagtgggcagacatcgaagccaaacagcagtatcccggaagcactcatgcaactttggtggcggc cactcagttttctctgccagtgtctggtgattttacaacgagatg (Seq ID No: 1230)
Homo sapiens aldolase A, fructose-bisphosphate (ALDOA) :
ccgcctcctgcgccgccccttccgaggctaaatcggctgcgttcctctcggaacgcgccgcagaag gggtcctggtgacgagtcccgcgttctctccttgaatccactcgccagcccgccgccctctgccgc cgcaccctgcacacccgcccctctcctgtgccaggaacttgctactaccagcaccatg
(Seq ID No: 1231)
Homo sapiens LY6/PLAUR domain containing 6 (LYPD6) :
cgctccttccctgagctcccgggctccggcagcgcgctggcggggcgccgcattgcacactctggg ggcgccgcagtgttcgtgggatggggcagcgggctgcagctggcggccggaatccgcgcgcagccc gggtgcaagttctctcctgttgccctgagtgcccactcccaggccctctgtatgagtgacacttca gtctgccatg (Seq ID No: 1232)
Homo sapiens butyrophilin, subfamily 3, member Al (BTN3A1) :
cagtctctgctttctttttcctttcttccagaaggagatttaaccatagtagaaagaatggagaac tattaactgcctttcttctgtgggctgtgattttcagaggggaatgctaagaggtgattttcaatg ttgggactcaaaggtgaagacactgaaggacagaatttttggcagaggaaagatcttcttcggtca ccatacttgagttagctctagggaagtggaggtttccatttggaattctatagcttcttccaggtc atagtgtctgccccccaccttccagtatctcctgatatgcagcatgaatg
(Seq ID No: 1233)
Homo sapiens lipoic acid synthetase (LIAS) :
ctgtcctttcccgggagttagcgatccctcaacccctgcactgcgctagtcctaaagaggaaatg (Seq ID No: 1234)
Homo sapiens C-type lectin domain family 7, member A (CLEC7A) : gattctcttttgtccacagacagtcatctcaggagcagaaagaaaagagctcccaaatgctatatc tattcaggggctctcaagaacaatg (Seq ID No: 1235)
Homo sapiens CD247 molecule (CD247) :
actccttttctcctaaccgtcccggccaccgctgcctcagcctctgcctcccagcctctttctgag ggaaaggacaagatg (Seq ID No: 1236)
Homo sapiens myeloid zinc finger 1 (MZF1) :
aagcctttctccattttgcggtctaggaagtagcagaggccccttcctgtagggagttgccatgga gacgcggtggggcaccgacggagttctaatgacggccgtgattggtgcaggatcctgctaatctca ggaaggcccgtagagaagtgaggaaaacgtggtggggggcatgcgcgatctggtaggcggtgctgc cgtctgttgtacctgagaggcttgcgcatgccgacgcacggattcgaggcggggagcatgggaaga agcggccaggagtatgacctgatcattgcgaccaccgctaggggaagggaggagagggtgtagaaa cggggacgagggtgggggaagggcaaggaggcgctcgagctggtgcgcggagcatcctgggagacg tagtccagcgggagggggaagtcgaagactgcgcgtgctcaggagcgcggagcggcccgctgagcg cagaggggcagacactggcctcagatacctgacctggtaccctctatg (Seq ID No: 1237)
Homo sapiens E2F transcription factor 6 (E2F6) :
cctcctctttttccgtctgcgtcgggagctcccgggcacgtgaggccgtgccgcgtttactggcgg gcgggacggcctagccgggcggcgcctcggaggaagccgcggaccccttaggtgctgggcccttgg aaatcggcgcgtggggggcggtgctcgagctgagcgcgagagggcgggagagctcgtggggtgcga ggggagcaggacgcccggccgggcagcatg (Seq ID No: 1238)
Homo sapiens purinergic receptor P2Y, G-protein coupled, 10
(P2RY10) :
cttcctctttcaacaacaaatgtgtcagttatcagcaggatccatgccgccagagtaaagctttct accctttactccctgcaaagaaacaagagtgcttatcccagctaagctccagggtaatgttatcat gacagcttcaacttttagaccacaggcaaatgctttgttaaaactctatgctggtcattcccttca ggatttggcactcaccaacatacccttctttcaagtgaaaaggcatctcttttaatggtcctgacc tttggaataggaagcatgtaccctggacagagcacttcaaactagaggaaccataaatccatg (Seq ID No: 1239)
Homo sapiens chromosome 9 open reading frame 85 (C9orf85) :
catccttttgcctgctcccggcgaggggtggctttgatttcggcgatg (Seq ID No: 1240)
Homo sapiens ERGIC and golgi 3 (ERGIC3) :
cgtcccctttccggccggtccccatg (Seq ID No: 1241)
Homo sapiens ankyrin repeat domain 46 (ANKRD46) :
ccctcccctccgcccgtcaccgcctccttgaagctgccgctgtcgctgctgctcgttcgagtcgca gatccttgccagcacattacagaatatttttgttgaaccttcttgagaattcagagaaactgctga gtgaccactgaacgaaaagatctaatcttaaggcttacgcctcactttgatgcccaggctggagtg ctgtggctcaatcacagctcatcgcaacctcgacctcccgggctcaagtgatcctctcacctcage gtcccgaacaggcgtgttccatccaccacatcagaacaatg (Seq ID No: 1242)
Homo sapiens Ras and Rab interactor-like (RINL) :
tcctctctccacttcctgctactgcaggcctctcctccgagaacagaggccaggtcatgactcact ggcttcctgcaacctgacgatggcccagccagaagacaaggcacctgaagtccccacagagggggt gaggtgaacaaagcagacaggacccctctaggggtcctcagcaccctagagccacttactcgcctg cagaggacatggggggtgtggcatgtgccagagctggatacccaggatgcggaggcccttgtgggg ctgtggccactagggagtttcttggtcacaggacgtgaccccagccaggccctggtgttgaggtca ggacctttaccaggagaagtcaatacctaccagatccagaagattcccagaggtgtgtccctggaa tcctccaacctctgcatg (Seq ID No: 1243)
Homo sapiens embigin (EMB) :
ccgccttttcttcagcgtcctacccgcggcactggctgcgagcgccgggccacctgcgagtgtgcg cagggactctggacacccgcggcggcgagctgagggagcagtctccacgaggacccaggcggaccc tctggcgccatg (Seq ID No: 1244)
Homo sapiens MS22-like, DNA repair protein (M S22L) :
ccgcctttccggagcgcgggcgcgcggtggcgggaatttcgcctgtttgcggtttagaccccaaag attcctgttggtggtctgggtcacaggaggcaggtttcgggagctggaaatgtgagcgggtacgac aggcaccgcgggtaaccgacgccccgggtccttgctgcagccgggtacgcgggataccggcacccc gccttctccgcccgagtgctgccaggcgtgggcctggaatctcttcacaccttctctttggagccc ttaatgatacgacgaaccccaagtgtttcagaacatgaagtaaacaatg
(Seq ID No: 1245)
Homo sapiens chromosome 19 open reading frame 54 (C19orf54) :
actcctttcctttttccagtggttatcgcggcgcccaccggcctctgatctctgagtcttctccaa cccacagacgttttttgttgctctggttccaggaccttctccacaactaggccattttccctgcca ggtgtcctttttgacctcttgacctctgactcaaagggcctgctccccctcatgtcttcggcctgg agaagagccagctcctgaaggaggcctttgataaggccggcccggtccccaagggcagagaagatg tgaagaggcttctgaaactacacaaggaccggttccgaggtgacctgcggtggatcctcttctgtg cagacctgccgtccctcatccaagaaggccctcaatg (Seq ID No: 1246) Homo sapiens zinc finger protein 621 (ZNF621) :
cgcccttccggctcggcctttagttagtgaccagctcctcggcgttctgcagagcgtgggtttcag cgagttctacgtgccaggtccgcccggtgccggcttcctcgctgcccctggcggctcgtcagcccc cactacccctgaacttggtcccaatggcggcccgcccctccttcacccggaccgtgggcatctggg cctcgccgaagccgtcaaggtggctgctcgggcttctagagcccgtgtccagccctttgccaccga ggcctgatcctcttttctgccctaaagaacttgccctgacagcctctggctcccgctcttgaggat cttgcttgtccaaacccagaagacagtgcatgaagccaggggacatccgccatg
(Seq ID No: 1247)
Homo sapiens family with sequence similarity 73, member A
(FAM73A) : ccgccttctccatg (Seq ID No: 1248)
Homo sapiens RNA binding motif protein 43 (RBM43) :
ccgcccttttcttcgtagcctccaagggagctggaacaaaaaacgaaaccaaaacctgcctgctcg ctcctctccccatcgcctgcgttccgctggttgtgggctttctgcggccgctgagggcgcgtctcc cctccgccatg (Seq ID No: 1249)
Homo sapiens spermatogenesis and centriole associated 1 (SPATC1) : caccctccttcagcccaggcaaggcctggggccctgggcagcctccaggtgcagtgccctcccgtg ggccgcacccttgccactgccccagggcatg (Seq ID No: 1250)
Homo sapiens carbonic anhydrase XIII (CA13) :
ctttctcttccttccaccccgagggaccatg (Seq ID No: 1251)
Homo sapiens transglutaminase 2
(C polypeptide, protein-glutamine-gamma-glutamyltransferase) (TGM2) :
cgctctccgcctcggcagtgccagccgccagtggtcgcacttggagggtctcgccgccagtggaag gagccaccgcccccgcccgaccatg (Seq ID No: 1252)
Homo sapiens NOP2/Sun domain family, member 4 (NSUN4) :
atttcctttcccttttttcgctcgtgtcccgccgggtggcgctcaccacctccccggaacacgcga gtctcctgtcgcggttccggtcggaattaccccgtggagcacgccgatatg
(Seq ID No: 1253)
Homo sapiens mitochondrial ribosome recycling factor (MRRF) :
gagtctttccttagtaacctgggcgatagctgtggatgtttccaaggattgtcttcagtcatg (Seq ID No: 1254)
Homo sapiens PHD finger protein 17 (PHF17) :
cttcctccataacaagccaaacgccagaccgagagtgcctccgtgcgcgagtgcccggtgtgtgcg cgccggcgagagcaggggcccgcccggctccccgcccgccgcggcccgaactcatgcagctccgag cgagcgagcggcgcccagcccagcgcctcggccgaacccctccgcagcaggctgcctgctgtttcc cggggagatcatg (Seq ID No: 1255)
Homo sapiens prolylcarboxypeptidase (angiotensinase C) (PRCP) : cctccttttcgccctcccacccgcactgcagtctccagcctgagccatg
(Seq ID No: 1256)
Homo sapiens proteolipid protein 1 (PLP1) :
aagcccttttcattgcaggagaagaggacaaagatactcagagagaaaaagtaaaagaccgaagaa ggaggctggagagaccaggatccttccagctgaacaaagtcagccacaaagcagactagccagccg gctacaattggagtcagagtcccaaagacatg (Seq ID No: 1257) Homo sapiens coiled-coil domain containing 80 (CCDC80) : cagccttctcactcctcactgagtccactctgaacgtgctaaaatgggaaggaggcggtgttttgc tgatctgttaaattcttagtgaagtttccttgatttccagtggctgctgttgtttgagtttggttt ggagcaaaactgaggtagtcctaacatttctgggactgaatccaggcaagagaaagaagaaaaaga agaagaaaaagaggaggaaaaaggtagggagaaataaagggaggagagaagcacagtgaaagaaaa aaaaagtGccttttcgacatcacattcctgtgttttccctcagcctggaaaacatattaatcccag tgcttttacgcccggaaacaaagagactaagccagactatgggggaaagggagataagaaggatcc tggaactttaaagagggaaagagtgagattcagaaatcgccaggactggactttaagggacgtcct gtgtcagcacaagggactggcacacacagacacacgagaccgaggagaaactgcagacaaatggag atacaaagacttagaaggacagctcctttcacctcatcctacttgtccagaaggtaaaaagacaca gccagaaagaaaaggcatcggctcagctctcagatcaggacaggctgtggatctgtggcggtactc tgaaagctggagctgcagcacaccccttttgtattgctcaccctcggtaaagagagagagggctgg gaggaaaagtagttcatctaggaaactgtcctgggaaccaaacttctgatttcttttgcaaccctc tgcattccatctctatgagccaccattggattacacaatg (Seq ID No: 1258)
Homo sapiens chromosome 20 open reading frame 44 (C20orf44) :
cgacctctttgcgcctgcgccccccttgccagtctttcgccggcaaaaggaggacgtagaaaaggg gacaccggaaactcactcttcacccggaaatggttattgaggaacatg (Seq ID No: 1259)
Homo sapiens tryptophanyl tRNA synthetase 2, mitochondrial
(WARS2 ) : cgcccttctcaagatg (Seq ID No: 1260)
Homo sapiens myotubularin related protein 2 ( TMR2) :
ctttccctgtgctgcccctgccgcgcgatggagaagagctcgagctgcgagagtcttggctcccag ccggcggcggctcggccgcccagcgtggactccttgtccagttaatgtgttaagagccattgacat ttgaagatcatcagaagtgaagataaaacatctcaaaaattataattgcctccacttctcattcag agaattcagtgcatacaaaatcagcttctgttgtatcatcagattccatttcaacttctgccgaca acttttctcctgatttgaggagggagtctcgctctatcccctaggctggagtgcattggcgccatc tcggctcatttgcaacctctgtctcccgggttcaagcgattctcctgcctcagcttcccgaggagc tgggattacaggtcctgagggagtctaacaagttagcagaaatg (Seq ID No: 1261)
Homo sapiens reticulon 3 (RTN3) :
cgccctctagctgcgctcggctgagtcagtcagtctgtcggagtctgtcctcggagcaggcggagt aaagggacttgagcgagccagttgccggattattctatttcccctccctctctcccgccccgtatc tcttttcacccttctcccaccctcgctcgcgtagccatg (Seq ID No: 1262)
Homo sapiens G protein-coupled receptor 56 (GPR56) :
gtccctccctctccgcactagctgtctgccctgccctgccgtaggagatgggctgggagcctccca cgctctccagctcactcggcaggcagcggggaccagggctggcaggttaagcctctgggggtggat cctgaaaggtggtccagccgcctggccctgcgtgggaccctccacctggcagcagacagggtctcg ctctgtcacacaggctggagtgcagtggtgtgatcttggctcatcgtaacctccacctcccgggtt caagtgattctcatgcctcagcctcccgagtagctgggattacaggtggtgacttccaagagtgac tccgtcggaggaaaatg (Seq ID No: 1263)
Homo sapiens immunoglobulin superfamily containing leucine-rich re peat (ISLR) :
gctcctccctgccgcctcctctcagtggatggttccaggcaccctgtctggggcagggagggcaca ggcctgcacatcgaaggtggggtgggaccaggctgcccctcgccccagcatccaagtcctcccttg ggcgcccgtggccctgcagactctcagggctaaggtcctctgttgctttttggttccaccttagaa gaggctccgcttgactaagagtagcttgaaggaggcaccatg (Seq ID No: 1264) Homo sapiens glycoprotein M6A (GPM6A) :
atttcttttccccattttaaatgcaaagcaagacttgtgaatcatagtgtctctgctcctgggatt cagaccaaatttccccccaaaattctcaggctatttgtttgaatacctgcttacagtggtacacaa tgggcagctttgagaagaaaaattgataatcttcacggaagagtaatttgaatgaaattacacttg acagcctgtctccaagcaaacaagaggaacgagggagcctgagctaagctctgaggacttgcccaa gccactgctgttggagcttcccaggaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaac accagtttttccaacatctaattgagcttttgattaattccgtgtaccagattctactgaagaaag gtagccatg (Seq ID No: 1265)
Homo sapiens splicing factor 1 (SF1) :
ctccctctttgtgcgtctcgcgccgccgccgcccgccgcgtgagaggacgggctccgcgcgctccg gcagcgcattcgggtcccctccccccgggaggcttgcgaaggagaagccgccgcagaggaaaagca ggtgccggtgcctgtccccgggggcgccatg (Seq ID No: 1266)
Homo sapiens cell cycle associated protein 1 (CAPRIN1) :
ccgcccctcgcgacccagagggctgctggctggctaagtccctcccgctcccggctctcgcctcac taggagcggctctcggtgcagcgggacagggcgaagcggcctgcgcccacggagcgcgcgacactg cccggaagggaccgccacccttgccccctcagctgcccactcgtgatttccagcggcctccgcgcg cgcacgatg (Seq ID No: 1267)
Homo sapiens hypothetical protein FLJ90297 (LOC388152) :
ctgccctcttgcgtgccccggccacccccgggcggcttgtagccggtgcgcggggtggctggggct acgtgcagagctgtcgcggagccggaacagcagcggtgaagcccctcggctcggccgagaccgccg tgcccattgctcgcctcggttgccgccgctttagccgcagccgctgctgccgccgccgggggagag gcagcctattgtctttctccgcggcgaaggtgaggagctgtctcggctcggcccgcgggggagccc cgggagccgcacggagatggaggaggacatctggacagtgagcaggaggcgcctcggcccatg (Seq ID No: 1268)
Homo sapiens kelch-like ECH-associated protein 1 (KEAPl ) :
cgccctctccccgcctccttttcgggcgtcccgaggccgctccccaaccgacaaccaagaccccgc aggccacgcagccctggagccgaggccccccgacggcggaggcgcccgcgggtcccctacagccaa ggtccctgagtgccagaggtggtggtgttgcttatcttctggaaccccatg
(Seq ID No: 1269)
Homo sapiens F-box protein 38 (FBX038):
ctccctctcaaccacaataacaggcggagggtcggcgtaggtactttgaactcaagtaaacaaaag ggaagattttctcgttgatactggagactgcacaacaatg (Seq ID No: 1270)
Homo sapiens musculoskeletal, embryonic nuclear protein 1
(MUSTN1) :
agatcttttccagcagctgctgcctgccagagaggcgccttcagagacccagcgcttacacaatac ccaccatg (Seq ID No: 1271)
Homo sapiens QKI, KH domain containing, RNA binding (QKI) :
cctcctctccggcggcggcggcggcggcggcgggcggagtgagctgcggagcctggaatatg (Seq ID No: 1272)
Homo sapiens protein phosphatase 1, catalytic subunit, beta isofor m (PPP1CB) :
gggcctctcttgtttatttatttattttccgtgggtgcctccgagtgtgcgcgcgctctcgctacc cggcggggagggggtggggggagggcccgggaaaagggggagttggagccggggtcgaaacgccgc gtgacttgtaggtgagagaacgccgagccgtcgccgcagcctccgccgccgagaagcccttgttcc cgctgctgggaaggagagtctgtgccgacaagatg (Seq ID No: 1273)
Homo sapiens methyltransferase like 21B (METTL21B) :
cagcctctaccccgctccggatccgggatctgagcgccggccgcggtgcccaggcactcccttggc gggccggatg (Seq ID No: 1274) Homo sapiens adaptor-related protein complex 3, mu 1 subunit (AP3M1) :
cggccttctcggcttctccagcttcggtaggagaggatccggcgccgaatcactgactggcacagg tgttgggatagtgtctcacttggtcacccaggctggagtgcagtggcgcaatcttagctctctaca gcgtcgatcttcctcctgggctcaagcaattctcctgcttcatcctcctgagtacctaggactaca gaaaatg (Seq ID No: 1275)
Homo sapiens muscleblind-like splicing regulator 1 (MBNL1) :
cagtcttttcactgcagctgaatgagttgtggcgcccacaatgctcccatgacaaggagctgacaa gttccattttccgtcgcgggcatcttggaatcatgactcccacaatgccttgggcacttggtcgac agtggggccgcctctgaaaaaaaaatgtgagaggttggtactaagaagtgcctttcctgacgtctc tgctgcttggaaccgcttctagagcagtctctgcttttgccttgcttgctgccagctagactgtga cgacagcacatccaccctccacctctagcccagacacccccatttctacttataatcaagagaaaa gctctaagtatctggcattgccctaggctgctttagtgttaaaagaaaagtttgctgaaaaagtaa gatatcttctgccaggaaatcaaggaggaaaaaaaaaatcattttctcgattttgctctaaactgc tgcatctgtctatgccaaactaatcaataccgattgcaccaccaaactccattgcaaattcagctg tgaggagattccctttcagacaactttgctgaaagcagcttggaaattcggtgtcgaagggtctgc cacgttttcatgcttgcattttgggctccaaattggcactgggaaggggttactgagagcacaagg ctgataccaggccctacttttaaacgttcatctacttacaatcctagtatttctctaaaaaccaaa acctctttgaattaacagtttcatgctgtgaatttctagtgggagatcttttccttgatattgacg acacaattttccatgtacttttaaagcagggagtggggaaaagtattttgaggggacattttcatc atcagttcagctttttttttttggttgttgctcttttttgggggggttgggtttgttggtttcact gaaacatttaactacctgtaaaatctaaacatg (Seq ID No: 1276)
Homo sapiens lipid phosphate phosphatase-related protein type 1 (LPPR1) :
cagccttttgctctttcctttcattaaacaaacaggagatcctgaaacctggaccctgtgcaagct gcagcgccaggaggaggcagcggaggaagcagagcgcgggatgggcgcccagcggcatctgtgatc ccgcgcacctccgccccacgggcgcgcgcacaaacacggacacacacatacacacactcgcgcaca cactcgcacaaacacacactcgtacacgcccgcgccgctcgctcgccggcttgctctcccacgcaa gcggaatgcagcagcgcctggagagcgtgtctcggaccgccgcctgaatgtacctcgctcccggga gccggacggcccagtagggcgcactggaggacgctccgctgcgggagcctggacagtttttgacgg tgcagtcttgctatatggtgtgagaaatg (Seq ID No: 1277)
Homo sapiens muscleblind-like splicing regulator 2 (MBNL2) :
ctgtctttgcttcatcatctgaaggtaaaattttccagatacggcagacggctttcagagtacaat aaacagggaatgagaactatttacatggaagtttctttctcatgatgcggtggagaagcctcggcc acttggttctgccagatgttcctggggttactgtaaatgggaaggacaggcagagctaaacaaggt ttatcatttaaaagtgcctgtgtgaagtcacttttgctggaaaactgcagcttgggagctttcttt gtattcacatcccactcttctgtcaagtacactttaccctgaccttatgagtggatgaagatacct cagttgtctgactttgccaattgcttaatttcagaatttaaaaaggggaaagaaaaacatcctgct aaaatatgaacatctgagtgtcttattttccaacatcgtcaatagctgtgagcgtcagcattaaat attctcccaaggagtgccatgatattgaagtcactttattaataacagctgtatctgcaaaacagt caagagactcggacgttgaaagccagagatgacactgagcatgcttttattgcggcctaccatctt taagtgggacatattgattgatgagtgattgcctgtccatacactctctcatcatcctgttccttg gattggacttcactaagcaatttatcactcaccttcagacttacatgtgggagttttcacaacagt agttttggaatcattagaacttggattgattteatcatttaacagaaacaaacagcccaaattact ttatcaccatg (Seq ID No: 1278)
Homo sapiens chromosome 3 open reading frame 25 (C3orf25) :
gcgcctttcgcacgacttggagttacggtttatctgataccgcggtacccctacgcaagcaagccc acatcgacacacattcacacacgcccttcagcaccccctcccagcaccacgaccatg
(Seq ID No: 1279) Homo sapiens testis expressed 19 (TEX19) :
cctcctcctttccctgggtgcccacatgaacagagacaccaggatgctctcctgagaccacagcaa ctgcagaagctgaagacatttccagaagttcaagcttccaccctctgcaggtccccactgagctgg gacccaggtcatccaccccaccccaaatccctggataggaaacccctttctcctcctgctccttgt ccccttcatccctgccgcccagcatcctactggcctcagcacctgtggccagaccgtccaagatcc tctgaaggcccagctcttgctgtccaccccggcagtaggcaggcagcctggccatg
(Seq ID No: 1280)
Homo sapiens protein kinase C, beta (PRKCB) :
gcctccctcccccgcagctggggccagcggtgccaagcgcagctggacgagcggcagcagctgggc gagtgacagccccggctccgcgcgccgcggccgccagagccggcgcaggggaagcgcccgcggccc cgggtgcagcagcggccgccgcctcccgcgcctccccggcccgcagcccgcggtcccgcggccccg gggccggcacctctcgggctccggctccccgcgcgcaagatg (Seq ID No: 1281)
Homo sapiens protein kinase Nl (PKN1) :
ccctccctccgcgcggggacccctggcgggcggcaggaggacatg (Seq ID No: 1282)
Homo sapiens hemochromatosis type 2 (juvenile) (HFE2) :
ccttctctggttccctgacctcagtgagacagcagccggcctggggacctgggggagacacggagg accccctggctggagctgacccacagagtagggaatcatggctggagaattggatagcagagtaat gtttgacctctggaaacatcacttacagggcttccggtcaaaattcactaggtaggagggtcatca gctgggaagaaccggcgcctgggaaacctggctggataggtatg (Seq ID No: 1283)
Homo sapiens ribosomal protein L9 (RPL9) :
cgttctttctttgctgcgtctactgcgagaatg (Seq ID No: 1284)
Homo sapiens ribosomal protein L3 (RPL3) :
cggcctctaccggcgggatttgatggcgtgatg (Seq ID No: 1285)
Homo sapiens ribosomal protein. L4 (RPL4):
acttccttttcctgtggcagcagccgggctgagaggagcgtggctgtctcctctctccgccatg (Seq ID No: 1286)
Homo sapiens ribosomal protein L5 (RPL5) :
tggcccttttcccaccccctagcgccgctgggcctgcaggtctctgtcgagcagcggacgccggtc tctgttccgcaggatg (Seq ID No: 1287)
Homo sapiens ribosomal protein L6 (RPL6) : aattctctttcccatcttgcaa- gatg (Seq ID No: 1288)
Homo sapiens ribosomal protein L7 (RPL7) : cttcctctttttccggctggaac- catg (Seq ID No: 1289)
Homo sapiens ribosomal protein L7a (RPL7A) :
ctttcctttctctctcctcccgccgcccaagatg (Seq ID No: 1290)
Homo sapiens ribosomal protein Lll (RPL11) : ctttctcttcctgctctccat- catg (Seq ID No: 1291)
Homo sapiens ribosomal protein L12 (RPL12) :
cggcctctcggctttcggctcggaggaggccaaggtgcaacttccttcggtcgtcccgaatccggg ttcatccgacaccagccgcctccaccatg (Seq ID No: 1292) Homo sapiens ribosomal protein L13 (RPL13) :
gcttcctttccgctcggctgttttcctgcgcaggagccgcagggccgtaggcagccatg
(Seq ID No: 1293)
Homo sapiens ribosomal protein L23 (RPL23) :
acttccttttttcttttttccggcgttcaagatg (Seq ID No: 1294)
Homo sapiens ribosomal protein L18 (RPL18) :
cgttctctctttccggacctggccgagcaggaggcgccatcatg (Seq ID No: 1295) Homo sapiens ribosomal protein L18a (RPL18A) :
acttccttttgcgggtggcggcgaacgcggagagcacgccatg (Seq ID No: 1296) Homo sapiens ribosomal protein L19 (RPL19) :
agctctttcctttcgctgctgcggccgcagccatg (Seq ID No: 1297)
Homo sapiens ribosomal protein L21 (RPL21) :
gcctctttcctttcggccggaaccgccatcttccagtaattcgccaaaatg
(Seq ID No: 1298)Homo sapiens ribosomal protein L22 (RPL22):
acctccctttctaactccgctgccgccatg (Seq ID No: 1299)
Homo sapiens ribosomal protein L23a (RPL23A) : agacccttttcacaagatg (Seq ID No: 1300)
Homo sapiens ribosomal protein L17 (RPL17) :
cgctcttcctctttccctaagcagcctgagggttgactggattggtgaggcccgtgtggctacttc tgtggaagcagtgctgtagttactggaagataaaagggaaagcaagcccttggtgggggaaagtat ggctgcgatgatggcatttcttaggacacctttggattaataatgaaaacaactactctctgagca gctgttcgaatcatctgatatttatactgaatgagttactgtaagtacgtattgacagaattacac tgtactttcctctaggtgatctgtgaaaatg (Seq ID No: 1301)
Homo sapiens ribosomal protein L24 (RPL24) :
ttctctctttcttttcgccatcttttgtctttccgtggagctgtcgccatg
(Seq ID No: 1302)
Homo sapiens ribosomal protein L26 (RPL26) :
agttctcttcccttttgcggccatcaccgaagcgggagcggccaaaatg
(Seq ID No: 1303)
Homo sapiens ribosomal protein L27 (RPL27) :
ctttcctttttgctggtagggccgggtggttgctgccgaaatg (Seq ID No: 1304)
Homo sapiens ribosomal protein L30 (RPL30) :
aagtctttcctttctcgttccccggccatcttagcggctgctgttggttgggggccgtcccgctcc taaggcaggaagatg (Seq ID No: 1305)
Homo sapiens ribosomal protein L27a (RPL27A) :
ccttcctttttcgtctgggctgccaacatg (Seq ID No: 1306)
Homo sapiens ribosomal protein L28 (RPL28):
cttcctctttccgtctcaggtcgccgctgcgaagggagccgccgccatg
(Seq ID No: 1307) Homo sapiens ribosomal protein L29 (RPL29) :
cagcccctttctcttccggttctaggcgcttcgggagccgcggcttatggtgcagacatg (Seq ID No: 1308)
Homo sapiens ribosomal protein L31 (RPL31) :
cgctcttcctttccaacttggacgctgcagaatg (Seq ID No: 1309)
Homo sapiens ribosomal protein L32 (RPL32) :
ccgtcccttctctcttcctcggcgctgcctacggaggtggcagccatctccttctcggcatcatg (Seq ID No: 1310)
Homo sapiens ribosomal protein L35a (RPL35A) :
cgtccttctcttaccgccatcttggctcctgtggaggcctgctgggaacgggacttctaaaaggaa ctatg (Seq ID No: 1311)
Homo sapiens ribosomal protein L37 (RPL37) :
ccttctcttccggtctttctggtctcggccgcagaagcgagatg (Seq ID No: 1312)
Homo sapiens ribosomal protein L37a (RPL37A) :
gcgtctcttcctttctgggctcggacctaggtcgcggcgacatg (Seq ID No: 1313)
Homo sapiens ribosomal protein L38 (RPL38) :
cgttctttttcgtccttttccccggttgctgcttgctgtgagtgtctctagggtgatacgtgggtg agaaaggtcctggtccgcgccagagcccagcgcgcctcgtcgccatg (Seq ID No: 1314)
Homo sapiens ribosomal protein L39 (RPL39) :
ccctcctcttcctttctccgccatcgtggtgtgttcttgactccgctgctcgccatg
(Seq ID No: 1315)
Homo sapiens ribosomal protein, large, P0 (RPLPO) :
aggcccttctctcgccaggcgtcctcgtggaagtgacatcgtctttaaaccctgcgtggcaatccc tgacgcaccgccgtgatg (Seq ID No: 1316)
Homo sapiens ribosomal protein, large, PI (RPLP1) :
cggtccttccgaggaagctaaggctgcgttggggtgaggccctcacttcatccggcgactagcacc gcgtccggcagcgccagccctacactcgcccgcgccatg (Seq ID No: 1317)
Homo sapiens ribosomal protein, large, P2 (RPLP2) :
ccttccttttcctccctgtcgccaccgaggtcgcacgcgtgagacttctccgccgcctccgccgca gacgccgccgcgatg (Seq ID No: 1318)
Homo sapiens ribosomal protein S3 (RPS3) :
acttcctttcctttcagcggagcgcggcggcaagatg (Seq ID No: 1319)
Homo sapiens ribosomal protein S3A (RPS3A) :
ccgcccttttggctctctgaccagcaccatg (Seq ID No: 1320)
Homo sapiens ribosomal protein S4, X-linked (RPS4X) :
ggtcctctttccttgcctaacgcagccatg (Seq ID No: 1321)
Homo sapiens ribosomal protein S4, Y-linked 1 (RPS4Y1) :
gattctcttccgtcgcagagtttcgccatg (Seq ID No: 1322)
Homo sapiens ribosomal protein S5 (RPS5) :
ttttcttcccagttaaaagtgttggcccgcggcgcgcggcctcttcctgtctgtaccagggcggcg cgtggtctacgccgagtgacagagacgctcaggctgtgttctcaggatg
(Seq ID No: 1323)
Homo sapiens ribosomal protein S6 (RPS6) :
ggccctcttttccgtggcgcctcggaggcgttcagctgcttcaagatg (Seq ID No: 1324) Homo sapiens ribosomal protein S7 (RPS7) :
gggtctcttcctaagccggcgctcggcaagttctcccaggagaaagccatg
(Seq ID No: 1325)
Homo sapiens ribosomal protein S8 (RPS8):
gtttctctttccagccagcgccgagcgatg (Seq ID No: 1326)
Homo sapiens ribosomal protein S9 (RPS9) :
gcgcctctttctcagtgaccgggtggtttgcttaggcgcagacggggaagcggagccaacatg (Seq ID No: 1327)
Homo sapiens ribosomal protein S10 (RPS10) :
gctccttcctttccagccccggtaccggaccctgcagccgcagagatg (Seq ID No: 1328) Homo sapiens ribosomal protein Sll (RPS11) :
ctgcccctttctttttttcaggcggccgggaagatg (Seq ID No: 1329)
Homo sapiens ribosomal protein S12 (RPS12) :
aggcctctttccctgccgccgccgagtcgcgcggaggcggaggcttgggtgcgttcaagattcaac ttcacccgtaacccaccgccatg (Seq ID No: 1330)
Homo sapiens ribosomal protein S13 (RPS13) :
cgctctcctttcgttgcctgatcgccgccatcatg (Seq ID No: 1331)
Homo sapiens ribosomal protein S15 (RPS15) :
cgatctcttctgaggatccggcaagatg (Seq ID No: 1332)
Homo sapiens ribosomal protein S15a (RPS15A) :
cgtcctctttccgccatctttccgcgccggtgagtagcactctctgagagctccaatttcatccgt ctgccatcggcgccatcctgcaatctaagccacaatg (Seq ID No: 1333)
Homo sapiens ribosomal protein S16 (RPS16) :
ctttccttttccggttgcggcgccgcgcggtgaggttgtctagtccacgctcggagccatg (Seq ID No: 1334)
Homo sapiens ribosomal protein S19 (RPS19) :
cgttccctttcccctggctggcagcgcggaggccgcacgatg (Seq ID No: 1335)
Homo sapiens ribosomal protein S20 (RPS20) :
ccacccctttctttttgaggaagacgcggtcgtaagggctgaggatttttggtccgcacgctcctg ctcctgactcaccgctgttcgctctcgccgaggaacaagtcggtcaggaagcccgcgcgcaacagc catg (Seq ID No: 1336)
Homo sapiens ribosomal protein S21 (RPS21) :
gcttcctttctctctcgcgcgcggtgtggtggcagcaggcgcagcccagcctcgaaatg
(Seq ID No: 1337)
Homo sapiens ribosomal protein S23 (RPS23) :
gcttctctctttcgctcaggcccgtggcgccgacaggatg (Seq ID No: 1338) Homo sapiens ribosomal protein S25 (RPS25) :
gcttcctttttgtccgacatcttgacgaggctgcggtgtctgctgctattctccgagcttcgcaat g (Seq ID No: 1339)
Homo sapiens ribosomal protein S26 (RPS26) :
ccgtctcctctctccggtccgtgcctccaagatg (Seq ID No: 1340)
Homo sapiens ribosomal protein S27 (RPS27) :
cgctcctttccggcggtgacgacctacgcacacgagaacatg (Seq ID No: 1341)
Homo sapiens ribosomal protein S28 (RPS28) :
actcctctccgccagaccgccgccgcgccgccatcatg (Seq ID No: 1342)
Homo sapiens ribosomal protein S29 (RPS29) :
gcttcttccttttacctcgttgcactgctgagagcaagatg (Seq ID No: 1343)
Homo sapiens ribosomal protein L15 (RPL15) :
agctctttcctttccgtctggcggcagccatcaggtaagccaagatg (Seq ID No: 1344)
Homo sapiens ribosomal protein S2 (RPS2) :
cgttcttcttttccgacaaaacaccaaatg (Seq ID No: 1345)
Homo sapiens ribosomal protein L14 (RPL14) :
gggtcttcttccttctcgcctaacgccgccaacatg (Seq ID No: 1346)
Homo sapiens ribosomal protein S14 (RPS14) :
ctctctttccggtgtggagtctggagacgacgtgcagaaatg (Seq ID No: 1347) Homo sapiens ribosomal protein L10 (RPL10) :
gcgcctctttcccttcggtgtgccactgaagatcctggtgtcgccatg (Seq ID No: 1348)
Homo sapiens ribosomal protein LlOa (RPL10A) :
tagtctcttttccggttagcgcggcgtgagaagccatg (Seq ID No: 1349)
Homo sapiens ribosomal protein L35 (RPL35) :
tcctctttccctcggagcgggcggcggcgttggcggcttgtgcagcaatg
(Seq ID No: 1350)
Homo sapiens ribosomal protein L13a (RPL13A) :
cctcctccttttccaagcggctgccgaagatg (Seq ID No: 1351)
Homo sapiens ribosomal protein L36 (RPL36) :
cagcccttccgccacggccgtctctggagagcagcagccatg (Seq ID No: 1352)
Homo sapiens ribosomal protein L36a (RPL36A) :
gtttctttctttccgcgccgatagcgctcacgcaagcatg (Seq ID No: 1353)
Homo sapiens ribosomal protein L41 (RPL41) :
tcgcc tttctctcggccttagcgccatttttttggaaacctctgcgccatg
(Seq ID No: 1354)
Homo sapiens ribosomal protein S18 (RPS18) :
cgctctctcttccacaggaggcctacacgccgccgcttgtgctgcagccatg
(Seq ID No: 1355) Homo sapiens ribosomal protein S24 (RPS24) :
ggttctcttttcctccttggctgtctgaagatagatcgccatcatg (Seq ID No: 1356) Homo sapiens ribosomal protein L8 (RPL8):
tttcctctttcggccgcgctggtgaacaggtaggtcatccttgcggccttgcggcatg
(Seq ID No: 1357)
Homo sapiens ribosomal protein L34 (RPL34) :
cttcctcttccggggacgttgtctgcaggtatg (Seq ID No: 1358)
Homo sapiens ribosomal protein S17 (RPS17) :
gtttcctcttttaccaaggacccgccaacatg (Seq ID No: 1359)
Homo sapiens ribosomal protein SA (RPSA) :
ctgtcttttccgtgctacctgcagaggggtccatacggcgttgttctggattcccgtcgtaactta aagggaaattttcacaatg (Seq ID No: 1360)
Homo sapiens eukaryotic translation initiation factor 3, subunit C (EIF3C) :
cttctctctcggcgtttccgctgtcagggccctgcggtgtgactcgcgggctcagctggtccggcc gtagcacctccgcgccgtcgccatg (Seq ID No: 1361)
Homo sapiens poly (A) binding protein, cytoplasmic 1 (PABPC1) :
cgctctcctcctctcacggaaaggtcgcggcctgtggccctgcgggcagccgtgccgagatg (Seq ID No: 1362)
Homo sapiens tubulin, beta 1 class VI (TUBB1) :
cactcccttccaaaagcatgacaggcagaaagcagagaagggccaggactggctgagggcggggag ctgggcctctggggtggacacacccttggtcacattgtgagggtagcttggttggccagtcccacc actgcagtgaccacagttgtgttgggctcacaccagtgaaccgaagctctggattctgagagtctg aggattccgtgaagatctcagacttgggctcagagcaaggatg (Seq ID No: 1363) PpLuc(GC) - A64N64
GGGAGAAAGCTTGAGGATGGAGGACGCCAAGAACATCAAGAAGGGCCCGGCGCCCTTCTA CCCGCTGGAGGACGGGACCGCCGGCGAGCAGCTCCACAAGGCCATGAAGCGGTACGCCCT GGTGCCGGGCACGATCGCCTTCACCGACGCCCACATCGAGGTCGACATCACCTACGCGGA GTACTTCGAGATGAGCGTGCGCCTGGCCGAGGCCATGAAGCGGTACGGCCTGAACACCAA CCACCGGATCGTGGTGTGCTCGGAGAACAGCCTGCAGTTCTTCATGCCGGTGCTGGGCGC CCTCTTCATCGGCGTGGCCGTCGCCCCGGCGAACGACATCTACAACGAGCGGGAGCTGCT GAACAGCATGGGGATCAGCCAGCCGACCGTGGTGTTCGTGAGCAAGAAGGGCCTGCAGAA G TCCTGAACGTGCAGAAGAAGCTGCCCATCATCCAGAAGATCATCATCATGGACAGCAA GACCGACTACCAGGGCTTCCAGTCGATGTACACGTTCGTGACCAGCCACCTCCCGCCGGG CTTCAACGAGTACGACTTCGTCCCGGAGAGCTTCGACCGGGACAAGACCATCGCCCTGAT CATGAACAGCAGCGGCAGCACCGGCCTGCCGAAGGGGGTGGCCCTGCCGCACCGGACCGC CTGCGTGCGCTTCTCGCACGCCCGGGACCCCATCTTCGGCAACCAGATCATCCCGGACAC CGCCATCCTGAGCGTGGTGCCGTTCCACCACGGCTTCGGCATGTTCACGACCCTGGGCTA CCTCATCTGCGGCTTCCGGGTGGTCCTGATGTACCGGTTCGAGGAGGAGCTGTTCCTGCG GAGCCTGCAGGACTACAAGATCCAGAGCGCGCTGCTCGTGCCGACCCTGTTCAGCTTCTT CGCCAAGAGCACCCTGATCGACAAGTACGACCTGTCGAACCTGCACGAGATCGCCAGCGG GGGCGCCCCGCTGAGCAAGGAGGTGGGCGAGGCCGTGGCCAAGCGGTTCCACCTCCCGGG CATCCGCCAGGGCTACGGCCTGACCGAGACCACGAGCGCGATCCTGATCACCCCCGAGGG GGACGACAAGCCGGGCGCCGTGGGCAAGGTGGTCCCGTTCTTCGAGGCCAAGGTGGTGGA CCTGGACACCGGCAAGACCCTGGGCGTGAACCAGCGGGGCGAGCTGTGCGTGCGGGGGCC GATGATCATGAGCGGCTACGTGAACAACCCGGAGGCCACCAACGCCCTCATCGACAAGGA CGGCTGGCTGCACAGCGGCGACATCGCCTACTGGGACGAGGACGAGCACTTCTTCATCGT CGACCGGCTGAAGTCGCTGATCAAGTACAAGGGCTACCAGGTGGCGCCGGCCGAGCTGGA GAGCATCCTGCTCCAGCACCCCAACATCTTCGACGCCGGCGTGGCCGGGCTGCCGGACGA CGACGCCGGCGAGCTGCCGGCCGCGGTGGTGGTGCTGGAGCACGGCAAGACCATGACGGA GAAGGAGATCGTCGACTACGTGGCCAGCCAGGTGACCACCGCCAAGAAGCTGCGGGGCGG CGTGGTGTTCGTGGACGAGGTCCCGAAGGGCCTGACCGGGAAGCTCGACGCCCGGAAGAT CCGCGAGATCCTGATCAAGGCCAAGAAGGGCGGCAAGATCGCCGTGTAAGACTAGTAGAT CTAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAATGCATCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCAAAGGCTCTTTTCAGAGC CACCAGAATT (SEQ ID No: 1364)
PpLuc(GC) - albumin7 - A64N64
GGGAGAAAGCTTGAGGATGGAGGACGCCAAGAACATCAAGAAGGGCCCGGCGCCCTTCTA CCCGCTGGAGGACGGGACCGCCGGCGAGCAGCTCCACAAGGCCATGAAGCGGTACGCCCT GGTGCCGGGCACGATCGCCTTCACCGACGCCCACATCGAGGTCGACATCACCTACGCGGA GTACTTCGAGATGAGCGTGCGCCTGGCCGAGGCCATGAAGCGGTACGGCCTGAACACCAA CCACCGGATCGTGGTGTGCTCGGAGAACAGCCTGCAGTTCTTCATGCCGGTGCTGGGCGC CGTCTTCATCGGCGTGGCCGTCGCCCCGGCGAACGACATCTACAACGAGCGGGAGCTGCT GAACAGCATGGGGATCAGCCAGCCGACCGTGGTGTTCGTGAGCAAGAAGGGCCTGCAGAA GATCCTGAACGTGCAGAAGAAGCTGCCCATCATCCAGAAGATCATCATCATGGACAGCAA GACCGACTACCAGGGCTTCCAGTCGATGTACACGTTCGTGACCAGCCACCTCCCGCCGGG CTTCAACGAGTACGACTTCGTCCCGGAGAGCTTCGACCGGGACAAGACCATCGCCCTGAT CATGAACAGCAGCGGCAGCACCGGCCTGCCGAAGGGGGTGGCCCTGCCGCACCGGACCGC CTGCGTGCGCTTCTCGCACGCCCGGGACCCCATCTTCGGCAACCAGATCATCCCGGACAC CGCCATCCTGAGCGTGGTGCCGTTCCACCACGGCTTCGGCATGTTCACGACCCTGGGCTA CCTCATCTGCGGCTTCCGGGTGGTCCTGATGTACCGGTTCGAGGAGGAGCTGTTCCTGCG GAGCCTGCAGGACTACAAGATCCAGAGCGCGCTGCTCGTGCCGACCCTGTTCAGCTTCTT CGCCAAGAGCACCCTGATCGACAAGTACGACCTGTCGAACCTGCACGAGATCGCCAGCGG GGGCGCCCCGCTGAGCAAGGAGGTGGGGGAGGCCGTGGCCAAGCGGTTCCACCTCCCGGG CATCCGCCAGGGCTACGGCCTGACCGAGACCACGAGCGCGATCCTGATCACCCCCGAGGG GGACGACAAGCCGGGCGCCGTGGGCAAGGTGGTCCCGTTCTTCGAGGCCAAGGTGGTGGA CCTGGACACCGGCAAGACCCTGGGCGTGAACCAGCGGGGCGAGCTGTGCGTGCGGGGGCC GATGATCATGAGCGGCTACGTGAACAACCCGGAGGCCACCAACGCCCTCATCGACAAGGA CGGCTGGCTGCACAGCGGCGACATCGCCTACTGGGACGAGGACGAGCACTTCTTCATCGT CGACCGGCTGAAGTCGCTGATCAAGTACAAGGGCTACCAGGTGGCGCCGGCCGAGCTGGA GAGCATCCTGCTCCAGCACCCCAACATCTTCGACGCCGGCGTGGCCGGGCTGCCGGACGA CGACGCCGGCGAGCTGCCGGCCGCGGTGGTGGTGCTGGAGCACGGCAAGACCATGACGGA GAAGGAGATCGTCGACTACGTGGCCAGCCAGGTGACCACCGCCAAGAAGCTGCGGGGCGG CGTGGTGTTCGTGGACGAGGTCCCGAAGGGCCTGACCGGGAAGCTCGACGCCCGGAAGAT CCGCGAGATCCTGATCAAGGCCAAGAAGGGCGGCAAGATCGCCGTGTAAGACTAGTGCAT CACATTTAAAAGCATCTCAGCCTACCATGAGAATAAGAGAAAGAAAATGAAGATCAATAG CTTATTCATCTCTTTTTCTTTTTCGTTGGTGTAAAGCCAACACCCTGTCTAAAAAACATA AATTTCTTTAATCATTTTGCCTCTTTTCTCTGTGCTTCAATTAATAAAAAATGGAAAGAA CCTAGATCTΑΑΆΑΑΆΑΑΑΑΑΑΑΑΆΑΑΑΑΑΑΑΑΑΑΑΆΑΑΑΑΑΑΑΑΆΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑ AAAAAAAAAAAAATGCATCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCAAAGGCTCTTT TCAGAGCCACCAGAATT (SEQ ID No: 1365) RPL32RPL32 - PpLuc(GC) - A64N64
GGGGCGCTGCCTACGGAGGTGGCAGCCATCTCCTTCTCGGCATCAAGCTTGAGGATGGAG GACGCCAAGAACATCAAGAAGGGCCCGGCGCCCTTCTACCCGCTGGAGGACGGGACCGCC GGCGAGCAGCTCCACAAGGCCATGAAGCGGTACGCCCTGGTGCCGGGCACGATCGCCTTC ACCGACGCCCACATCGAGGTCGACATCACCTACGCGGAGTACTTCGAGATGAGCGTGCGC CTGGCCGAGGCCATGAAGCGGTACGGCCTGAACACCAACCACCGGATCGTGGTGTGCTCG GAGAACAGCCTGCAGTTCTTCATGCCGGTGCTGGGCGCCCTCTTCATCGGCGTGGCCGTC GCCCCGGCGAACGACATCTACAACGAGCGGGAGCTGCTGAACAGCATGGGGATCAGCCAG CCGACCGTGGTGTTCGTGAGCAAGAAGGGCCTGCAGAAGATCCTGAACGTGCAGAAGAAG CTGCCCATCATCCAGAAGATCATCATCATGGACAGCAAGACCGACTACCAGGGCTTCCAG TCGATGTACACGTTCGTGACCAGCCACCTCCCGCCGGGCTTCAACGAGTACGACTTCGTC CCGGAGAGCTTCGACCGGGACAAGACCATCGCCCTGATCATGAACAGCAGCGGCAGCACC GGCCTGCCGAAGGGGGTGGCCCTGCCGCACCGGACCGCCTGCGTGCGCTTCTCGCACGCC CGGGACCCCATCTTCGGCAACCAGATCATCCCGGACACCGCCATCCTGAGCGTGGTGCCG TTCCACCACGGCTTCGGCATGTTCACGACCCTGGGCTACCTCATCTGCGGCTTCCGGGTG GTCCTGATGTACCGGTTCGAGGAGGAGCTGTTCCTGCGGAGCCTGCAGGACTACAAGATC CAGAGCGCGCTGCTCGTGCCGACCCTGTTCAGCTTCTTCGCCAAGAGCACCCTGATCGAC AAGTACGACCTGTCGAACCTGCACGAGATCGCCAGCGGGGGCGCCCCGCTGAGCAAGGAG GTGGGCGAGGCCGTGGCCAAGCGGTTCCACCTCCCGGGCATCCGCCAGGGCTACGGCCTG ACCGAGACCACGAGCGCGATCCTGATCACCCCCGAGGGGGACGACAAGCCGGGCGCCGTG GGCAAGGTGGTCCCGTTCTTCGAGGCCAAGGTGGTGGACCTGGACACCGGCAAGACCCTG GGCGTGAACCAGCGGGGCGAGCTGTGCGTGCGGGGGCCGATGATCATGAGCGGCTACGTG AACAACCCGGAGGCCACCAACGCCCTCATCGACAAGGACGGCTGGCTGCACAGCGGCGAC ATCGCCTACTGGGACGAGGACGAGCACTTCTTCATCGTCGACCGGCTGAAGTCGCTGATC AAGTACAAGGGCTACCAGGTGGCGCCGGCCGAGCTGGAGAGCATCCTGCTCCAGCACCCC AACATCTTCGAGGCCGGCGTGGCCGGGCTGCCGGACGACGACGCCGGCGAGCTGCCGGCC GCGGTGGTGGTGCTGGAGCACGGCAAGACCATGACGGAGAAGGAGATCGTCGACTACGTG GGCAGCGAGGTGACCACCGCCAAGAAGCTGCGGGGCGGCGTGGTGTTCGTGGACGAGGTC CCGAAGGGCCTGACCGGGAAGCTCGACGCCCGGAAGATCCGCGAGATCCTGATCAAGGCC AAGAAGGGCGGCAAGATCGCCGTGTAAGACTAGTAGATCTAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAATGCATCCCCCCCCCCC CCCCCCCCCCCCCCCCCCCCAAAGGCTCTTTTCAGAGCCACCAGAATT (SEQ ID No: 1366)
RPL32 - PpLuc(GC) - albumin7 - A64N64
GGGGCGCTGCCTACGGAGGTGGCAGCCATCTCCTTCTCGGCATCAAGCTTGAGGATGGAG GACGCCAAGAACATCAAGAAGGGCCCGGCGCCCTTCTACCCGCTGGAGGACGGGACCGCC GGCGAGCAGCTCCACAAGGCCATGAAGCGGTACGCCCTGGTGCCGGGCACGATCGCCTTC ACCGACGCCCACATCGAGGTCGACATCACCTACGCGGAGTACTTCGAGATGAGCGTGCGC CTGGCCGAGGCCATGAAGCGGTACGGCCTGAACACCAACCACCGGATCGTGGTGTGCTCG GAGAACAGCCTGCAGTTCTTCATGCCGGTGCTGGGCGCCCTCTTCATCGGCGTGGCCGTC GCCCCGGCGAACGACATCTACAACGAGCGGGAGCTGCTGAACAGCATGGGGATCAGCCAG CCGACCGTGGTGTTCGTGAGCAAGAAGGGCCTGCAGAAGATCCTGAACGTGCAGAAGAAG CTGCCCATCATCCAGAAGATCATCATCATGGACAGCAAGACCGACTACCAGGGCTTCCAG TCGATGTACACGTTCGTGACCAGCCACCTCCCGCCGGGCTTCAACGAGTACGACTTCGTC CCGGAGAGCTTCGACCGGGACAAGACCATCGCCCTGATCATGAACAGCAGCGGCAGCACC GGCCTGCCGAAGGGGGTGGCCCTGCCGCACCGGACCGCCTGCGTGCGCTTCTCGCACGCC CGGGACCCCATCTTCGGCAACCAGATCATCCCGGACACCGCCATCCTGAGCGTGGTGCCG TTCCACCACGGCTTCGGCATGTTCACGACCCTGGGCTACCTCATCTGCGGCTTCCGGGTG GTCCTGATGTACCGGTTCGAGGAGGAGCTGTTCCTGCGGAGCCTGCAGGACTACAAGATC CAGAGCGCGCTGCTCGTGCCGACCCTGTTCAGCTTCTTCGCCAAGAGCACCCTGATCGAC AAGTACGACCTGTCGAACCTGCACGAGATCGCCAGCGGGGGCGCCCCGCTGAGCAAGGAG GTGGGCGAGGCCGTGGCCAAGCGGTTCCACCTCCCGGGCATCCGCCAGGGCTACGGCCTG ACCGAGACCACGAGCGCGATCCTGATCACCCCCGAGGGGGACGACAAGCCGGGCGCCGTG GGCAAGGTGGTCCCGTTCTTCGAGGCCAAGGTGGTGGACCTGGACACCGGCAAGACCCTG GGCGTGAACCAGCGGGGCGAGCTGTGCGTGCGGGGGCCGATGATCATGAGCGGCTACGTG AACAACCCGGAGGCCACCAACGCCCTCATCGACAAGGACGGCTGGCTGCACAGCGGCGAC ATGGCCTACTGGGACGAGGACGAGCACTTCTTCATCGTCGACCGGCTGAAGTCGCTGATC AAGTACAAGGGCTACCAGGTGGCGCCGGCCGAGCTGGAGAGCATCCTGCTCCAGCACCCC AACATCTTCGACGCCGGCGTGGCCGGGCTGCCGGACGACGACGCCGGCGAGCTGCCGGCC GCGGTGGTGGTGCTGGAGCACGGCAAGACCATGACGGAGAAGGAGATCGTCGACTACGTG GCCAGCCAGGTGACCACCGCCAAGAAGCTGCGGGGCGGCGTGGTGTTCGTGGACGAGGTC CCGAAGGGCCTGACCGGGAAGCTCGACGCCCGGAAGATCCGCGAGATCCTGATCAAGGCC AAGAAGGGCGGCAAGATCGCCGTGTAAGACTAGTGCATCACATTTAAAAGCATCTCAGCC TACCATGAGAATAAGAGAAAGAAAATGAAGATCAATAGCTTATTCATCTCTTTTTCTTTT TCGTTGGTGTAAAGCCAACACCCTGTCTAAAAAACATAAATTTCTTTAATCATTTTGCCT CTTTTCTCTGTGCTTCAATTAATAAAAAATGGAAAGAACCTAGATCTAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAATGCATCCCC CCCCCCCCCCCCCCCCCCCCCCCCCCCAAAGGCTCTTTTCAGAGCCACCAGAATT (SEQ ID No: 1367)
5'UTR of human ribosomal protein Large 32 (RPL32) lacking the 5' terminal oligopyrimidine tract
GGCGCTGCCTACGGAGGTGGCAGCCATCTCCTTCTCGGCATC (SEQ ID No. 1368) Human albumin 3'UTR
CATCACATTT AAAAGCATCT CAGCCTACCA TGAGAATAAG AGAAAGAAAA TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT TGCCTCTTTT CTCTGTGCTT CAATTAATAA AAAATGGAAA GAATCT (SEQ ID No: 1369)
3'UTR of Homo sapiens hemoglobin, alpha 1 (HBAl)
gctggagcctcggtggccatgcttcttgccccttgggcctccccccagcccctcctccccttcctg cacccgtacccccgtggtctttgaataaagtctgagtgggcggc (SEQ ID No: 1370) 3'UTR of Homo sapiens hemoglobin, alpha 2 (HBA2)
gctggagcctcggtagccgttcctcctgcccgctgggcctcccaacgggccctcctcccctccttg caccggcccttcctggtctttgaataaagtctgagtgggcag (SEQ ID No: 1371)
3'UTR of Homo sapiens hemoglobin, beta (HBB)
Gctcgctttcttgctgtccaatttctattaaaggttcctttgttccctaagtccaactactaaact gggggatattatgaagggccttgagcatctggattctgcctaataaaaaacatttattttcattgc (SEQ ID No: 1372)
3'UTR of Homo sapiens tyrosine hydroxylase (TH)
gtgcacggcgtccctgagggcccttcccaacctcccctggtcctgcactgtcccggagctcaggcc ctggtgaggggctgggtcccgggtgccccccatgccctccctgctgccaggctcccactgcccctg cacctgcttctcagcgcaacagctgtgtgtgcccgtggtgaggttgtgctgcctgtggtgaggtcc tgtcctggctcccagggtcctgggggctgctgcactgccctccgcccttccctgacactgtctgct gccccaatcaccgtcacaataaaagaaactgtggtctcta (SEQ ID No: 1373)
3'UTR of Homo sapiens arachidonate 15-lipoxygenase (ALOX15) gcgtcgccaccctttggttatttcagcccccatcacccaagccacaagctgaccccttcgtggtta tagccctgccctcccaagtcccaccctcttcccatgtcccaccctccctagaggggcaccttttca tggtctctgcacccagtgaacacattttactctagaggcatcacctgggaccttactcctctttcc ttccttcctcctttcctatcttccttcctctctctcttcctctttcttcattcagatctatatggc aaatagccacaattatataaatcatttcaagactagaatagggggatataatacatattactccac accttttatgaatcaaatatgatttttttgttgttgttaagacagagtctcactttgacacccagg ctggagtgcagtggtgccatcaccacggctcactgcagcctcagcgtcctgggctcaaatgatcct cccacctcagcctcctgagtagctgggactacaggctcatgccatcatgcccagctaatatttttt tattttcgtggagacggggcctcactatgttgcctaggctggaaataggattttgaacccaaattg agtttaacaataataaaaagttgttttacgctaaagatggaaaagaactaggactgaactatttta aataaaatattggc (SEQ ID No: 1374)
3'UTR of Homo sapiens collagen, type I, alpha 1 (COL1A1)
actccctccatcccaacctggctccctcccacccaaccaactttccccccaacccggaaacagaca agcaacccaaactgaaccccctcaaaagccaaaaaatgggagacaatttcacatggactttggaaa atatttttttcctttgcattcatctctcaaacttagtttttatctttgaccaaccgaacatgacca aaaaccaaaagtgcattcaaccttaccaaaaaaaaaaaaaaaaaaagaataaataaataacttttt aaaaaaggaagcttggtccacttgcttgaagacccatgcgggggtaagtccctttctgcccgttgg gcttatgaaaccccaatgctgccctttctgctcctttctccacaccccccttggggcctcccctcc actccttcccaaatctgtctccccagaagacacaggaaacaatgtattgtctgcccagcaatcaaa ggcaatgctcaaacacccaagtggcccccaccctcagcccgctcctgcccgcccagcacccccagg ccctgggggacctggggttctcagactgGcaaagaagccttgccatctggcgctcccatggctctt gcaacatctccccttcgtttttgagggggtcatgccgggggagccaccagcccctcactgggttcg gaggagagtcaggaagggccacgacaaagcagaaacatcggatttggggaacgcgtgtcaatccct tgtgccgcagggctgggcgggagagactgttctgttccttgtgtaactgtgttgctgaaagactac ctcgttcttgtcttgatgtgtcaccggggcaactgcctgggggcggggatgggggcagggtggaag cggctccccattttataccaaaggtgctacatctatgtgatgggtggggtggggagggaatcactg gtgctatagaaattgagatgcccccccaggccagcaaatgttcctttttgttcaaagtctattttt attccttgatatttttctttttttttttttttttttgtggatggggacttgtgaatttttctaaag gtgctatttaacatgggaggagagcgtgtgcggctccagcccagcccgctgctcactttccaccct ctctccacctgcctctggcttctcaggcctctgctctccgacctctctcctctgaaaccctcctcc acagctgcagcccatcctcccggctccctcctagtctgtcctgcgtcctctgtccccgggtttcag agacaacttcccaaagcacaaagcagtttttccccctaggggtgggaggaagcaaaagactctgta cctattttgtatgtgtataataatttgagatgtttttaattattttgattgctggaataaagcatg tggaaatgacccaaacataa (SEQ ID No: 1375) albumin7 3'UTR
CATCACATTTAAAAGCATCTCAGCCTACCATGAGAATAAGAGAAAGAAAATGAAGATCAATAGCTT ATTCATCTCTTTTTCTTTTTCGTTGGTGTAAAGCCAACACCCTGTCTAAAAAACATAAATTTCTTT AATCATTTTGCCTCTTTTCTCTGTGCTTCAATTAATAAAAAATGGAAAGAACCT (SEQ ID No: 1376) Human albumin 3'UTR + poly (A) sequence
CATCACATTT AAAAGCATCT CAGCCTACCA TGAGAATAAG AGAAAGAAAA TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT TGCCTCTTTT CTCTGTGCTT CAATTAATAA AAAATGGAAA GAATCTAGAT CTAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAAAAAA AAAAAA (SEQ ID No: 1377) Human albumin 3'UTR fragment 1
AAAAGCATCT CAGCCTACCA TGAGAATAAG AGAAAGAAAA TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT TGCCTCTTTT CTCTGTGCTT CAATT (SEQ ID NO: 1378)
Human albumin 3'UTR fragment 2
CATCACATTT AAAAGCATCT CAGCCTACCA TGAGAATAAG AGAAAGAAAA TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG (SEQ ID No: 1379)
Human albumin 3'UTR fragment 3
AAAAGCATCT CAGCCTACCA TGAGAATAAG AGAAAGAAAA TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC (SEQ ID No: 1380)
Human albumin 3'UTR fragment 4
CAGCCTACCA TGAGAATAAG AGAAAGAAAA TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT (SEQ ID No: 1381)
Human albumin 3'UTR fragment 5
TGAGAATAAG AGAAAGAAAA TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT (SEQ ID No: 1382)
Human albumin 3'UTR fragment 6
AGAAAGAAAA TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT TGCCTCTTTT (SEQ ID No: 1383)
Human albumin 3'UTR fragment 7
TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT TGCCTCTTTT CTCTGTGCTT (SEQ ID No: 1384)
Human albumin 3'UTR fragment 8
AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT TGCCTCTTTT CTCTGTGCTT CAATTAATAA (SEQ ID No: 1385)
Human albumin 3'UTR fragment 9
ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT TGCCTCTTTT CTCTGTGCTT CAATTAATAA AAAATGGAAA (SEQ ID No: 1386) Human albumin 3'UTR fragment 10
CAGCCTACCA TGAGAATAAG AGAAAGAAAA TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT TGCCTCTTTT CTCTGTGCTT CAATTAATAA A (SEQ ID No: 1387)
Human albumin 3'UTR fragment 11
TGAAGATCAA AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT TGCCTCTTTT CTCTGTGCTT CAATTAATAA
A (SEQ ID No: 1388)
Human albumin 3'UTR fragment 12
CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC ATAAATTTCT TTAATCATTT TGCCTCTTTT CTCTGTGCTT CAATTAATAA A (SEQ ID No: 1389) Human albumin 3'UTR fragment 13
AAGCTTATTC ATCTGTTTTT CTTTTTCGTT GGTGTAAAGC CAACACCCTG TCTAAAAAAC
(SEQ ID No: 1390)
Albumin7 3'UTR - poly (A) sequence - poly(C) sequence - HL
CATCACATTTAAAAGCATCTCAGCCTACCATGAGAATAAGAGAAAGAAAATGAAGATCAATAGCTT ATTCATCTCTTTTTCTTTTTCGTTGGTGTAAAGCCAACACCCTGTCTAAAAAACATAAATTTCTTT AATCATTTTGCCTCTTTTCTCTGTGCTTCAATTAATAAAAAATGGAAAGAACCTAGATCTAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAATGCATCCC CCCCCCCCCCCCCCCCCCCCCCCCCCCCAAAGGCTCTTTTCAGAGCCACCAGAATT (SEQ ID No: 1391)
Albumin7 3'UTR - poly (A) sequence - poly(C) sequence
CATCACATTTAAAAGCATCTCAGCCTACCATGAGAA AAGAGAAAGAAAATGAAGATCAATAGCTT ATTCATCTCTTTTTCTTTTTCGTTGGTGTAAAGCCAACACCCTGTCTAAAAAACATAAATTTCTTT AATCATTTTGCCTCTTTTCTCTGTGCTTCAATTAATAAAAAATGGAAAGAACCTAGATCTAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAATGCATCCC CCCCCCCCCCCCCCCCCCCCCCCCCCCC (SEQ ID No: 1392) Center, cc-complex-binding portion of the 3'UTR of an a-globin gene GCCCGATGGGCCTCCCAACGGGCCCTCCTCCCCTCCTTGCACCG (SEQ ID NO: 1393)
Histone stem-loop
CAAAGGCTCTTTTCAGAGCCACCA (SEQ ID NO: 1394)
ATP synthase lipid-binding protein, mitochondrial (atp5g2) tagttt ctcctctcga acgccaggtg gagcaaccgg ccggataccg ccacagccct ggcaggcggc gctgtgatg (SEQ ID NO: 1395) RPL35 - PpLuc(GC) - albumin7 - A64N64
GGGGAGCGGGCGGCGGCGTTGGCGGCTTGTGCAGCAAAGCTTGAGGATGGAGGACGCCAA GAACATCAAGAAGGGCCCGGCGCCCTTCTACCCGCTGGAGGACGGGACCGCCGGCGAGCA GCTCCACAAGGCCATGAAGCGGTACGCCCTGGTGCCGGGCACGATCGCCTTCACCGACGC CCACATCGAGGTCGACATCACCTACGCGGAGTACTTCGAGATGAGCGTGCGCCTGGCCGA GGCCATGAAGCGGTACGGCCTGAACACCAACCACCGGATCGTGGTGTGCTCGGAGAACAG CCTGCAGTTCTTCATGCCGGTGCTGGGCGCCCTCTTCATCGGCGTGGCCGTCGCCCCGGC GAACGACATCTACAACGAGCGGGAGCTGCTGAACAGCATGGGGATCAGCCAGCCGACCGT GGTGTTCGTGAGCAAGAAGGGCCTGCAGAAGATCCTGAACGTGCAGAAGAAGCTGCCCAT CATCCAGAAGATCATCATCATGGACAGCAAGACCGACTACCAGGGCTTCCAGTCGATGTA CACGTTCGTGACCAGCCACCTCCCGCCGGGCTTCAACGAGTACGACTTCGTCCCGGAGAG CTTCGACCGGGACAAGACCATCGCCCTGATCATGAACAGCAGCGGCAGCACCGGCCTGCC GAAGGGGGTGGCCCTGCCGCACCGGACCGCCTGCGTGCGCTTCTCGCACGCCCGGGACCC CATCTTCGGCAACCAGATCATCCCGGACACCGCCATCCTGAGCGTGGTGCCGTTCCACCA CGGCTTCGGCATGTTCACGACCCTGGGCTACCTCATCTGCGGCTTCCGGGTGGTCCTGAT GTACCGGTTCGAGGAGGAGCTGTTCCTGCGGAGCCTGCAGGACTACAAGATCCAGAGCGC GCTGCTCGTGCCGACCCTGTTCAGCTTCTTCGCCAAGAGCACCCTGATCGACAAGTACGA CCTGTCGAACCTGCACGAGATCGCCAGCGGGGGCGCCCCGCTGAGCAAGGAGGTGGGCGA GGCCGTGGCCAAGCGGTTCCACCTCCCGGGCATCCGCCAGGGCTACGGCCTGACCGAGAC CACGAGCGCGATCCTGATCACCCCCGAGGGGGACGACAAGCCGGGCGCCGTGGGCAAGGT GGTCCCGTTCTTCGAGGCCAAGGTGGTGGACCTGGACACCGGCAAGACCCTGGGCGTGAA CCAGCGGGGCGAGCTGTGCGTGCGGGGGCCGATGATCATGAGCGGCTACGTGAACAACCC GGAGGCCACCAACGCCCTCATCGACAAGGACGGCTGGCTGCACAGCGGCGACATCGCCTA CTGGGAGGAGGACGAGCACTTCTTCATCGTCGACCGGCTGAAGTCGCTGATCAAGTACAA GGGCTACCAGGTGGCGCCGGCCGAGCTGGAGAGCATCCTGCTCCAGCACCCCAACATCTT CGACGCCGGCGTGGCCGGGCTGCCGGACGACGACGCCGGCGAGCTGCCGGCCGCGGTGGT GGTGCTGGAGCACGGCAAGACCATGACGGAGAAGGAGATCGTCGACTACGTGGCCAGCCA GGTGACCACCGCCAAGAAGCTGCGGGGCGGCGTGGTGTTCGTGGACGAGGTCCCGAAGGG CCTGACCGGGAAGCTCGACGCCCGGAAGATCCGCGAGATCCTGATCAAGGCCAAGAAGGG CGGCAAGATCGCCGTGTAAGACTAGTGCATCACATTTAAAAGCATCTCAGCCTACCATGA GAATAAGAGAAAGAAAATGAAGATCAATAGCTTATTCATCTCTTTTTCTTTTTCGTTGGT GTAAAGCCAACACCCTGTCTAAAAAACATAAATTTCTTTAATCATTTTGCCTCTTTTCTC TGTGCTTCAAT AA AAAAAATGGAAAGAACC AGATC ΑΑΑΑΑΑΑΑΑΑΑΑΑΑΆΑΑΆΑΑΑ AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAATGCATCCCCCCCCCCCC CCCCCCCCCCCCCCCCCCCAAAGGCTCTTTTCAGAGCCACCAGAATT (SEQ ID NO: 1396)
RPL21 - PpLuc(GC) - albumin7 - A64N64
GGGGCCGGAACCGCCATCTTCCAGTAATTCGCCAAAAAGCTTGAGGATGGAGGACGCCAA GAACATCAAGAAGGGCCCGGCGCCCTTCTACCCGCTGGAGGACGGGACCGCCGGCGAGCA GCTCCACAAGGCCATGAAGCGGTACGCCCTGGTGCCGGGCACGATCGCCTTCACCGACGC CCACATCGAGGTCGACATCACCTACGCGGAGTACTTCGAGATGAGCGTGCGCCTGGCCGA GGCCATGAAGCGGTACGGCCTGAACACCAACCACCGGATCGTGGTGTGCTCGGAGAACAG CCTGCAGTTCTTCATGCCGGTGCTGGGCGCCCTCTTCATCGGCGTGGCCGTCGCCCCGGC GAACGACATCTACAACGAGCGGGAGCTGCTGAACAGCATGGGGATCAGCCAGCCGACCGT GGTGTTCGTGAGCAAGAAGGGCCTGCAGAAGATCCTGAACGTGCAGAAGAAGCTGCCCAT CATCCAGAAGATCATCATCATGGACAGCAAGACCGACTACCAGGGCTTCCAGTCGATGTA CACGTTCGTGACCAGCCACCTCCCGCCGGGCTTCAACGAGTACGACTTCGTCCCGGAGAG CTTCGACCGGGACAAGACCATCGCCCTGATCATGAACAGCAGCGGCAGCACCGGCCTGCC GAAGGGGGTGGCCCTGCCGCACCGGACCGCCTGCGTGCGCTTCTCGCACGCCCGGGACCC CATCTTCGGCAACCAGATCATCCCGGACACCGCCATCCTGAGCGTGGTGCCGTTCCACCA CGGCTTCGGCATGTTCACGACCCTGGGCTACCTCATCTGCGGCTTCCGGGTGGTCCTGAT GTACCGGTTCGAGGAGGAGCTGTTCCTGCGGAGCCTGCAGGACTACAAGATCCAGAGCGC GCTGCTCGTGCCGACCCTGTTCAGCTTCTTCGCCAAGAGCACCCTGATCGACAAGTACGA CCTGTCGAACCTGCACGAGATCGCCAGCGGGGGCGCCCCGCTGAGCAAGGAGGTGGGCGA GGCCGTGGCCAAGCGGTTCCACCTCCCGGGCATCCGCCAGGGCTACGGCCTGACCGAGAC CACGAGCGCGATCCTGATCACCCCCGAGGGGGACGACAAGCCGGGCGCCGTGGGCAAGGT GGTCCCGTTCTTCGAGGCCAAGGTGGTGGACCTGGACACCGGCAAGACCCTGGGCGTGAA CCAGCGGGGCGAGCTGTGCGTGCGGGGGCCGATGATCATGAGCGGCTACGTGAACAACCC GGAGGCCACCAACGCCCTCATCGACAAGGACGGCTGGCTGCACAGCGGCGACATCGCCTA CTGGGACGAGGACGAGCACTTCTTCATCGTCGACCGGCTGAAGTCGCTGATCAAGTACAA GGGCTACCAGGTGGCGCCGGCCGAGCTGGAGAGCATCCTGCTCCAGCACCCCAACATCTT CGACGCCGGCGTGGCCGGGCTGCCGGACGACGACGCCGGCGAGCTGCCGGCCGCGGTGGT GGTGCTGGAGCACGGCAAGACCATGACGGAGAAGGAGATCGTCGACTACGTGGCCAGCCA GGTGACCACCGCCAAGAAGCTGCGGGGCGGCGTGGTGTTCGTGGACGAGGTCCCGAAGGG CCTGACCGGGAAGCTCGACGCCCGGAAGATCCGCGAGATCCTGATCAAGGCCAAGAAGGG CGGCAAGATCGCCGTGTAAGACTAGTGCATCACATTTAAAAGCATCTCAGCCTACCATGA GAATAAGAGAAAGAAAATGAAGATCAATAGCTTATTCATCTCTTTTTCTTTTTCGTTGGT GTAAAGCCAACACCCTGTCTAAAAAACATAAATTTCTTTAATCATTTTGCCTCTTTTCTC TGTGCTTCAAT AATAAAAAATGGAAAGAACCTAGATCTAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAATGCATCCCCCCCCCCCC CCCCCCCCCCCCCCCCCCCAAAGGCTCTTTTCAGAGCCACCAGAATT (SEQ ID NO: 1397)
ATP5A1 - PpLuc(GC) - albumin7 - A64N64
GGGCGGCTCGGCCATTTTGTCCCAGTCAGTCCGGAGGCTGCGGCTGCAGAAGTACCGCCT GCGGAGTAACTGCAAAG AGCTTGAGGATGGAGGACGCCAAGAACATCAAGAAGGGCCCG GCGCCCTTCTACCCGCTGGAGGACGGGACCGCCGGCGAGCAGCTCCACAAGGCCATGAAG CGGTACGCCCTGGTGCCGGGCACGATCGCCTTCACCGACGCCCACATCGAGGTCGACATC ACCTACGCGGAGTACTTCGAGATGAGCGTGCGCCTGGCCGAGGCCATGAAGCGGTACGGC CTGAACACCAACCACCGGATCGTGGTGTGCTCGGAGAACAGCCTGCAGTTCTTCATGCCG GTGCTGGGCGCCCTCTTCATCGGCGTGGCCGTCGCCCCGGCGAACGACATCTACAACGAG CGGGAGCTGCTGAACAGCATGGGGATCAGCCAGCCGACCGTGGTGTTCGTGAGCAAGAAG GGCCTGCAGAAGATCCTGAACGTGCAGAAGAAGCTGCCCATCATCCAGAAGATCATCATC ATGGACAGCAAGACCGACTACCAGGGCTTCCAGTCGATGTACACGTTCGTGACCAGCCAC CTCCCGCCGGGCTTCAACGAGTACGACTTCGTCCCGGAGAGCTTCGACCGGGACAAGACC ATCGCCCTGATCATGAACAGCAGCGGCAGCACCGGCCTGCCGAAGGGGGTGGCCCTGCCG CACCGGACCGCCTGCGTGCGCTTCTCGCACGCCCGGGACCCCATCTTCGGCAACCAGATC ATCCCGGACACCGCCATCCTGAGCGTGGTGCCGTTCCACCACGGCTTCGGCATGTTCACG ACCCTGGGCTACCTCATCTGCGGCTTCCGGGTGGTCCTGATGTACCGGTTCGAGGAGGAG CTGTTCCTGCGGAGCCTGCAGGACTACAAGATCCAGAGCGCGCTGCTCGTGCCGACCCTG TTCAGCTTCTTCGCCAAGAGCACCCTGATCGACAAGTACGACCTGTCGAACCTGCACGAG ATCGCCAGCGGGGGCGCCCCGCTGAGCAAGGAGGTGGGCGAGGCCGTGGCCAAGCGGTTC CACCTCCCGGGCATCCGCCAGGGCTACGGCCTGACCGAGACCACGAGCGCGATCCTGATC ACCCCCGAGGGGGACGACAAGCCGGGCGCCGTGGGCAAGGTGGTCCCGTTCTTCGAGGCC AAGGTGGTGGACCTGGACACCGGCAAGACCCTGGGCGTGAACCAGCGGGGCGAGCTGTGC GTGCGGGGGCCGATGATCATGAGCGGCTACGTGAACAACCCGGAGGCCACCAACGCCCTC ATCGACAAGGACGGCTGGCTGCACAGCGGCGACATCGCCTACTGGGACGAGGACGAGCAC TTCTTCATCGTCGACCGGCTGAAGTCGCTGATCAAGTACAAGGGCTACCAGGTGGCGCCG GCCGAGCTGGAGAGCATCCTGCTCCAGCACCCCAACATCTTCGACGCCGGCGTGGCCGGG CTGCCGGACGACGACGCCGGCGAGCTGCCGGCCGCGGTGGTGGTGCTGGAGCACGGCAAG ACCATGACGGAGAAGGAGATCGTCGACTACGTGGCCAGCCAGGTGACCACCGCCAAGAAG CTGCGGGGCGGCGTGGTGTTCGTGGACGAGGTCCCGAAGGGCCTGACCGGGAAGCTCGAC GCCCGGAAGATCCGCGAGATCCTGATCAAGGCCAAGAAGGGCGGCAAGATCGCCGTGTAA GACTAGTGCATCACATT AAAAGCATCTCAGCCTACCATGAGAATAAGAGAAAGAAAATG AAGATCAATAGCTTATTCATCTCTTTTTCTTTTTCGTTGGTGTAAAGCCAACACCCTGTC TAAAAAACATAAATTTCTTTAATCATTTTGCCTCTTTTCTCTGTGCTTCAATTAATAAAA AATGGAAAGAACCTAGATCTΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΆΑΑΑΆΑΑΑΑΑΑΆΑ AAAAAAAAAAAAAAAAAAAAAAAATGCATCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCC AAAGGCTCTTTTCAGAGCCACCAGAATT (SEQ ID NO: 1398) HSD17B4 - PpLuc(GC) - albumin7 - A64N64
GGGTCCCGCAGTCGGCGTCCAGCGGCTCTGCTTGTTCGTGTGTGTGTCGTTGCAGGCCTT ATTCAAGGTTGAGGATGGAGGACGCCAAGAACATCAAGAAGGGCCCGGCGCCCTTCTACC CGCTGGAGGACGGGACCGCCGGCGAGCAGCTCCACAAGGCCATGAAGCGGTACGCCCTGG TGCCGGGCACGATCGCCTTCACCGACGCCCACATCGAGGTCGACATCACCTACGCGGAGT ACTTGGAGATGAGCGTGCGCCTGGCCGAGGCCATGAAGCGGTACGGCCTGAACACCAACC ACCGGATCGTGGTGTGCTCGGAGAACAGCCTGCAGTTCTTCATGCCGGTGCTGGGCGCCC TCTTCATCGGCGTGGCCGTCGCCCCGGCGAACGACATCTACAACGAGCGGGAGCTGCTGA ACAGCATGGGGATGAGCCAGCCGACCGTGGTGTTCGTGAGCAAGAAGGGCCTGCAGAAGA TCCTGAACGTGCAGAAGAAGCTGCCCATCATCCAGAAGATCATCATCATGGACAGCAAGA CCGACTACCAGGGCTTCCAGTCGATGTACACGTTCGTGACCAGCCACCTCCCGCCGGGCT TCAACGAGTACGACTTCGTCCCGGAGAGCTTCGACCGGGACAAGACCATCGCCCTGATCA TGAACAGCAGCGGCAGCACCGGCCTGCCGAAGGGGGTGGCCCTGCCGCACCGGACCGCCT GCGTGCGCTTCTCGCACGCCCGGGACCCCATCTTCGGCAACCAGATCATCCCGGACACCG CCATCCTGAGCGTGGTGCCGTTCCACCACGGCTTCGGCATGTTCACGACCCTGGGCTACC TCATCTGCGGCTTCCGGGTGGTCCTGATGTACCGGTTCGAGGAGGAGCTGTTCCTGCGGA GCCTGCAGGACTACAAGATCCAGAGCGCGCTGCTCGTGCCGACCCTGTTCAGCTTCTTCG CCAAGAGCACCCTGATCGACAAGTACGACCTGTCGAACCTGCACGAGATCGCCAGCGGGG GCGCCCCGCTGAGCAAGGAGGTGGGCGAGGCCGTGGCCAAGCGGTTCCACCTCCCGGGCA TCCGCCAGGGCTACGGCCTGACCGAGACCACGAGCGCGATCCTGATCACCCCCGAGGGGG ACGACAAGCCGGGCGCCGTGGGCAAGGTGGTCCCGTTCTTCGAGGCCAAGGTGGTGGACC TGGACACCGGCAAGACCCTGGGCGTGAACCAGCGGGGCGAGCTGTGCGTGCGGGGGCCGA TGATCATGAGCGGCTACGTGAACAACCCGGAGGCCACCAACGCCCTCATCGACAAGGACG GCTGGCTGCACAGCGGCGACATCGCCTACTGGGACGAGGACGAGCACTTCTTCATCGTCG ACCGGCTGAAGTCGCTGATCAAGTACAAGGGCTACCAGGTGGCGCCGGCCGAGCTGGAGA GCATCCTGCTCCAGCAGCCCAAGATCTTCGACGCCGGCGTGGCCGGGCTGCCGGACGACG ACGCCGGCGAGCTGCCGGCCGCGGTGGTGGTGCTGGAGCACGGCAAGACCATGACGGAGA AGGAGATCGTCGACTACGTGGCCAGCCAGGTGACCACCGCCAAGAAGCTGCGGGGCGGCG TGGTGTTCGTGGACGAGGTCCCGAAGGGCCTGACCGGGAAGCTCGACGCCCGGAAGATCC GCGAGATCCTGATCAAGGCCAAGAAGGGCGGCAAGATCGCCGTGTAAGACTAGTGCATCA CATTTAAAAGCATCTCAGCCTACCATGAGAATAAGAGAAAGAAAATGAAGATCAATAGCT TATTCATCTCTTTTTCTTTTTCGTTGGTGTAAAGCCAACACCCTGTCTAAAAAACATAAA TTTCTTTAATCATTTTGCCTCTTTTCTCTGTGCTTCAATTAATAAAAAATGGAAAGAACC TAGATCTAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAATGCATCCGCCCCCCCCCCCCCCCCCCCCCCCCCCCCAAAGGCTCTTTTC AGAGCCACCAGAATT (SEQ ID NO: 1399)
AIG1 - PpLuc(GC) - albumin7 - A64N64
GGGCCGCCGAGCCGGTCCAGGCCTCTGGCGAACAAGCTTGAGGATGGAGGACGCCAAGAA CATCAAGAAGGGCCCGGCGCCCTTCTACCCGCTGGAGGACGGGACCGCCGGCGAGCAGCT CCACAAGGCCATGAAGCGGTACGCCCTGGTGCCGGGCACGATCGCCTTCACCGACGCCCA CATCGAGGTCGACATCACCTACGCGGAGTACTTCGAGATGAGCGTGCGCCTGGCCGAGGC CATGAAGCGGTACGGCCTGAACACCAACCACCGGATCGTGGTGTGCTCGGAGAACAGCCT GCAGTTCTTCATGCCGGTGCTGGGCGCCCTCTTCATCGGCGTGGCCGTCGCCCCGGCGAA CGACATCTACAACGAGCGGGAGCTGCTGAACAGCATGGGGATCAGCCAGCCGACCGTGGT GTTCGTGAGCAAGAAGGGCCTGCAGAAGATCCTGAACGTGCAGAAGAAGCTGCCCATCAT CCAGAAGATCATCATCATGGACAGCAAGACCGACTACCAGGGCTTCCAGTCGATGTACAC GTTCGTGACCAGCCACCTCCCGCCGGGCTTCAACGAGTACGACTTCGTCCCGGAGAGCTT CGACCGGGACAAGACCATCGCCCTGATCATGAACAGCAGCGGCAGCACCGGCCTGCCGAA GGGGGTGGCCCTGCCGCACCGGACCGCCTGCGTGCGCTTCTCGCACGCCCGGGACCCCAT CTTCGGCAACCAGATCATCCCGGACACCGCCATCCTGAGCGTGGTGCCGTTCCACCACGG CTTCGGCATGTTCACGACCCTGGGCTACCTCATCTGCGGCTTCCGGGTGGTCCTGATGTA CCGGTTCGAGGAGGAGCTGTTCGTGCGGAGCCTGCAGGACTACAAGATCCAGAGCGCGCT GCTCGTGCCGACCCTGTTCAGCTTCTTCGCCAAGAGCACCCTGATCGACAAGTACGACCT GTCGAACCTGCACGAGATCGCCAGCGGGGGCGCCCCGCTGAGCAAGGAGGTGGGCGAGGC CGTGGCCAAGCGGTTCCACCTCCCGGGCATCCGCCAGGGCTACGGCCTGACCGAGACCAC GAGCGCGATCCTGATCACCCCCGAGGGGGACGACAAGCCGGGCGCCGTGGGCAAGGTGGT CCCGTTCTTCGAGGCCAAGGTGGTGGACCTGGACACCGGCAAGACCCTGGGCGTGAACCA GCGGGGCGAGCTGTGCGTGCGGGGGCCGATGATCATGAGCGGCTACGTGAACAACCCGGA GGCCACCAACGCCCTCATCGACAAGGACGGCTGGCTGCACAGCGGCGACATCGCCTACTG GGACGAGGACGAGCACTTCTTCATCGTCGACCGGCTGAAGTCGCTGATCAAGTACAAGGG CTACCAGGTGGCGCCGGCCGAGCTGGAGAGCATCCTGCTCCAGCACCCCAACATCTTCGA CGCCGGCGTGGCCGGGCTGCCGGACGACGACGCCGGCGAGCTGCCGGCCGCGGTGGTGGT GCTGGAGCACGGCAAGACCATGACGGAGAAGGAGATCGTCGACTACGTGGCCAGCCAGGT GACCACCGCCAAGAAGCTGCGGGGCGGCGTGGTGTTCGTGGACGAGGTCCCGAAGGGCCT GACCGGGAAGCTCGACGCCCGGAAGATCCGCGAGATCCTGATCAAGGCCAAGAAGGGCGG CAAGATCGCCGTGTAAGACTAGTGCATCACATTTAAAAGCATCTCAGCCTACCATGAGAA TAAGAGAAAGAAAATGAAGATCAATAGCTTATTCATCTCTTTTTCTTTTTCGTTGGTGTA AAGCCAACACCCTGTCTAAAAAACATAAATTTCTTTAATCATTTTGCCTCTTTTCTCTGT GCTTCAAT ΑΑΤΆΑΑΑΑΑΤGGAAAGAACC AGATCTΑΑΑΑΑΑΑΑΑΑΑΑΑΆΑΑΆΑΑΑΑΑΑΑ AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAATGCATCCCCCCCCCCCCCCC CCCCCCCCCCCCCCCCAAAGGCTCTTTTCAGAGCCACCAGAATT (SEQ ID NO: 1400) COX6C - PpLuc(GC) - albumin7 - A64N64
GGAGTCAGGAAGGACGTTGGTGTTGAGGTTAGCATACGTATCAAGGACAGTAACTACCAA GCTTGAGGATGGAGGACGCCAAGAACATCAAGAAGGGCCCGGCGCCCTTCTACCCGCTGG AGGACGGGACCGCCGGCGAGCAGCTCCACAAGGCCATGAAGCGGTACGCCCTGGTGCCGG GCACGATCGCCTTCACCGACGCCCACATCGAGGTCGACATCACCTACGCGGAGTACTTCG AGATGAGCGTGCGCCTGGCCGAGGCCATGAAGCGGTACGGCCTGAACACCAACCACCGGA TCGTGGTGTGCTCGGAGAACAGCCTGCAGTTCTTCATGCCGGTGCTGGGCGCCCTCTTCA TCGGCGTGGCCGTCGCCCCGGCGAACGACATCTACAACGAGCGGGAGCTGCTGAACAGCA TGGGGATCAGCCAGCCGACCGTGGTGTTCGTGAGCAAGAAGGGCCTGCAGAAGATCCTGA ACGTGCAGAAGAAGCTGCCCATCATCCAGAAGATCATCATCATGGACAGCAAGACCGACT ACCAGGGCTTCCAGTCGATGTACACGTTCGTGACCAGCCACCTCCCGCCGGGCTTCAACG AGTACGACTTCGTCCCGGAGAGCTTCGACCGGGACAAGACCATCGCCCTGATCATGAACA GCAGCGGCAGCACCGGCCTGCCGAAGGGGGTGGCCCTGCCGCACCGGACCGCCTGCGTGC GCTTCTCGCAGGCCCGGGACCCCATCTTCGGCAACCAGATCATCCCGGACACCGCCATCC TGAGCGTGGTGCCGTTCCACCACGGCTTCGGCATGTTCACGACCCTGGGCTACCTCATCT GCGGCTTCCGGGTGGTCCTGATGTACCGGTTCGAGGAGGAGCTGTTCCTGCGGAGCCTGC AGGACTACAAGATCCAGAGCGCGCTGCTCGTGCCGACCCTGTTCAGCTTCTTCGCCAAGA GCACCCTGATCGACAAGTACGACCTGTCGAACCTGCACGAGATCGCCAGCGGGGGCGCCC CGCTGAGCAAGGAGGTGGGCGAGGCCGTGGCCAAGCGGTTCCACCTCCCGGGCATCCGCC AGGGCTACGGCCTGACCGAGACCACGAGCGCGATCCTGATCACCCCCGAGGGGGACGACA AGCCGGGCGCCGTGGGCAAGGTGGTCCCGTTCTTCGAGGCCAAGGTGGTGGACCTGGACA CCGGCAAGACCCTGGGCGTGAACCAGCGGGGCGAGCTGTGCGTGCGGGGGCCGATGATCA TGAGCGGCTACGTGAACAACCCGGAGGCCACCAACGCCCTCATCGACAAGGACGGCTGGC TGCACAGCGGCGACATCGCCTACTGGGACGAGGACGAGCACTTCTTCATCGTCGACCGGC TGAAGTCGCTGATCAAGTACAAGGGCTACCAGGTGGCGCCGGCCGAGCTGGAGAGCATCC TGCTCCAGCACCCCAACATCTTCGACGCCGGCGTGGCCGGGCTGCCGGACGACGACGCCG GCGAGCTGCCGGCCGCGGTGGTGGTGCTGGAGCACGGCAAGACCATGACGGAGAAGGAGA TCGTCGACTACGTGGCCAGCCAGGTGACCACCGCCAAGAAGCTGCGGGGCGGCGTGGTGT TCGTGGACGAGGTCCCGAAGGGCCTGACCGGGAAGCTCGACGCCCGGAAGATCCGCGAGA TCCTGATCAAGGCCAAGAAGGGCGGCAAGATCGCCGTGTAAGACTAGTGCATCACATTTA AAAGCATCTCAGCCTACCATG GAATAAGAGAAAGAAAATGAAGATCAA AGCT ATTCA TCTCTTTTTCTTTTTCGTTGGTGTAAAGCCAACACCCTGTCTAAAAAACATAAATTTCTT TAATCATTTTGCCTCTTTTCTCTGTGCTTCAATTAATAAAAAATGGAAAGAACCTAGATC ΤΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΆΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑ AAAAATGCATCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCAAAGGCTCTTTTCAGAGCC ACCAGAATT (SEQ ID NO: 1401)
ASAH1 - PpLuc(GC) - albumin7 - A64N64
GGGCCTCTGCTGGAGTCCGGGGAGTGGCGTTGGCTGCTAGAGCGAAGCTTGAGGATGGAG GACGCCAAGAACATCAAGAAGGGCCCGGCGCCCTTCTACCCGCTGGAGGACGGGACCGCC GGCGAGCAGCTCCACAAGGCCATGAAGCGGTACGCCCTGGTGCCGGGCACGATCGCCTTC ACCGACGCCCACATCGAGGTCGACATCACCTACGCGGAGTACTTCGAGATGAGCGTGCGC CTGGCCGAGGCGATGAAGCGGTACGGCCTGAACACCAACCACCGGATCGTGGTGTGCTCG GAGAACAGCCTGCAGTTCTTCATGCCGGTGCTGGGCGCCCTCTTCATCGGCGTGGCCGTC GCCCCGGCGAACGACATCTACAACGAGCGGGAGCTGCTGAACAGCATGGGGATCAGCCAG CCGACCGTGGTGTTCGTGAGCAAGAAGGGCCTGCAGAAGATCCTGAACGTGCAGAAGAAG CTGCCCATCATCCAGAAGATCATCATCATGGACAGCAAGACCGACTACCAGGGCTTCCAG TCGATGTACACGTTCGTGACCAGCCACCTCCCGCCGGGCTTCAACGAGTACGACTTCGTC CCGGAGAGCTTCGACCGGGACAAGACCATCGCCCTGATCATGAACAGCAGCGGCAGCACC GGCCTGCCGAAGGGGGTGGCCCTGCCGCACCGGACCGCCTGCGTGCGCTTCTCGCACGCC CGGGACCCCATCTTCGGCAACCAGATCATCCCGGACACCGCCATCCTGAGCGTGGTGCCG TTCCACCACGGCTTCGGCATGTTCACGACCCTGGGCTACCTCATCTGCGGCTTCCGGGTG GTCCTGATGTACCGGTTCGAGGAGGAGCTGTTCCTGCGGAGCCTGCAGGACTACAAGATC CAGAGCGCGCTGCTCGTGCCGACCCTGTTCAGCTTCTTCGCCAAGAGCACCCTGATCGAC AAGTACGACCTGTCGAACCTGCACGAGATCGCCAGCGGGGGCGCCCCGCTGAGCAAGGAG GTGGGCGAGGCCGTGGCCAAGCGGTTCCACCTCCCGGGCATCCGCCAGGGCTACGGCCTG ACCGAGACCACGAGCGCGATCCTGATCACCCCCGAGGGGGACGACAAGCCGGGCGCCGTG GGCAAGGTGGTCCCGTTCTTCGAGGCCAAGGTGGTGGACCTGGACACCGGCAAGACCCTG GGCGTGAACCAGCGGGGCGAGCTGTGCGTGCGGGGGCCGATGATCATGAGCGGCTACGTG AACAACCCGGAGGCCACCAACGCCCTCATCGACAAGGACGGCTGGCTGCACAGCGGCGAC ATCGCCTACTGGGACGAGGACGAGCACTTCTTCATCGTCGACCGGCTGAAGTCGCTGATC AAGTACAAGGGCTACCAGGTGGCGCCGGCCGAGCTGGAGAGCATCCTGCTCCAGCACCCC AACATCTTCGACGCCGGCGTGGCCGGGCTGCCGGACGACGACGCCGGCGAGCTGCCGGCC GCGGTGGTGGTGCTGGAGCACGGCAAGACCATGACGGAGAAGGAGATCGTCGACTACGTG GCCAGCCAGGTGACCACCGCCAAGAAGCTGCGGGGCGGCGTGGTGTTCGTGGACGAGGTC CCGAAGGGCCTGACCGGGAAGCTCGACGCCCGGAAGATCCGCGAGATCCTGATCAAGGCC AAGAAGGGCGGCAAGATCGCCGTGTAAGACTAGTGCATCACATTTAAAAGCATCTCAGCC TACCATGAGAATAAGAGAAAGAAAATGAAGATCAATAGCTTATTCATCTCTTTTTCTTTT TCGTTGGTGTAAAGCCAACACCCTGTCTAAAAAACATAAATTTCTTTAATCATTTTGCCT CTTTTCTCTGTGCTTCAATTAATAAAAAATGGAAAGAACCTAGATCTAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAATGCATCCCC CCCCCCCCCCCCCCCCCCCCCCCCCCCAAAGGCTCTTTTCAGAGCCACCAGAATT (SEQ ID NO: 1402) mRPL21 - PpLuc(GC) - albumin7 - A64N64
GGGGCCGCCGCAGCCATCTTCCAGTAACTCGCCAAAAAGCTTGAGGATGGAGGACGCCAA GAACATCAAGAAGGGCCCGGCGCCCTTCTACCCGCTGGAGGACGGGACCGCCGGCGAGCA GCTCCACAAGGCCATGAAGCGGTACGCCCTGGTGCCGGGCACGATCGCCTTCACCGACGC CCACATCGAGGTCGACATCACCTACGCGGAGTACTTCGAGATGAGCGTGCGCCTGGCCGA GGCCATGAAGCGGTACGGCCTGAACACCAACCACCGGATCGTGGTGTGCTCGGAGAACAG CCTGCAGTTCTTCATGCCGGTGCTGGGCGCCCTCTTCATCGGCGTGGCCGTCGCCCCGGC GAACGACATCTACAACGAGCGGGAGCTGCTGAACAGCATGGGGATCAGCCAGCCGACCGT GGTGTTCGTGAGCAAGAAGGGCCTGCAGAAGATCCTGAACGTGCAGAAGAAGCTGCCCAT CATCCAGAAGATCATCATCATGGACAGCAAGACCGACTACCAGGGCTTCCAGTCGATGTA CACGTTCGTGACCAGCCACCTCCCGCCGGGCTTCAACGAGTACGACTTCGTCCCGGAGAG CTTCGACCGGGACAAGACCATCGCCCTGATCATGAACAGCAGCGGCAGCACCGGCCTGCC GAAGGGGGTGGCCCTGCCGCACCGGACCGCCTGCGTGCGCTTCTCGCACGCCCGGGACCC CATCTTCGGCAACCAGATCATCCCGGACACCGCCATCCTGAGCGTGGTGCCGTTCCACCA CGGCTTCGGCATGTTCACGACCCTGGGCTACCTCATCTGCGGCTTCCGGGTGGTCCTGAT GTACCGGTTCGAGGAGGAGCTGTTCCTGCGGAGCCTGCAGGACTACAAGATCCAGAGCGC GCTGCTCGTGCCGACCCTGTTCAGCTTCTTCGCCAAGAGCACCCTGATCGACAAGTACGA GCTGTCGAACCTGCACGAGATCGCCAGCGGGGGCGCCCCGCTGAGCAAGGAGGTGGGCGA GGCCGTGGCCAAGCGGTTCCACCTCCCGGGCATCCGCCAGGGCTACGGCCTGACCGAGAC CACGAGCGCGATCCTGATCACCCCCGAGGGGGACGACAAGCCGGGCGCCGTGGGCAAGGT GGTCCCGTTCTTCGAGGCCAAGGTGGTGGACCTGGACACCGGCAAGACCCTGGGCGTGAA CCAGCGGGGCGAGCTGTGCGTGCGGGGGCCGATGATCATGAGCGGCTACGTGAACAACCC GGAGGCCACCAACGCCCTCATCGACAAGGACGGCTGGCTGCACAGCGGCGACATCGCCTA CTGGGAGGAGGACGAGCACTTCTTCATCGTCGACCGGCTGAAGTCGCTGATCAAGTACAA GGGCTACCAGGTGGCGCCGGCCGAGCTGGAGAGCATCCTGCTCCAGCACCCCAACATCTT CGACGCCGGCGTGGCCGGGCTGCCGGACGACGACGCCGGCGAGCTGCCGGCCGCGGTGGT GGTGCTGGAGGACGGCAAGACCATGACGGAGAAGGAGATCGTCGACTACGTGGCCAGCCA GGTGACCACCGCCAAGAAGCTGCGGGGCGGCGTGGTGTTCGTGGACGAGGTCCCGAAGGG CCTGACCGGGAAGCTCGACGCCCGGAAGATCCGCGAGATCCTGATCAAGGCCAAGAAGGG CGGCAAGATCGCCGTGTAAGACTAGTGCATCACATTTAAAAGCATCTCAGCCTACCATGA GAATAAGAGAAAGAAAATGAAGATCAATAGCTTATTCATCTCTTTTTCTTTTTCGTTGGT GTAAAGCCAACACCCTGTCTAAAAAACATAAATTTCTTTAATCATTTTGCCTCTTTTCTC T GT GC T T CAAT T AAT AAAAAAT GGAAAGAAC C TAG AT C ΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΆ AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAATGCATCCCCCCCCCCCC CCCCCCCCCCCCCCCCCCCAAAGGCTCTTTTCAGAGCCACCAGAATT ( SEQ I D NO : 1403 ) rtiRPL35A - PpLuc ( GC ) - albumin7 - A64N64
GGGCCATCTTGGCGCCTGTGGAGGCCTGCTGGGAACAGGACTTCTAACAGCAAGTAAGCT TGAGGATGGAGGACGCCAAGAACATCAAGAAGGGCCCGGCGCCCTTCTACCCGCTGGAGG ACGGGACCGCCGGCGAGCAGCTCCACAAGGCCATGAAGCGGTACGCCCTGGTGCCGGGCA CGATCGCCTTCACCGACGCCCACATCGAGGTCGACATCACCTACGCGGAGTACTTCGAGA TGAGCGTGCGCCTGGCCGAGGCCATGAAGCGGTACGGCCTGAACACCAACCACCGGATCG TGGTGTGCTCGGAGAACAGCCTGCAGTTCTTCATGCCGGTGCTGGGCGCCCTCTTCATCG GCGTGGCCGTCGCCCCGGCGAACGACATCTACAACGAGCGGGAGCTGCTGAACAGCATGG GGATCAGCCAGCCGACCGTGGTGTTCGTGAGCAAGAAGGGCCTGCAGAAGATCCTGAACG TGCAGAAGAAGCTGCCCATCATCCAGAAGATCATCATCATGGACAGCAAGACCGACTACC AGGGCTTCCAGTCGATGTACACGTTCGTGACCAGCCACCTCCCGCCGGGCTTCAACGAGT ACGACTTCGTCCCGGAGAGCTTCGACCGGGACAAGACCATCGCCCTGATCATGAACAGCA GCGGCAGCACCGGCCTGCCGAAGGGGGTGGCCCTGCCGCACCGGACCGCCTGCGTGCGCT TCTCGCACGCCCGGGACCCCATCTTCGGCAACCAGATCATCCCGGACACCGCCATCCTGA GCGTGGTGCCGTTCCACCACGGCTTCGGCATGTTCACGACCCTGGGCTACCTCATCTGCG GCTTCCGGGTGGTCCTGATGTACCGGTTCGAGGAGGAGCTGTTCCTGCGGAGCCTGCAGG ACTACAAGATCCAGAGCGCGCTGCTCGTGCCGACCCTGTTCAGCTTCTTCGCCAAGAGCA CCCTGATCGACAAGTACGACCTGTCGAACCTGCACGAGATCGCCAGCGGGGGCGCCCCGC TGAGCAAGGAGGTGGGCGAGGCCGTGGCCAAGCGGTTCCACCTCCCGGGCATCCGCCAGG GCTACGGCCTGACCGAGACCACGAGCGCGATCCTGATCACCCCCGAGGGGGACGACAAGC CGGGCGCCGTGGGCAAGGTGGTCCCGTTCTTCGAGGCCAAGGTGGTGGACCTGGACACCG GCAAGACCCTGGGCGTGAACCAGCGGGGCGAGCTGTGCGTGCGGGGGCCGATGATCATGA GCGGCTACGTGAACAACCCGGAGGCCACCAACGCCCTCATCGACAAGGACGGCTGGCTGC ACAGCGGCGACATCGCCTACTGGGACGAGGACGAGCACTTCTTCATCGTCGACCGGCTGA AGTCGCTGATCAAGTACAAGGGCTACCAGGTGGCGCCGGCCGAGCTGGAGAGCATCCTGC TCCAGCACCCCAACATCTTCGACGCCGGCGTGGCCGGGCTGCCGGACGACGACGCCGGCG AGCTGCCGGCCGCGGTGGTGGTGCTGGAGCACGGCAAGACCATGACGGAGAAGGAGATCG TCGACTACGTGGCCAGCCAGGTGACCACCGCCAAGAAGCTGCGGGGCGGCGTGGTGTTCG TGGACGAGGTCCCGAAGGGCCTGACCGGGAAGCTCGACGCCCGGAAGATCCGCGAGATCC TGATCAAGGCCAAGAAGGGCGGCAAGATCGCCGTGTAAGACTAGTGCATCACATTTAAAA GCATCTCAGCCTACCATGAGAATAAGAGAAAGAAAATGAAGATCAATAGCTTAT CATCT CTTTTTCTTTTTCGTTGGTGTAAAGCCAACACCCTGTCTAAAAAACATAAATTTCTTTAA TCATTTTGCCTCTTTTCTCTGTGCTTCAATTAATAAAAAATGGAAAGAACCTAGATCTAA ΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΆΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑ AATGCATCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCAAAGGCTCTTTTCAGAGCCACC AGAATT (SEQ ID NO: 1404) RPL35 - PpLuc(GC) - A64N64
GGGGAGCGGGCGGCGGCGTTGGCGGCTTGTGCAGCAAAGCTTGAGGATGGAGGACGCCAA GAACATCAAGAAGGGCCCGGCGCCCTTCTACCCGCTGGAGGACGGGACCGCCGGCGAGCA GCTCCACAAGGCCATGAAGCGGTACGCCCTGGTGCCGGGCACGATCGCCTTCACCGACGC CCACATCGAGGTCGACATCACCTACGCGGAGTACTTCGAGATGAGCGTGCGCCTGGCCGA GGCCATGAAGCGGTACGGCCTGAACACCAACCACCGGATCGTGGTGTGCTCGGAGAACAG CCTGCAGTTCTTCATGCCGGTGCTGGGCGCCCTCTTCATCGGCGTGGCCGTCGCCCCGGC GAACGACATCTACAACGAGCGGGAGCTGCTGAACAGCATGGGGATCAGCCAGCCGACCGT GGTGTTCGTGAGCAAGAAGGGCCTGCAGAAGATCCTGAACGTGCAGAAGAAGCTGCCCAT CATCCAGAAGATCATCATCATGGACAGCAAGACCGACTACCAGGGCTTCCAGTCGATGTA CACGTTCGTGACCAGCCACCTCCCGCCGGGCTTCAACGAGTACGACTTCGTCCCGGAGAG CTTCGACCGGGACAAGACCATCGCCCTGATCATGAACAGCAGCGGCAGCACCGGCCTGCC GAAGGGGGTGGCCCTGCCGCACCGGACCGCCTGCGTGCGCTTCTCGCACGCCCGGGACCC CATCTTCGGCAACCAGATCATCCCGGACACCGCCATCCTGAGCGTGGTGCCGTTCCACCA CGGCTTCGGCATGTTCACGACCCTGGGCTACCTCATCTGCGGCTTCCGGGTGGTCCTGAT GTACCGGTTCGAGGAGGAGCTGTTCCTGCGGAGCCTGCAGGACTACAAGATCCAGAGCGC GCTGCTCGTGCCGACCCTGTTCAGCTTCTTCGCCAAGAGCACCCTGATCGACAAGTACGA CCTGTCGAACCTGCACGAGATCGCCAGCGGGGGCGCCCCGCTGAGCAAGGAGGTGGGCGA GGCCGTGGCCAAGCGGTTCCACCTCCCGGGCATCCGCCAGGGCTACGGCCTGACCGAGAC CACGAGCGCGATCCTGATCACCCCCGAGGGGGACGACAAGCCGGGCGCCGTGGGCAAGGT GGTCCCGTTCTTCGAGGCCAAGGTGGTGGACCTGGACACCGGCAAGACCCTGGGCGTGAA CCAGCGGGGCGAGCTGTGCGTGCGGGGGCCGATGATCATGAGCGGCTACGTGAACAACCC GGAGGCCACCAACGCCCTCATCGACAAGGACGGCTGGCTGCACAGCGGCGACATCGCCTA CTGGGACGAGGACGAGCACTTCTTCATCGTCGACCGGCTGAAGTCGCTGATCAAGTACAA GGGCTACCAGGTGGCGCCGGCCGAGCTGGAGAGCATCCTGCTCCAGCACCCCAACATCTT CGACGCCGGCGTGGCCGGGCTGCCGGACGACGACGCCGGCGAGCTGCCGGCCGCGGTGGT GGTGCTGGAGCACGGCAAGACCATGACGGAGAAGGAGATCGTCGACTACGTGGCCAGCCA GGTGACCACCGCCAAGAAGCTGCGGGGCGGCGTGGTGTTCGTGGACGAGGTCCCGAAGGG CCTGACCGGGAAGCTCGACGCCCGGAAGATCCGCGAGATCCTGATCAAGGCCAAGAAGGG CGGCAAGATCGCCGTGTAAGACTAGTAGATCTAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAATGCATCCCCCCCCCCCCCCCCCCC CCCCCCCCCCCCAAAGGCTCTTTTCAGAGCCACCAGAATT (SEQ ID NO: 1405) RPL21 - PpLuc(GC) - A64N64
GGGGCCGGAACCGCCATCTTCCAGTAATTCGCCAAAAAGCTTGAGGATGGAGGACGCCAA GAACATCAAGAAGGGCCCGGCGCCCTTCTACCCGCTGGAGGACGGGACCGCCGGCGAGCA GCTCCACAAGGCCATGAAGCGGTACGCCCTGGTGCCGGGCACGATCGCCTTCACCGACGC CCACATCGAGGTCGACATCACCTACGCGGAGTACTTCGAGATGAGCGTGCGCCTGGCCGA GGCCATGAAGCGGTACGGCCTGAACACCAACCACCGGATCGTGGTGTGCTCGGAGAACAG CCTGCAGTTCTTCATGCCGGTGCTGGGCGCCCTCTTCATCGGCGTGGCCGTCGCCCCGGC GAACGACATCTACAACGAGCGGGAGCTGCTGAACAGCATGGGGATCAGCCAGCCGACCGT GGTGTTCGTGAGCAAGAAGGGCCTGCAGAAGATCCTGAACGTGCAGAAGAAGCTGCCCAT CATCCAGAAGATCATCATCATGGACAGCAAGACCGACTACCAGGGCTTCCAGTCGATGTA CACGTTCGTGACCAGCCACCTCCCGCCGGGCTTCAACGAGTACGACTTCGTCCCGGAGAG GTTCGACCGGGACAAGACCATCGCCCTGATCATGAACAGCAGCGGCAGCACCGGCCTGCC GAAGGGGGTGGCCCTGCCGCACCGGACCGCCTGCGTGCGCTTCTCGCACGCCCGGGACCC CATCTTCGGCAACCAGATCATCCCGGACACCGCCATCCTGAGCGTGGTGCCGTTCCACCA CGGCTTCGGCATGTTCACGACCCTGGGCTACCTCATCTGCGGCTTCCGGGTGGTCCTGAT GTAGCGGTTCGAGGAGGAGCTGTTCCTGCGGAGCCTGCAGGACTACAAGATCCAGAGCGC GCTGCTCGTGCCGACCCTGTTCAGCTTCTTCGCCAAGAGCACCCTGATCGACAAGTACGA CCTGTCGAACCTGCACGAGATCGCCAGCGGGGGCGCCCCGCTGAGCAAGGAGGTGGGCGA GGCCGTGGCCAAGCGGTTCCACGTCCCGGGCATCCGCCAGGGCTACGGCCTGACCGAGAC CACGAGCGCGATCCTGATCACCCCCGAGGGGGACGACAAGCCGGGCGCCGTGGGCAAGGT GGTCCCGTTCTTCGAGGCCAAGGTGGTGGACCTGGACACCGGCAAGACCCTGGGCGTGAA CCAGCGGGGCGAGCTGTGCGTGCGGGGGCCGATGATCATGAGCGGCTACGTGAACAACCC GGAGGCCACCAACGCCCTCATCGACAAGGACGGCTGGCTGCACAGCGGCGACATCGCCTA CTGGGACGAGGACGAGCACTTCTTCATCGTCGACCGGCTGAAGTCGCTGATCAAGTACAA GGGCTACCAGGTGGCGCCGGCCGAGCTGGAGAGCATCCTGCTCCAGCACCCCAACATCTT CGACGCCGGCGTGGCCGGGCTGCCGGACGACGACGCCGGCGAGCTGCCGGCCGCGGTGGT GGTGCTGGAGCACGGCAAGACCATGACGGAGAAGGAGATCGTCGACTACGTGGCCAGCCA GGTGACCACCGCCAAGAAGCTGCGGGGCGGCGTGGTGTTCGTGGACGAGGTCCCGAAGGG CCTGACCGGGAAGCTCGACGCCCGGAAGATCCGCGAGATCCTGATCAAGGCCAAGAAGGG CGGCAAGATCGCCGTGTAAGACTAGTAGATCTAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAATGCATCCCCCCCCCCCCCCCCCCC CCCCCCCCCCCCAAAGGCTCTTTTCAGAGCCACCAGAATT (SEQ ID NO: 1406) ATP5A1 - PpLuc(GC) - A64N64
GGGCGGCTCGGCCATTTTGTCCCAGTCAGTCCGGAGGCTGCGGCTGCAGAAGTACCGCCT GCGGAGTAACTGCAAAGAAGCTTGAGGATGGAGGACGCCAAGAACATCAAGAAGGGCCCG GCGCCCTTCTACCCGCTGGAGGACGGGACCGCCGGCGAGCAGCTCCACAAGGCCATGAAG CGGTACGCCCTGGTGCCGGGCACGATCGCCTTCACCGACGCCCACATCGAGGTCGACATC ACCTACGCGGAGTACTTCGAGATGAGCGTGCGCCTGGCCGAGGCCATGAAGCGGTACGGC CTGAACACCAACCACCGGATCGTGGTGTGCTCGGAGAACAGCCTGCAGTTCTTCATGCCG GTGCTGGGCGCCCTCTTCATCGGCGTGGCCGTCGCCCCGGCGAACGACATCTACAACGAG CGGGAGCTGCTGAACAGCATGGGGATCAGCCAGCCGACCGTGGTGTTCGTGAGCAAGAAG GGCCTGCAGAAGATCCTGAACGTGCAGAAGAAGCTGCCCATCATCCAGAAGATCATCATC ATGGACAGCAAGACCGACTACCAGGGCTTCCAGTCGATGTACACGTTCGTGACCAGCCAC CTCCCGCCGGGCTTCAACGAGTACGACTTCGTCCCGGAGAGCTTCGACCGGGACAAGACC ATCGCCCTGATCATGAACAGCAGCGGCAGCACCGGCCTGCCGAAGGGGGTGGCCCTGCCG CACCGGACCGCCTGCGTGCGCTTCTCGCACGCCCGGGACCCCATCTTCGGCAACCAGATC ATCCCGGACACCGCCATCCTGAGCGTGGTGCCGTTCCACCACGGCTTCGGCATGTTCACG ACCCTGGGCTACCTCATCTGCGGCTTCCGGGTGGTCCTGATGTACCGGTTCGAGGAGGAG CTGTTCCTGCGGAGCCTGCAGGACTACAAGATCCAGAGCGCGCTGCTCGTGCCGACCCTG TTCAGCTTCTTCGCCAAGAGCACCCTGATCGACAAGTACGACCTGTCGAACCTGCACGAG ATCGCCAGCGGGGGCGCCCCGCTGAGCAAGGAGGTGGGCGAGGCCGTGGCCAAGCGGTTC CACCTCCCGGGCATCCGCCAGGGCTACGGCCTGACCGAGACCACGAGCGCGATCCTGATC ACCCCCGAGGGGGACGACAAGCCGGGCGCCGTGGGCAAGGTGGTCCCGTTCTTCGAGGCC AAGGTGGTGGACCTGGACACCGGCAAGACCCTGGGCGTGAACCAGCGGGGCGAGCTGTGC GTGCGGGGGCCGATGATCATGAGCGGCTACGTGAACAACCCGGAGGCCACCAACGCCCTC ATCGACAAGGACGGCTGGCTGCACAGCGGCGACATCGCCTACTGGGACGAGGACGAGCAC TTCTTCATCGTCGACGGGCTGAAGTCGCTGATCAAGTACAAGGGCTACCAGGTGGCGCCG GCCGAGCTGGAGAGCATCCTGCTCCAGCACCCCAACATCTTCGACGCCGGCGTGGCCGGG CTGCCGGACGACGACGCCGGCGAGCTGCCGGCCGCGGTGGTGGTGCTGGAGCACGGCAAG ACCATGACGGAGAAGGAGATCGTCGACTACGTGGCCAGCCAGGTGACCACCGCCAAGAAG CTGCGGGGCGGCGTGGTGTTCGTGGACGAGGTCCCGAAGGGCCTGACCGGGAAGCTCGAC GCCCGGAAGATCCGGGAGATCCTGATCAAGGCCAAGAAGGGCGGCAAGATCGCCGTGTAA GACTAGTAGATCTΑΑΑΑΑΑΑΑΆΑΑΑΑΑΑΆΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΑΆΑΑΑΑΑΑΑΑ AAAAAAAAAAAAAAAAATGCATCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCAAAGGCT CTTTTCAGAGCCACCAGAATT (SEQ ID NO: 1407)
HSD17B4 - PpLuc(GC) - A64N64
GGGTCCCGCAGTCGGCGTCCAGCGGCTCTGCTTGTTCGTGTGTGTGTCGTTGCAGGCCTT ATTCAAGCTTGAGGATGGAGGACGCCAAGAACATCAAGAAGGGCCCGGCGCCCTTCTACC CGCTGGAGGACGGGACCGCCGGCGAGCAGCTCCACAAGGCCATGAAGCGGTACGCCCTGG TGCCGGGCACGATCGCCTTCACCGACGCCCACATCGAGGTCGACATCACCTACGCGGAGT ACTTCGAGATGAGCGTGCGCCTGGCCGAGGCCATGAAGCGGTACGGCCTGAACACCAACC ACCGGATCGTGGTGTGCTCGGAGAACAGCCTGCAGTTCTTCATGCCGGTGCTGGGCGCCC TCTTCATCGGCGTGGCCGTCGCCCCGGCGAACGACATCTACAACGAGCGGGAGCTGCTGA ACAGCATGGGGATCAGCCAGCCGACCGTGGTGTTCGTGAGCAAGAAGGGCCTGCAGAAGA TCCTGAACGTGCAGAAGAAGCTGCCCATCATCCAGAAGATCATCATCATGGACAGCAAGA CCGACTACCAGGGCTTCCAGTCGATGTACACGTTCGTGACCAGCCACCTCCCGCCGGGCT TCAACGAGTACGACTTCGTCCCGGAGAGCTTCGACCGGGACAAGACCATCGCCCTGATCA TGAACAGCAGCGGCAGCACCGGCCTGCCGAAGGGGGTGGCCCTGCCGCACCGGACCGCCT GCGTGCGCTTCTCGCACGCCCGGGACCCCATCTTCGGCAACCAGATCATCCCGGACACCG CCATCCTGAGCGTGGTGCCGTTCCACCACGGCTTCGGCATGTTCACGACCCTGGGCTACC TCATCTGCGGCTTCCGGGTGGTCCTGATGTACCGGTTCGAGGAGGAGCTGTTCCTGCGGA GCCTGCAGGACTACAAGATCCAGAGCGCGCTGCTCGTGCCGACCCTGTTCAGCTTCTTCG CCAAGAGCACCCTGATCGACAAGTACGACCTGTCGAACCTGCACGAGATCGCCAGCGGGG GCGCCCCGCTGAGCAAGGAGGTGGGCGAGGCCGTGGCCAAGCGGTTCCACCTCCCGGGCA TCCGCCAGGGCTACGGCCTGACCGAGACCACGAGCGCGATCCTGATCACCCCCGAGGGGG ACGACAAGCCGGGCGCCGTGGGCAAGGTGGTCCCGTTCTTCGAGGCCAAGGTGGTGGACC TGGACACCGGCAAGACCCTGGGCGTGAACCAGCGGGGCGAGCTGTGCGTGCGGGGGCCGA TGATCATGAGCGGCTACGTGAACAACCCGGAGGCCACCAACGCCCTCATCGACAAGGACG GCTGGCTGCACAGCGGCGACATCGCCTACTGGGACGAGGACGAGCACTTCTTCATCGTCG ACCGGCTGAAGTCGCTGATCAAGTACAAGGGCTACCAGGTGGCGCCGGCCGAGCTGGAGA GCATCCTGCTCCAGCACCCCAACATCTTCGACGCCGGCGTGGCCGGGCTGCCGGACGACG ACGCCGGCGAGCTGCCGGCCGCGGTGGTGGTGCTGGAGCACGGCAAGACCATGACGGAGA AGGAGATCGTCGACTACGTGGCCAGCCAGGTGACCACCGCCAAGAAGCTGCGGGGCGGCG TGGTGTTCGTGGACGAGGTCCCGAAGGGCCTGACCGGGAAGCTCGACGCCCGGAAGATCC GCGAGATCCTGATCAAGGCCAAGAAGGGCGGCAAGATCGCCGTGTAAGACTAGTAGATCT AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA AAAATGCATCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCAAAGGCTCTTTTCAGAGCCA CCAGAATT (SEQ ID NO: 1408) AIG1 - PpLuc(GC) - A64N64
GGGCCGCCCAGCCGGTCCAGGCCTCTGGCGAACAAGCTTGAGGATGGAGGACGCCAAGAA CATCAAGAAGGGCCCGGCGCCCTTCTACCCGCTGGAGGACGGGACCGCCGGCGAGCAGCT CCACAAGGCCATGAAGCGGTACGCCCTGGTGCCGGGCACGATCGCCTTCACCGACGCCCA CATCGAGGTCGACATCACCTACGCGGAGTACTTCGAGATGAGCGTGCGCCTGGCCGAGGC CATGAAGCGGTACGGCCTGAACACCAACCACCGGATCGTGGTGTGCTCGGAGAACAGCCT GCAGTTCTTCATGCCGGTGCTGGGCGCCCTCTTCATCGGCGTGGCCGTCGCCCCGGCGAA CGACATCTACAACGAGCGGGAGCTGCTGAACAGCATGGGGATCAGCCAGCCGACCGTGGT GTTCGTGAGCAAGAAGGGCCTGCAGAAGATCCTGAACGTGCAGAAGAAGCTGCCCATCAT CCAGAAGATCATCATCATGGACAGCAAGACCGACTACCAGGGCTTCCAGTCGATGTACAC GTTCGTGACCAGCCACCTCCCGCCGGGCTTCAACGAGTACGACTTCGTCCCGGAGAGCTT CGACCGGGACAAGACCATCGCCCTGATCATGAACAGCAGCGGCAGCACCGGCCTGCCGAA GGGGGTGGCCCTGCCGCACCGGACCGCCTGCGTGCGCTTCTCGCACGCCCGGGACCCCAT CTTCGGGAACCAGATCATCCCGGACACCGCCATCCTGAGCGTGGTGCCGTTCCACCACGG CTTCGGCATGTTCACGACCCTGGGCTACCTCATCTGCGGCTTCCGGGTGGTCCTGATGTA CCGGTTCGAGGAGGAGCTGTTCCTGCGGAGCCTGCAGGACTACAAGATCCAGAGCGCGCT GCTCGTGCCGACCCTGTTCAGCTTCTTCGCCAAGAGCACCCTGATCGACAAGTACGACCT GTCGAACCTGCACGAGATCGCCAGCGGGGGCGCCCCGCTGAGCAAGGAGGTGGGCGAGGC CGTGGCCAAGCGGTTCCACCTCCCGGGCATCCGCCAGGGCTACGGCCTGACCGAGACCAC GAGCGCGATCCTGATCACCCCCGAGGGGGACGACAAGCCGGGCGCCGTGGGCAAGGTGGT GCCGTTCTTCGAGGCCAAGGTGGTGGACCTGGACACCGGCAAGACCCTGGGCGTGAACCA GCGGGGCGAGCTGTGCGTGCGGGGGCCGATGATCATGAGCGGCTACGTGAACAACCCGGA GGCCACCAACGCCCTCATCGACAAGGACGGCTGGCTGCACAGCGGCGACATCGCCTACTG GGACGAGGACGAGCACTTCTTCATCGTCGACCGGCTGAAGTCGCTGATCAAGTACAAGGG CTACCAGGTGGCGCCGGCCGAGCTGGAGAGCATCCTGCTCCAGCACCCCAACATCTTCGA CGCCGGGGTGGCCGGGCTGCCGGACGACGACGCCGGCGAGCTGCCGGCCGCGGTGGTGGT GCTGGAGCACGGCAAGACCATGACGGAGAAGGAGATCGTCGACTACGTGGCCAGCCAGGT GACCACCGCCAAGAAGCTGCGGGGCGGCGTGGTGTTCGTGGACGAGGTCCCGAAGGGCCT GACCGGGAAGCTCGACGCCCGGAAGATCCGCGAGATCCTGATCAAGGCCAAGAAGGGCGG CAAGATCGCCGTGTAAGACTAGTAGATC ΑΑΑΑΆΑΑΑΑΆΑΑΑΆΑΑΑΑΑΑΑΆΑΑΑΑΑΑΑΑΑ AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAATGCATCCCCCCCCCCCCCCCCCCCCCC CCCCCCCCCAAAGGCTCTTTTCAGAGCCACCAGAATT (SEQ ID NO: 1409) COX6C - PpLuc(GC) - A64N64
GGAGTCAGGAAGGACGTTGGTGTTGAGGTTAGCATACGTATCAAGGACAGTAACTACCAA GCTTGAGGATGGAGGACGCCAAGAACATCAAGAAGGGCCCGGCGCCCTTCTACCCGCTGG AGGACGGGACCGCCGGCGAGCAGCTCCACAAGGCCATGAAGCGGTACGCCCTGGTGCCGG GCACGATCGCCTTCACCGACGCCCACATCGAGGTCGACATCACCTACGCGGAGTACTTCG AGATGAGCGTGCGCCTGGCCGAGGCCATGAAGCGGTACGGCCTGAACACCAACCACCGGA TCGTGGTGTGCTCGGAGAACAGCCTGCAGTTCTTCATGCCGGTGCTGGGCGCCCTCTTCA TCGGCGTGGCCGTCGCCCCGGCGAACGACATCTACAACGAGCGGGAGCTGCTGAACAGCA TGGGGATCAGCCAGCCGACCGTGGTGTTCGTGAGCAAGAAGGGCCTGCAGAAGATCCTGA ACGTGCAGAAGAAGCTGCCCATCATCCAGAAGATCATCATCATGGACAGCAAGACCGACT ACCAGGGCTTCCAGTCGATGTACACGTTCGTGACCAGCCACCTCCCGCCGGGCTTCAACG AGTACGACTTCGTCCCGGAGAGCTTCGACCGGGACAAGACCATCGCCCTGATCATGAACA GCAGCGGCAGCACCGGCCTGCCGAAGGGGGTGGCCCTGCCGCACCGGACCGCCTGCGTGC GCTTCTCGCACGCCCGGGACCCCATCTTCGGCAACCAGATCATCCCGGACACCGCCATCC TGAGCGTGGTGCCGTTCCACCACGGCTTCGGCATGTTCACGACCCTGGGCTACCTCATCT GCGGCTTCCGGGTGGTCGTGATGTACCGGTTCGAGGAGGAGCTGTTCCTGCGGAGCCTGC AGGACTACAAGATCCAGAGCGCGCTGCTCGTGCCGACCCTGTTCAGCTTCTTCGCCAAGA GCACCCTGATCGACAAGTACGAGCTGTCGAACCTGCACGAGATCGCCAGCGGGGGCGCCC CGCTGAGCAAGGAGGTGGGCGAGGCCGTGGCCAAGCGGTTCCACCTCCCGGGCATCCGCC AGGGCTACGGCCTGACCGAGACCACGAGCGCGATCCTGATCACCCCCGAGGGGGACGACA AGCCGGGCGCCGTGGGCAAGGTGGTCCCGTTCTTCGAGGCCAAGGTGGTGGACCTGGACA CCGGCAAGACCCTGGGCGTGAACCAGCGGGGCGAGCTGTGCGTGCGGGGGCCGATGATCA TGAGCGGCTACGTGAACAACCCGGAGGCCACCAACGCCCTCATCGACAAGGACGGCTGGC TGCACAGCGGCGACATCGCCTACTGGGACGAGGACGAGCACTTCTTCATCGTCGACCGGC TGAAGTCGCTGATCAAGTACAAGGGCTACCAGGTGGCGCCGGCCGAGCTGGAGAGCATCC TGCTCCAGCACCCCAACATCTTCGACGCCGGCGTGGCCGGGCTGCCGGACGACGACGCCG GCGAGCTGCCGGCCGCGGTGGTGGTGCTGGAGCACGGCAAGACCATGACGGAGAAGGAGA TCGTCGACTACGTGGCCAGCCAGGTGACCACCGCCAAGAAGCTGCGGGGCGGCGTGGTGT TCGTGGACGAGGTCCCGAAGGGCCTGACCGGGAAGCTCGACGCCCGGAAGATCCGCGAGA TCCTGATCAAGGCCAAGAAGGGCGGCAAGATCGCCGTGTAAGACTAGTAGATCTAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAATG CATCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCCAAAGGCTCTTTTCAGAGCCACCAGAA TT (SEQ ID NO: 1410)
ASAH1 - PpLuc(GC) - A64N64
GGGCCTCTGCTGGAGTCCGGGGAGTGGCGTTGGCTGCTAGAGCGAAGCTTGAGGATGGAG GACGCCAAGAACATCAAGAAGGGCCCGGCGCCCTTCTACCCGCTGGAGGACGGGACCGCC GGCGAGCAGCTCCACAAGGCCATGAAGCGGTACGCCCTGGTGCCGGGCACGATCGCCTTC ACCGACGCCCACATCGAGGTCGACATCACCTACGCGGAGTACTTCGAGATGAGCGTGCGC CTGGCCGAGGCCATGAAGCGGTACGGCCTGAACACCAACCACCGGATCGTGGTGTGCTCG GAGAACAGCCTGCAGTTCTTCATGCCGGTGCTGGGCGCCCTCTTCATCGGCGTGGCCGTC GCCCCGGCGAACGACATCTACAACGAGCGGGAGCTGCTGAACAGCATGGGGATCAGCCAG CCGACCGTGGTGTTCGTGAGCAAGAAGGGCCTGCAGAAGATCCTGAACGTGCAGAAGAAG CTGCCCATCATCCAGAAGATCATCATCATGGACAGCAAGACCGACTACCAGGGCTTCCAG TCGATGTACACGTTCGTGACCAGCCACCTCCCGCCGGGCTTCAACGAGTACGACTTCGTC CCGGAGAGCTTCGACCGGGACAAGACCATCGCCCTGATCATGAACAGCAGCGGCAGCACC GGCCTGCCGAAGGGGGTGGCCCTGCCGCACCGGACCGCCTGCGTGCGCTTCTCGCACGCC CGGGACCCCATCTTCGGCAACCAGATCATCCCGGACACCGCCATCCTGAGCGTGGTGCCG TTCCACCACGGCTTCGGCATGTTCACGACCCTGGGCTACCTCATCTGCGGCTTCCGGGTG GTCCTGATGTACCGGTTCGAGGAGGAGCTGTTCCTGCGGAGCCTGCAGGACTACAAGATC CAGAGCGCGCTGCTCGTGCCGACCCTGTTCAGCTTCTTCGCCAAGAGCACCCTGATCGAC AAGTACGACCTGTCGAACCTGCACGAGATCGCCAGCGGGGGCGCCCCGCTGAGCAAGGAG GTGGGCGAGGCCGTGGCCAAGCGGTTCCACCTCCCGGGCATCCGCCAGGGCTACGGCCTG ACCGAGACCACGAGCGCGATCCTGATCACCCCCGAGGGGGACGACAAGCCGGGCGCCGTG GGCAAGGTGGTCCCGTTCTTCGAGGCCAAGGTGGTGGACCTGGACACCGGCAAGACCCTG GGCGTGAACCAGCGGGGCGAGCTGTGCGTGCGGGGGCCGATGATCATGAGCGGCTACGTG AACAACCCGGAGGCCACCAACGCCCTCATCGACAAGGACGGCTGGCTGCACAGCGGCGAC ATCGCCTACTGGGACGAGGACGAGCACTTCTTCATCGTCGACCGGCTGAAGTCGCTGATC AAGTACAAGGGCTACCAGGTGGCGCCGGCCGAGCTGGAGAGCATCCTGCTCCAGCACCCC AACATCTTCGACGCCGGCGTGGCCGGGCTGCCGGACGACGACGCCGGCGAGCTGCCGGCC GCGGTGGTGGTGCTGGAGCACGGCAAGACCATGACGGAGAAGGAGATCGTCGACTACGTG GCCAGCCAGGTGACCACCGCCAAGAAGCTGCGGGGCGGCGTGGTGTTCGTGGACGAGGTC CCGAAGGGCCTGACCGGGAAGCTCGACGCCCGGAAGATCCGCGAGATCCTGATCAAGGCC AAGAAGGGCGGCAAGATCGCCGTGTAAGACTAGTAGATCTAAAAAAAAAAAAAAAAAAAA AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAATGCATCCCCCCCCCCC CCCCCCCCCCCCCCCCCCCCAAAGGCTCTTTTCAGAGCCACCAGAATT (SEQ ID NO: 1411) 5'UTR of human ribosomal protein Large 35 (RPL35) lacking the 5' terminal oligopyrimidine tract
GGAGCGGGCGGCGGCGTTGGCGGCTTGTGCAGCA (SEQ ID NO: 1412) 5'UTR of human ribosomal protein Large 21 (RPL21) lacking the 5' terminal oli- gopyrimidine tract
GGCCGGAACCGCCATCTTCCAGTAATTCGCCAAA (SEQ ID NO: 1413)
5'UTR of human ATP synthase, H+ transporting, mitochondrial Fl complex, alpha subunit 1, cardiac muscle (ATP5A1) lacking the 5' terminal oligopyrimidine tract
GCGGCTCGGCCATTTTGTCCCAGTCAGTCCGGAGGCTGCGGCTGCAGAAGTACCGCCTGCGGAGTA ACTGCAAAG (SEQ ID NO: 1414)
5'UTR of human hydroxysteroid (17-beta) dehydrogenase 4 (HSD17B4) lacking the 5' terminal oligopyrimidine tract
GTCCCGCAGTCGGCGTCCAGCGGCTCTGCTTGTTCGTGTGTGTGTCGTTGCAGGCCTTATTC
(SEQ ID NO: 1415)
5'UTR of human androgen-induced 1 (AIG1) lacking the 5' terminal oligopyrimidine tract
GCCGCCCAGCCGGTCCAGGCCTCTGGCGAAC (SEQ ID NO: 1416)
5'UTR of human cytochrome c oxidase subunit Vic (COX6C) lacking the 5' terminal oligopyrimidine tract
AGTCAGGAAGGACGTTGGTGTTGAGGTTAGCATACGTATCAAGGACAGTAACTACC (SEQ ID NO: 1417)
5'UTR of human N-acylsphingosine amidohydrolase (acid ceramidase) 1 (ASAH1) lacking the 5' terminal oligopyrimidine tract
GCCTCTGCTGGAGTCCGGGGAGTGGCGTTGGCTGCTAGAGCG (SEQ ID NO: 1418)
5'UTR of mouse ribosomal protein Large 21 (mRPL21) lacking the 5' terminal oligopyrimidine tract
GGCCGCCGCAGCCATCTTCCAGTAACTCGCCAAA (SEQ ID NO: 1419)
5'UTR of mouse ribosomal protein large 35A (mRPL35A) lacking the 5' terminal oligopyrimidine tract
GCCATCTTGGCGCCTGTGGAGGCCTGCTGGGAACAGGACTTCTAACAGCAAGT (SEQ ID NO: 1420)
Mouse ribosomal protein Large 21 (mRPL21)
TCCTCCTTTCGGCCGCCGCAGCCATCTTCCAGTAACTCGCCAAAATGCCATCTTCCAGTAACTCGC CAAAATG (SEQ ID NO: 1421)
mouse ribosomal protein large 35A (mRPL35A)
CTTCCTCTTTCCGCCATCTTGGCGCCTGTGGAGGCCTGCTGGGAACAGGACTTCTAACAGCAAGTA TG (SEQ ID NO: 1422)

Claims

Claims
An artificial nucleic acid molecule comprising: a. at least one 5'-untranslated region element (5'UTR element) which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a TOP gene or which is derived from a variant of the 5'UTR of a TOP gene; and b. at least one open reading frame (ORF).
The artificial nucleic acid molecule according to claim 1 further comprisingc. at least one 3'UTR element which comprises or consists of a nucleic acid sequence derived from the 3'UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene, or from a variant of the 3'UTR of a chordate gene, preferably from a variant of the 3'UTR of a vertebrate gene, more preferably from a variant of the 3'UTR of a mammalian gene, most preferably from a variant of the 3'UTR of a human gene, wherein the at least one 3'UTR element preferably comprises or consists of a nucleic acid sequence which is derived from a 3'UTR of a gene providing a stable mRNA or from a variant of the 3'UTR of a gene providing a stable mRNA.
The artificial nucleic acid molecule according to claim 1 or 2, wherein the 3'UTR element comprises or consists of a nucleic acid sequence derived from a 3'UTR of a gene selected from the group consisting of an albumin gene, an a-globin gene, a β-globin gene, a tyrosine hydroxylase gene, a lipoxygenase gene, and a collagen alpha gene, or from a variant of a 3'UTR of a gene selected from the group consisting of an albumin gene, an a-globin gene, a β-globin gene, a tyrosine hydroxylase gene, a lipoxygenase gene, and a collagen alpha gene.
The artificial nucleic acid molecule according to any one of claims 1 -3, wherein the at least one 3'UTR element comprises or consist of a nucleic acid sequence which is derived from the 3'UTR of a vertebrate albumin gene or from a variant thereof, preferably from the 3'UTR of a mammalian albumin gene or from a variant thereof, more preferably from the 3'UTR of a human albumin gene or from a variant thereof, even more preferably from the 3'UTR of the human albumin gene according to GenBank Accession number NM_000477.5 or from a variant thereof.
5. The artificial nucleic acid molecule according to any one of claims 1 -4, wherein the at least one 3'UTR element exhibits a length of at least about 50 nucleotides, preferably of at least about 75 nucleotides, more preferably of at least about 100 nucleotides, even more preferably of at least about 125 nucleotides, most preferably of at least about 150 nucleotides.
6. The artificial nucleic acid molecule according to claims 1 -5, wherein the 5'UTR element and the open reading frame are heterologous and wherein the 5'UTR lacks the 5'TOP motif or the 5'UTR does not contain a functional 5'TOP motif, e.g. by insertions, deletions or substitutions of the 5'TOP motif..
7. The artificial nucleic acid molecule according to claim 1 to 6, wherein the 5'UTR element is suitable for increasing protein production from the artificial nucleic acid molecule.
8. The artificial nucleic acid molecule according to any one of claims 1 -7, wherein the 5'UTR element does not comprise a TOP-motif, preferably wherein the nucleic acid sequence which is derived from a 5'UTR of a TOP gene, preferably the 5'UTR element, starts at its 5'-end with a nucleotide located at position 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 downstream of the TOP-motif of the 5'UTR of the TOP gene.
9. The artificial nucleic acid molecule according to any one of claims 1 -8, wherein the nucleic acid sequence which is derived from a 5'UTR of a TOP gene, preferably the 5'UTR element terminates at its 3'-end with a nucleotide located at position 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 upstream of the start codon of the open reading frame of the gene or mRNA it is derived from.
10. The artificial nucleic acid molecule according to any one of claims 1 -9, wherein the nucleic acid sequence which is derived from the 5'UTR of a TOP gene is derived from the 5'UTR of a eukaryotic TOP gene or from a variant thereof, preferably from the 5'UTR of a plant or animal TOP gene or from a variant thereof, more preferably from the 5'UTR of a chordate TOP gene or from a variant thereof, even more preferably from the 5'UTR of a vertebrate TOP gene or from a variant thereof, most preferably from the 5'UTR of a mammalian TOP gene, such as a human TOP gene, or from a variant thereof.
1 1 . The artificial nucleic acid molecule according to any of claims 1 to 10, wherein the at least one 3'UTR element and the at least one 5'UTR element act at least additively, preferably synergistically to increase protein production from said artificial nucleic acid molecule.
12. The artificial nucleic acid molecule according to any one of claims 1 -1 1 , further comprising d. a poly(A) sequence and/or a polyadenylation signal.
13. The artificial nucleic acid molecule according to claim 12, wherein the polyadenylation signal is located within the 3'UTR element.
14. The artificial nucleic acid molecule according to claim 12 or 13, wherein the polyadenylation signal comprises the consensus sequence NN(U/T)ANA, with N = A or U, preferably AA(U/T)AAA or A(U/T)(U/T)AAA.
15. The artificial nucleic acid molecule according to any one of claims 12-14, wherein the polyadenylation signal, preferably the consensus sequence NNUANA, is located less than about 50 nucleotides upstream of the 3'-end of the 3'UTR.
16. The artificial nucleic acid molecule according to any one of claims 12-15, wherein the poly(A) sequence has a length of about 20 to about 300 adenine nucleotides, preferably of about 40 to about 200 adenine nucleotides, more preferably of about 50 to about 100 adenine nucleotides. The artificial nucleic acid molecule according to any one of claims 1 -16, wherein the 5'UTR element is derived from a 5'UTR of a TOP gene encoding a ribosomal Large protein (RPL) or from a variant of a 5'UTR of a TOP gene encoding a ribosomal Large protein (RPL), wherein the 5'UTR lacks the 5'TOP motif or the 5'UTR does not contain a functional 5'TOP motif, e.g. by insertions, deletions or substitutions of the 5'TOP motif.
The artificial nucleic acid molecule according to any one of claims 1 -1 7, wherein the 5'UTR element comprises or consists of a nucleic acid sequence having an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to the 5'UTR of a nucleic acid sequence according to any of SEQ ID NOs. 67, 259, 1284-1318, 1344, 1346, 1348-1354, 1357, 1358, 1421 or 1422 or to a corresponding RNA sequence, preferably lacking the 5'TOP motif, or wherein the at least one 5'UTR element comprises or consists of a fragment of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to the 5'UTR of a nucleic acid sequence according to SEQ ID No. SEQ ID NOs: 67, 259, 1284-1318, 1344, 1346, 1348-1354, 1357, and 1358, 1421 or 1422 or to a corresponding RNA sequence, preferably lacking the 5'TOP motif.
The artificial nucleic acid molecule according to any one of claims 1 -18, wherein the 5'UTR element comprises or consists of a nucleic acid sequence which is derived from the 5'UTR a ribosomal protein Large 32 gene (RPL32), a ribosomal protein Large 35 gene (RPL35), a ribosomal protein Large 21 gene (RPL21 ), an ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 , cardiac muscle (ATP5A1 ) gene, an hydroxysteroid (1 7- beta) dehydrogenase 4 gene (HSD1 7B4), an androgen-induced 1 gene (AIG1 ), cytochrome c oxidase subunit Vic gene (COX6C), or a N-acylsphingosine amidohydrolase (acid ceramidase) 1 gene (ASAH1 ) or from a variant thereof, preferably from a vertebrate ribosomal protein Large 32 gene (RPL32), a vertebrate ribosomal protein Large 35 gene (RPL35), a vertebrate ribosomal protein Large 21 gene (RPL21 ), a vertebrate ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 , cardiac muscle (ATP5A1 ) gene, a vertebrate hydroxysteroid (1 7-beta) dehydrogenase 4 gene (HSD1 7B4), a vertebrate androgen-induced 1 gene (AIG1 ), a vertebrate cytochrome c oxidase subunit Vic gene (COX6C), or a vertebrate N- acylsphingosine amidohydrolase (acid ceramidase) 1 gene (ASAH1 ) or from a variant thereof, more preferably from a mammalian ribosomal protein Large 32 gene (RPL32), a ribosomal protein Large 35 gene (RPL35), a ribosomal protein Large 21 gene (RPL21 ), a mammalian ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 , cardiac muscle (ATP5A1 ) gene, a mammalian hydroxysteroid (1 7-beta) dehydrogenase 4 gene (HSD1 7B4), a mammalian androgen-induced 1 gene (AIG1 ), a mammalian cytochrome c oxidase subunit Vic gene (COX6C), or a mammalian N- acylsphingosine amidohydrolase (acid ceramidase) 1 gene (ASAH1 ) or from a variant thereof, most preferably from a human ribosomal protein Large 32 gene (RPL32), a human ribosomal protein Large 35 gene (RPL35), a human ribosomal protein Large 21 gene (RPL21 ), a human ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 , cardiac muscle (ATP5A1 ) gene, a human hydroxysteroid (1 7-beta) dehydrogenase 4 gene (HSD1 7B4), a human androgen-induced 1 gene (AIG1 ), a human cytochrome c oxidase subunit Vic gene (COX6C), or a human N-acylsphingosine amidohydrolase (acid ceramidase) 1 gene (ASAH1 ) or from a variant thereof, wherein preferably the 5'UTR element does not comprise the 5'TOP motif of said gene.
The artificial nucleic acid molecule according to any one of claims 1 -19, wherein the 5'UTR element comprises or consists of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to the nucleic acid sequence according to SEQ ID NO. 1368 or SEQ ID NOs 1412-1420, or to a corresponding RNA sequence, or wherein the at least one 5'UTR element comprises or consists of a fragment of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to the nucleic acid sequence according to SEQ ID No. 1368 or SEQ ID NOs 1412-1420, or to a corresponding RNA sequence.
The artificial nucleic acid molecule according to any one of claims 18 or 20, , wherein the fragment consists of a continuous stretch of nucleotides corresponding to a continuous stretch of nucleotides in the full-length sequence, which represents at least 20%, preferably at least 30%, more preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, and most preferably at least 90% of the full-length sequence the fragment is derived from.
The artificial nucleic acid molecule according to any one of claims 1 -21 , wherein the at least one 5'UTR element exhibits a length of at least about 20 nucleotides, preferably of at least about 30 nucleotides, more preferably of at least about 40 nucleotides.
The artificial nucleic acid molecule according to any one of claims 1 -22, wherein the at least one 3'UTR element comprises or consists of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to a nucleic acid sequence selected from SEQ ID NOs. 1369-1393 or to a corresponding RNA sequence, or wherein the at least one 3'UTR element comprises or consists of a fragment of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to a nucleic acid sequence selected from SEQ ID NOs. 1369-1393 or to a corresponding RNA sequence.
24. The artificial nucleic acid molecule according to claim 23, wherein the fragment consists of a continuous stretch of nucleotides corresponding to a continuous stretch of nucleotides in the full-length sequence, which represents at least 20%, preferably at least 30%, more preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, and most preferably at least 90% of the full- length sequence the fragment is derived from.
25. The artificial nucleic acid molecule according to claim 23 or 24, wherein the fragment exhibits a length of at least about 50 nucleotides, preferably of at least about 75 nucleotides, more preferably of at least about 100 nucleotides, even more preferably of at least about 125 nucleotides, most preferably of at least about 150 nucleotides.
26. The artificial nucleic acid molecule according to any one of claims 1 -25, wherein the at least one 3'UTR element exhibits a length of at least about 50 nucleotides, preferably of at least about 75 nucleotides, more preferably of at least about 100 nucleotides, even more preferably of at least about 125 nucleotides, most preferably of at least about 150 nucleotides.
27. The artificial nucleic acid molecule according to any one of claims 1 -26, wherein the open reading frame does not code for a reporter protein, such as a GFP protein, a luciferase protein, a globin protein, human growth hormon, or human albumin, preferably not for albumin.
28. The artificial nucleic acid molecule according to any one of claims 1 -27, further comprising a 5'-cap structure, a poly(C) sequence and/or an IRES-motif.
29. The artificial nucleic acid molecule according to any one of claims 1 -28, further comprising a promoter containing-sequence. The artificial nucleic acid molecule according to any one of claims 1 -29, wherein the artificial nucleic acid molecule, preferably the open reading frame, is at least partially G/C modified, preferably wherein the G/C content of the open reading frame is increased compared to the wild type open reading frame.
The artificial nucleic acid molecule according to any one of claims 1 -30, wherein the open reading frame comprises a codon-optimized region, preferably, wherein the open reading frame is codon-optimized.
The artificial nucleic acid molecule according to any one of claims 1 -31 , which is an RNA, preferably an mRNA molecule.
A vector comprising: a. at least one 5'-untranslated region element (5'UTR element) which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a TOP gene or which is derived from a variant of the 5'UTR of a TOP gene; and b. at least one open reading frame (ORF) and/or at least one cloning site. The vector according to claim 33 further comprising c. at least one 3'UTR element which comprises or consists of a nucleic acid sequence derived from the 3'UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene, or from a variant of the 3'UTR of a chordate gene, preferably from a variant of the 3'UTR of a vertebrate gene, more preferably from a variant of the 3'UTR of a mammalian gene, most preferably from a variant of the 3'UTR of a human gene, wherein the at least one 3'UTR element preferably comprises or consists of a nucleic acid sequence which is derived from a 3'UTR of a gene providing a stable mRNA or from a variant of the 3'UTR of a gene providing a stable mRNA.
The vector according to any one of claims 33 or 34, wherein the 3'UTR element comprises or consists of a nucleic acid sequence derived from a 3'UTR of a gene selected from the group consisting of an albumin gene, an a-globin gene, a β- globin gene, a tyrosine hydroxylase gene, a lipoxygenase gene, and a collagen alpha gene, or from a variant of a 3'UTR of a gene selected from the group consisting of an albumin gene, an a-globin gene, a β-globin gene, a tyrosine hydroxylase gene, a lipoxygenase gene, and a collagen alpha gene.
36. The vector according to any one of claims 33-35, wherein the at least one 3'UTR element comprises or consist of a nucleic acid sequence which is derived from the 3'UTR of a vertebrate albumin gene or from a variant thereof, preferably from the 3'UTR of a mammalian albumin gene or from a variant thereof, more preferably from the 3'UTR of a human albumin gene or from a variant thereof, even more preferably from the 3'UTR of the human albumin gene according to GenBank Accession number NM_000477.5 or from a variant thereof.
37. The vector according to any of claims 33 to 36, wherein the 5'UTR element and the open reading frame are heterologous.
38. The vector according to any of claims 33 to 37, wherein the 5'UTR element is suitable for increasing protein production from the vector.
39. The vector according to any one of claims 33 to 38, wherein the 5'UTR element does not comprise a TOP-motif, preferably wherein the nucleic acid sequence which is derived from a 5'UTR of a TOP gene, preferably the 5'UTR element, starts at its 5'-end with a nucleotide located at position 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 downstream of the TOP-motif of the 5'UTR of the TOP gene.
40. The vector according to any one of claims 33-39, wherein the nucleic acid sequence which is derived from a 5'UTR of a TOP gene, preferably the 5'UTR element terminates at its 3'-end with a nucleotide located at position 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 upstream of the start codon of the open reading frame of the gene or mRNA it is derived from.
41 . The vector according to any one of claims 33-40, wherein the nucleic acid sequence which is derived from the 5'UTR of a TOP gene is derived from a eukaryotic TOP gene, preferably a plant or animal TOP gene, more preferably a chordate TOP gene, even more preferably a vertebrate TOP gene, most preferably a mammalian TOP gene, such as a human TOP gene.
42. The vector according to any of claims 34 to 41 , wherein the at least one 3'UTR element and the at least one 5'UTR element act at least additively, preferably synergistically to increase protein production from said artificial nucleic acid molecule.
43. The vector according to any one of claims 33-42, further comprising d. a poly(A) sequence and/or a polyadenylation signal.
44. The vector according to claim 43, wherein the polyadenylation signal is located within the 3'UTR element.
45. The vector according to claim 43 or 44, wherein the polyadenylation signal comprises the consensus sequence NN(U T)ANA, with N = A or U, preferably AA(U/T)AAA or A(UAT)(U/T)AAA.
46. The vector according to any one of claims 43-45, wherein the polyadenylation signal, preferably the consensus sequence NNUANA, is located less than about 50 nucleotides upstream of the 3'-end of the 3'UTR.
47. The vector according to any one of claims 43-46, wherein the poly(A) sequence has a length of about 20 to about 300 adenine nucleotides, preferably of about 40 to about 200 adenine nucleotides, more preferably of about 50 to about 100 adenine nucleotides.
48. The vector according to any one of claims 33-47, wherein the 5'UTR element comprises or consists of a nucleic acid sequence which is derived from a 5'UTR of a TOP gene encoding a ribosomal protein or from a variant of a 5'UTR of a TOP gene encoding a ribosomal protein, preferably from a 5'UTR of a ribosomal protein selected from RPSA, RPS2, RPS3, RPS3A, RPS4, RPS5, RPS6, RPS7, RPS8, RPS9, RPS10, RPS1 1 , RPS12, RPS1 3, RPS14, RPS1 5, RPS1 5 A, RPS1 6, RPS1 7, RPS18, RPS1 9, RPS20, RPS21 , RPS23, RPS24, RPS25, RPS26, RPS27, RPS27A, RPS28, RPS29, RPS30, RPL3, RPL4, RPL5, RPL6, RPL7, RPL7A, RPL8, RPL9, RPL10, RPL10A, RPL1 1 , RPL12, RPL1 3, RPL1 3A, RPL14, RPL1 5, RPL1 7, RPL1 8, RPL1 8A, RPL19, RPL21 , RPL22, RPL23, RPL23A, RPL24, RPL26, RPL27, RPL27A, RPL28, RPL29, RPL30, RPL31 , RPL32, RPL34, RPL35, RPL35A, RPL36, RPL36A, RPL37, RPL37A, RPL38, RPL39, RPL40, RPL41 , RPLPO, RPLP1 , RPLP2, RPLP3, UBA52 ,more preferably from a 5'UTR of a nucleic acid sequence according to any of SEQ ID NOs: 67, 1 70, 193, 244, 259, 554, 650, 675, 700, 721 , 913, 101 6, 1063, 1 120, 1 138, and 1284-1360, a corresponding RNA sequence, a homolog thereof, or a variant thereof as described herein, preferably lacking the 5'TOP motif.
The vector according to any one of claims 33-48, wherein the 5'UTR element comprises or consists of a nucleic acid sequence which is derived from the 5'UTR a ribosomal protein Large 32 gene (RPL32), a ribosomal protein Large 35 gene (RPL35), a ribosomal protein Large 21 gene (RPL21 ), an ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 , cardiac muscle (ATP5A1 ) gene, an hydroxysteroid (1 7-beta) dehydrogenase 4 gene (HSD1 7B4), an androgen-induced 1 gene (AIG1 ), cytochrome c oxidase subunit Vic gene (COX6C), or a N-acylsphingosine amidohydrolase (acid ceramidase) 1 gene (ASAH1 ) or from a variant thereof, preferably from a vertebrate ribosomal protein Large 32 gene (RPL32), a ribosomal protein Large 35 gene (RPL35), a ribosomal protein Large 21 gene (RPL21 ), an ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 , cardiac muscle (ATP5A1 ) gene, an hydroxysteroid (1 7-beta) dehydrogenase 4 gene (HSD1 7B4), an androgen- induced 1 gene (AIG1 ), cytochrome c oxidase subunit Vic gene (COX6C), or a N-acylsphingosine amidohydrolase (acid ceramidase) 1 gene (ASAH1 ) or from a variant thereof, more preferably from a mammalian ribosomal protein Large 32 gene (RPL32), a ribosomal protein Large 35 gene (RPL35), a ribosomal protein Large 21 gene (RPL21 ), an ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 , cardiac muscle (ATP5A1 ) gene, an hydroxysteroid (1 7-beta) dehydrogenase 4 gene (HSD1 7B4), an androgen-induced 1 gene (AIG1 ), cytochrome c oxidase subunit Vic gene (COX6C), or a N- acylsphingosine amidohydrolase (acid ceramidase) 1 gene (ASAH1 ) or from a variant thereof, most preferably from a human ribosomal protein Large 32 gene (RPL32), a ribosomal protein Large 35 gene (RPL35), a ribosomal protein Large 21 gene (RPL21 ), an ATP synthase, H+ transporting, mitochondrial F1 complex, alpha subunit 1 , cardiac muscle (ATP5A1 ) gene, an hydroxysteroid (1 7- beta) dehydrogenase 4 gene (HSD1 7B4), an androgen-induced 1 gene (AIG1 ), cytochrome c oxidase subunit Vic gene (COX6C), or a N-acylsphingosine amidohydrolase (acid ceramidase) 1 gene (ASAH1 ) or from a variant thereof, wherein preferably the 5'UTR element does not comprise the 5'TOP of said gene.
50. The vector according to any one of claims 33-49, wherein the 5'UTR element comprises or consists of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to the nucleic acid sequence according to SEQ ID No. 1368 or SEQ ID NOs 1412-1420, or to a corresponding R A sequence, or wherein the at least one 5'UTR element comprises or consists of a fragment of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to the nucleic acid sequence according to SEQ ID No. 1368 or SEQ ID NOs 1412-1420, or to a corresponding RNA sequence.
51 . The vector according to claim 50, wherein the fragment consists of a continuous stretch of nucleotides corresponding to a continuous stretch of nucleotides in the full-length sequence, which represents at least 20%, preferably at least 30%, more preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, and most preferably at least 90% of the full-length sequence the fragment is derived from.
The vector according to any one of claims 33-51 , wherein the at least one 5'UTR element exhibits a length of at least about 20 nucleotides, preferably of at least about 30 nucleotides, more preferably of at least about 40 nucleotides.
The vector according to any one of claims 34-52, wherein the at least one 3'UTR element comprises or consists of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to a nucleic acid sequence selected from SEQ ID NOs. 1369-1393 or to a corresponding RNA sequence, or wherein the at least one 3'UTR element comprises or consists of a fragment of a nucleic acid sequence which has an identity of at least about 40%, preferably of at least about 50%, preferably of at least about 60%, preferably of at least about 70%, more preferably of at least about 80%, more preferably of at least about 90%, even more preferably of at least about 95%, even more preferably of at least about 99% to a nucleic acid sequence selected from SEQ ID NOs. 1369-1393 or to a corresponding RNA sequence.
The vector according to claim 53, wherein the fragment consists of a continuous stretch of nucleotides corresponding to a continuous stretch of nucleotides in the full-length sequence, which represents at least 20%, preferably at least 30%, more preferably at least 40%, more preferably at least 50%, even more preferably at least 60%, even more preferably at least 70%, even more preferably at least 80%, and most preferably at least 90% of the full-length sequence the fragment is derived from.
The vector according to claim 53 or 54, wherein the fragment exhibits a length of at least about 40 nucleotides, preferably of at least about 50 nucleotides, preferably of at least about 75 nucleotides, more preferably of at least about 100 nucleotides, even more preferably of at least about 125 nucleotides, most preferably of at least about 150 nucleotides.
56. The vector according to any one of claims 34-55, wherein the at least one 3'UTR element exhibits a length of at least about 40 nucleotides, preferably of at least about 50 nucleotides, preferably of at least about 75 nucleotides, more preferably of at least about 100 nucleotides, even more preferably of at least about 125 nucleotides, most preferably of at least about 150 nucleotides.
57. The vector according to any one of claims 33-56, wherein the open reading frame does not code for a reporter protein, such as a GFP protein, a luciferase protein, a globin protein, human growth factor or human albumin, preferably not for albumin.
58. The vector according to any one of claims 33-57, further comprising a 5'-cap structure, a poly(C) sequence and/or an IRES-motif.
59. The vector according to any one of claims 33-58, further comprising a promoter containing-sequence.
60. The vector according to any one of claims 33-59, wherein the vector, preferably the open reading frame, is at least partially G/C modified, preferably wherein the G/C content of the open reading frame is increased compared to the wild type open reading frame.
61 . The vector according to any one of claims 33-60, wherein the open reading frame comprises a codon-optimized region, preferably, wherein the open reading frame is codon-optimized.
62. The vector according to any one of claims 33-61 , which is an RNA vector.
63. The vector according to any one of claims 33-62, which is a DNA vector.
64. The vector according to any one of claims 33-63, which is a plasmid vector or a viral vector, preferably a plasmid vector.
65. The vector according to any one of claims 33-64, which comprises or codes for an artificial nucleic acid molecule according to any one of claims 1 -39.
66. The vector according to any one of claims 33-65, which is a circular molecule.
67. The vector according to claim 66, wherein the O F, the poly(A) sequence or the 3'UTR element of the coding strand is followed in 5'- 3' direction by a restriction site for linearization of the circular vector molecule.
68. A cell comprising the artificial nucleic acid molecule according to any one of claims 1 -32 or the vector according to any one of claims 33-67.
69. The cell according to claim 68, which is a mammalian cell.
70. The cell according to claim 68 or 69, which is a cell of a mammalian subject, preferably an isolated cell of a mammalian subject, preferably of a human subject.
71 . A pharmaceutical composition comprising the artificial nucleic acid molecule according to any one of claims 1 -32, the vector according to any one of claims 33-67, or the cell according to any one of claims 68-70.
72. The pharmaceutical composition according to claim 71 , further comprising one or more pharmaceutically acceptable diluents and/or excipients and/or one or more adjuvants.
73. The artificial nucleic acid molecule according to any one of claims 1 -32, the vector according to any one of claims 33-67, the cell according to any one of claims 68-70, or the pharmaceutical composition according to claim 71 or 72 for use as a medicament.
74. The artificial nucleic acid molecule according to any one of claims 1 -32, the vector according to any one of claims 33-67, the cell according to any one of claims 68-70, or the pharmaceutical composition according to claim 71 or 72 for use as a vaccine or for use in gene therapy.
75. A method for treating or preventing a disorder comprising administering the artificial nucleic acid molecule according to any one of claims 1 -32, the vector according to any one of claims 33-67, the cell according to any one of claims 68-70, or the pharmaceutical composition according to claim 71 or 72 to a subject in need thereof.
76. A method of treating or preventing a disorder comprising transfection of a cell with the artificial nucleic acid molecule according to any one of claims 1 -32 or the vector according to any one of claims 33-67.
77. The method according to claim 76, wherein transfection of a cell is performed in vitro/ex vivo and the transfected cell is administered to a subject in need thereof, preferably to a human patient.
78. The method according to claim 77, wherein the cell which is to be transfected in vitro '\s an isolated cell of the subject, preferably of the human patient.
79. The method according to any one of claims 75-78, which is a vaccination method or a gene therapy method.
80. A method for increasing protein production from an artificial nucleic acid molecule, comprising the step of providing the artificial nucleic acid molecule with: i. at least one 5 '-untranslated region element (5'UTR element) which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a TOP gene or which is derived from a variant of the 5'UTR of a TOP gene.
81 . The method according to claim 80, wherein the 5'UTR element does not comprise a TOP-motif, preferably wherein the nucleic acid sequence which is derived from a 5'UTR of a TOP gene, preferably the 5'UTR element, starts at its 5'-end with a nucleotide located at position 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 downstream of the TOP-motif of the 5'UTR of the TOP gene.
82. The method according to claim 80 or 81 , wherein the 5'UTR lacks the 5'TOP motif or the 5'UTR does not contain a functional 5'TOP motif, e.g. by insertions, deletions or substitutions of the 5'TOP motif.
83. The method according to any of claims 80 to 82, further comprising providing the artificial nucleic acid molecule with: ii. at least one 3'UTR element which comprises or consists of a nucleic acid sequence derived from the 3'UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene, or from a variant of the 3'UTR of a chordate gene, preferably from a variant of the 3'UTR of a vertebrate gene, more preferably from a variant of the 3'UTR of a mammalian gene, most preferably from a variant of the 3'UTR of a human gene. 84. Use of a 5'UTR element which comprises or consists of a nucleic acid sequence which is derived from the 5'UTR of a TOP gene or which is derived from a variant of the 5'UTR of a TOP gene for increasing protein production from a nucleic acid molecule.
85. Use according to claim 84, wherein the 5'UTR element does not comprise a TOP-motif, preferably wherein the nucleic acid sequence which is derived from a 5'UTR of a TOP gene, preferably the 5'UTR element, starts at its 5'-end with a nucleotide located at position 1 , 2, 3, 4, 5, 6, 7, 8, 9 or 10 downstream of the TOP-motif of the 5'UTR of the TOP gene.
86. The use according to claim 84 or 85, wherein the 5'UTR lacks the 5'TOP motif or the 5'UTR does not contain a functional 5'TOP motif, e.g. by insertions, deletions or substitutions of the 5'TOP motif.
87. Use according to any of claims 84 to 86, wherein the 5'UTR element is used in combination with a 3'UTR element which comprises or consists of a nucleic acid sequence derived from the 3'UTR of a chordate gene, preferably a vertebrate gene, more preferably a mammalian gene, most preferably a human gene, or from a variant of the 3'UTR of a chordate gene, preferably from a variant of the 3'UTR of a vertebrate gene, more preferably from a variant of the 3'UTR of a mammalian gene, most preferably from a variant of the 3'UTR of a human gene. 88. A kit or kit of parts comprising an artificial nucleic acid molecule according to any one of claims 1 -32, the vector according to any one of claims 34-67, or the cell according to any one of claims 68-70, and/or the pharmaceutical composition according to claim 71 or 72.
The kit according to claim 88, further comprising instructions for use, cells for transfection, an adjuvant, a means for administration of the pharmaceutical composition, a pharmaceutically acceptable carrier and/or a pharmaceutically acceptable solution for dissolution or dilution of the artificial nucleic acid molecule, the vector or the pharmaceutical composition.
PCT/EP2013/000938 2012-03-27 2013-03-27 Artificial nucleic acid molecules comprising a 5'top utr WO2013143700A2 (en)

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ES13713359.1T ES2660129T3 (en) 2012-03-27 2013-03-27 Artificial nucleic acid molecules comprising a 5'UTR-TOP
US14/388,224 US10080809B2 (en) 2012-03-27 2013-03-27 Artificial nucleic acid molecules comprising a 5′TOP UTR
RU2014142881A RU2660565C2 (en) 2012-03-27 2013-03-27 Artificial nucleic acid molecules comprising 5'top utr
JP2015502143A JP6301906B2 (en) 2012-03-27 2013-03-27 Artificial nucleic acid molecule containing 5 'TOPUTR
KR1020147030143A KR20140139101A (en) 2012-03-27 2013-03-27 Artificial nucleic acid molecules comprising a 5'top utr
BR112014023898A BR112014023898A2 (en) 2012-03-27 2013-03-27 artificial nucleic acid molecules comprising 5''utr top
CN201380016968.7A CN104321432B (en) 2012-03-27 2013-03-27 Include the artificial nucleic acid molecule of 5 ' TOP UTR
SG11201405545XA SG11201405545XA (en) 2012-03-27 2013-03-27 Artificial nucleic acid molecules comprising a 5'top utr
MX2014011625A MX358706B (en) 2012-03-27 2013-03-27 Artificial nucleic acid molecules comprising a 5'top utr.
EP13713359.1A EP2831240B1 (en) 2012-03-27 2013-03-27 Artificial nucleic acid molecules comprising a 5'top utr
CA2866945A CA2866945C (en) 2012-03-27 2013-03-27 Artificial nucleic acid molecules comprising a 5'top utr
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BR112014023898A2 (en) 2017-07-11
AU2013242405A1 (en) 2014-09-25
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