WO2008052770A2 - (base-)modified rna for increasing the expression of a protein - Google Patents
(base-)modified rna for increasing the expression of a protein Download PDFInfo
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- WO2008052770A2 WO2008052770A2 PCT/EP2007/009469 EP2007009469W WO2008052770A2 WO 2008052770 A2 WO2008052770 A2 WO 2008052770A2 EP 2007009469 W EP2007009469 W EP 2007009469W WO 2008052770 A2 WO2008052770 A2 WO 2008052770A2
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- base
- triphosphate
- rna
- modified
- syndrome
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Definitions
- the present application describes a base-modified RNA and the use thereof for increasing the expression of a protein and for the preparation of a pharmaceutical composition, especially a vaccine, for the treatment of tumours and cancer diseases, heart and circulatory diseases, infectious diseases, autoimmune diseases or monogenetic diseases, for example in gene therapy.
- the present invention further describes an in vitro transcription method, in vitro methods for increasing the expression of a protein using the base-modified RNA, and an ex vivo and in vivo method.
- tumours and cancer diseases Apart from heart and circulatory diseases and infectious diseases, the occurrence of rumours and cancer diseases is one of the most frequent causes of death in modern society and in most cases is associated with considerable costs in terms of therapy and subsequent rehabilitation measures.
- the treatment of tumours and cancer diseases is greatly dependent, for example, on the type of tumour that occurs and is nowadays .conventionally carried out by the use of radiation therapy or chemotherapy in addition to invasive operations.
- therapies place extraordinary stress on the immune system and in some cases can be used to only a limited extent.
- most of these forms of therapy require long intervals between the individual treatments in order for the immune system to regenerate.
- inventional measures in particular gene therapeutic approaches or genetic vaccination have been found to be highly promising for treatment or for supporting such therapies.
- monogenetic diseases are also to the fore, that is to say (inherited) diseases that are caused by a single gene defect and are inherited according to Mendel's laws.
- monogenetic diseases include inter alia mucoviscidosis (cystic fibrosis) and sickle cell anaemia.
- Gene therapy and genetic vaccination are molecular medical methods whose use generally in the therapy and prevention of diseases has considerable effects on medical practice. Both methods are based on the introduction of nucleic acids into the patient's cells or tissue and the subsequent processing by the cells or tissue of the information coded for by the nucleic acids that have been introduced, that is to say the expression of the desired polypeptides.
- the conventional procedure in current methods of gene therapy and genetic vaccination is the use of DNA for inserting the required genetic information into the cell.
- Various methods have been developed in this connection for introducing DNA into cells, such as, for example, calcium phosphate transfection, polyprene transfection, protoplast fusion, electroporation, microinjection and lipofection, lipofection in particular having been found to be a suitable method.
- a further method that has been proposed in particular in genetic vaccination methods is the use of DNA viruses as DNA vehicles.
- DNA viruses have the advantage that a very high rate of transfection is to be achieved owing to their infectious properties.
- the viruses that are used are genetically altered so that no functional infectious particles are formed in the transfected cell.
- a certain risk of the uncontrolled propagation of the gene-therapeutically active and viral genes that have been introduced cannot be ruled out owing to possible recombination events.
- the DNA introduced into the cell is usually integrated to a certain extent into the genome of the transfected cell.
- this phenomenon can exert a desired effect, because a long-lasting action of the DNA that has been introduced can be achieved thereby.
- integration into the genome brings a substantial risk for gene therapy.
- the introduced DNA will be inserted into an intact gene, which in turn represents a mutation which impedes or even totally eliminates the function of the endogenous gene.
- vital enzyme systems for the cell can be eliminated on the one hand, and on the other hand there is also the risk of transformation of the cell so altered into a degenerate state, if a gene critical for the regulation of cell growth is changed by integration of the foreign DNA.
- the corresponding DNA vehicles contain a strong promoter, for example the viral CMV promoter.
- the integration of such promoters into the genome of the treated cell can lead to undesirable changes in the regulation of gene expression in the cell.
- a further disadvantage of the use of DNA as gene therapeutic agents and as vaccines is the induction of undesired anti-DNA antibodies in the patient, triggering a possible fatal immune response.
- RNA In contrast to DNA, the use of RNA as a gene therapeutic agent or as a vaccine is to be categorised as substantially safer. In particular, RNA does not involve the risk of being stably integrated into the genome of the transfected cell. Furthermore, no viral sequences, such as promoters, are required for effective transcription. Moreover, RNA is degraded substantially more simply in vivo. No anti-RNA antibodies have hitherto been detected, presumably because of the relatively short half-life of RNA in the blood circulation as compared with DNA. RNA can therefore be regarded as the molecule of choice for molecular medical methods of therapy.
- expression systems based on the introduction of nucleic acids into the patient's cells or tissue and the subsequent expression of the desired polypeptides coded for thereby in many cases do not exhibit the desired, or even the required, level of expression in order to enable an effective therapy to be carried out, irrespective of whether DNA or RNA is used.
- DE 101 19 005 (Roche Diagnostics GmbH), for example, describes methods of protein expression based on DNA molecules, wherein an improvement in the stability of the linear short DNA is achieved by various measures and consequently improved expression takes place owing to reduced degradation by exonucl eases. Accordingly, DE 101 19 005 describes the incorporation of exonuclease-resistant nucleotide analogues or other molecules at the 3' end of the linear short DNA. In addition, DE 101 19 005 also describes the binding of large molecules to the ends of the linear short DNA, such as, for example, biotin, avidin or streptavidin.
- DE 101 19 005 exonucleases can also be inactivated or inhibited by the addition of competitive or non-competitive inhibitors.
- DE 101 19 005 describes an increase in the expression of the protein only by improving the stability of the linear short DNA that is used.
- DE 101 19 005 does not show any modifications for RNA, however.
- EP-A- 1083232 proposes, for example, for solving the problem of the instability of RNA ex vivo, a method for introducing RNA, especially mRNA, into cells and organisms, in which the RNA is present in the form of a complex with a cationic peptide or protein.
- WO 99/14346 describes methods for stabilising mRNA, especially modifications of the mRNA, which stabilise the mRNA species against degradation by RNases. Such modifications relate on the one hand to stabilisation by sequence modifications, in particular the reduction of the C and/or U content by base elimination or base substitution.
- chemical modifications are proposed, such as, for example, the use of mucleotide analogues, as well as 5'- and 3'-blocking groups, an increased length of the poly-A tail and the complexing of the mRNA with stabilising agents, and combinations of the mentioned measures, but without achieving an increase in the expression of the proteins coded for by the mRNAs.
- Optimised mRNAs are also described in application WO 02/098443 (CureVac GmbH).
- WO 02/098443 describes mRNAs that are stabilised in general form and optimised for translation in their coding regions and discloses, for example, a method for determining sequence modifications.
- WO 02/098443 further describes possibilities for substitution of adenosine and uracil nucleotides in mRNA sequences in order to increase the G/C content of the sequences. According to WO 02/098443, such substitutions and adaptations for increasing the G/C content can be used in gene therapeutic applications and also as genetic vaccines for the treatment of cancer.
- WO 02/098443 generally mentions sequences in which the modified mRNA codes for at least one biologically active peptide or polypeptide which is formed in the patient to be treated, for example, either not at all or inadequately or with faults.
- WO 02/098443 proposes mRNAs coding for a cancer antigen as the base sequence for such modifications.
- modifications have to be introduced into gene sequences first by complex and in most cases expensive processes, for example by means of replacement of nucleotides in nucleotide sequences by means of nucleic acid syntheses using DNA/RNA synthesis devices, etc. This generally increases the costs both for studying the stability and expression of modified gene sequences and for the in vitro and in vivo use thereof for the expression of the proteins coded for thereby.
- the prior art does not exhibit a targeted method or uses which deliberately increase the expression of proteins starting from RNA template molecules in vitro or in vivo with a sensible cost/benefit ratio and at the same time maximum variability of the reaction.
- the object underlying the present invention is, therefore, to provide a method and uses for gene therapy and genetic vaccination which avoid the disadvantages of the use of DNA as a gene therapeutic agent or vaccine and nevertheless, on the basis of mRNA, achieve increased protein expression in the target cell system.
- a base-modified RNA sequence for increasing the expression of a protein the base-modified RNA sequence containing at least one base modification and coding for a protein. While the present invention relates to the use of the base-modified RNA for increasing the expression level of the encoded protein/peptide, the base-modified RNA as such (containing the (preferred) features disclosed herein alone or in any combination) is also subject-matter of the present invention.
- a base-modified RNA used according to the invention comprises any RNA that codes for at least one protein/peptide.
- the base-modified RNA used according to the invention can be single-stranded or double-stranded, linear or circular or can be in the form of mRNA.
- the base-modified RNA used according to the invention is particularly preferably in the form of single-stranded RNA, more preferably in the form of mRNA.
- a base-modified RNA used according to the invention preferably has a length of from 50 to 15,000 nucleotides, more preferably a length of from 50 to 10,000 nucleotides, yet more preferably a length of from 500 to 10,000 nucleotides and most preferably a length of from 500 to 5000 nucleotides.
- the inventive base- modified RNA codes for at least one protein/peptide sequence.
- a coding RNA is typically an mRNA, which is composed of several structural elements, e.g. an optional 5'- UTR region, an upstream positioned ribosomal binding site followed by a coding region, an optional 3'-UTR region, which may be followed by a poly-A tail (and/or a poly-C-tail).
- Significant in this case means an increase in the expression of the protein compared with the expression of the native RNA sequence by at least 20%, preferably at least 30%, 40%, 50% or 60%, more preferably by at least 70%, 80%, 90% or even 100% and most preferably by at least 150%, 200% or even 300%.
- a nucleotide having a base modification of the base-modified RNA used according to the invention is preferably selected from the group of the base-modified nucleotides consisting of:
- 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.
- the inventors attribute an increase in the expression of the protein coded for by the base-modified RNA inter alia to the improvement in the stabilisation of secondary structures and optionally to the resulting "more rigid" structure of the RNA and the increased "base stacking".
- pseudouridine-5 '- triphosphate is known to occur naturally in structural RNAs (tRNA, rRNA and snRNA) in both eukaryotes and prokaryotes.
- pseudouridine is necessary in rRNA for stabilising secondary structures
- the amount of pseudouridine in the RNA has increased and it has been possible to show, surprisingly, that translation is dependent on the presence of pseudouridine in the tRNA and rRNA, the interaction betweeen tRNA and mRNA presumably being increased thereby.
- the conversion of uridine to pseudouridine takes place posttranscriptionally by pseudouridine synthase.
- a posttranscriptional modification of RNA also takes place, which is catalysed by methyltransferases.
- a further increase in the amount of pseudouridine and the base modification of other nucleotides presumably leads to similar effects, which, unlike the naturally occurring increased amounts of pseudouridine in the sequence, can be carried out in a targeted manner and with substantially greater variability.
- a similar mechanism as for pseudouridine-5 '-triphosphate is therefore assumed for 5- methylcytidine-5 '-triphosphate and the other base modifications mentioned herein, that is to say an improved stabilisation of secondary structures and, based thereon, an improved translation efficiency.
- a positive effect on translation is also supposed independently of the stabilisation of secondary structures and a "more rigid" structure of the RNA. Further causes of increased expression are optionally also the lower rate of degradation of the mRNA sequences by RNAses in vitro or in vivo.
- the base modification(s) of the RNA used according to the invention can be introduced into the RNA by means of methods known to a person skilled in the art. Suitable methods are, for example, synthesis methods using (automatic or semi-automatic) oligonucleotide synthesis devices, biochemical methods, such as, for example, in vitro transcription methods, etc. In this connection there can preferably be used in the case of (relatively short) sequences, whose length generally does not exceed from 50 to 100 nucleotides, synthesis methods using (automatic or semi-automatic) oligonucleotide synthesis devices as well as in vitro transcription methods.
- biochemical methods are preferably suitable, such as, for example, in vitro transcription methods, preferably an in vitro transcription method according to the invention as described hereinbelow.
- in vitro transcription methods preferably an in vitro transcription method according to the invention as described hereinbelow.
- even longer base-modified RNA molecules may be synthesized synthetically by coupling various synthesized fragments covalently.
- Base modifications of base-modified RNA sequences used according to the invention typically occur on at least one (base-modifiable) nucleotide of the base-modified RNA sequence, preferably on at least 2, 3, 4, 5, 6, 7, 8, 9 or 10 (base-modifiable) nucleotides, more preferably on at least 10 to 20 (base-modifiable) nucleotides, yet more preferably on at least 10 to 100 (base-modifiable) nucleotides and most preferably on at least 10 to 200 or more (base-modifiable) nucleotides.
- base modifications in a base-modified RNA sequence used according to the invention typically occur on at least one (base-modifiable) nucleotide of the base-modified RNA sequence, preferably on at least 10% of all (base- modifiable) nucleotides, more preferably on at least 25% of all (base-modifiable) nucleotides, yet more preferably on at least 50% of all (base-modifiable) nucleotides, even more preferably on at least 75% of all (base-modifiable) nucleotides and most preferably on 100% of the (base-modifiable) nucleotides contained in the base-modified RNA sequence used according to the invention.
- the above preferred percentage values may also hold for the coding region(s) of the base-modified RNA, that is e.g. preferably 10%, more preferably 25%, more preferably at least 50%, more preferably at least 75% and etc. of the nucleotides of the coding region of the base-modified RNA may be substituted.
- a “base-modifiable nucleotide” in this connection is any (preferably naturally occurring (natural, native) and hence unmodified) nucleotide that is to be replaced by a base-modified nucleotide as described above. It is thereby possible for all the nucleotides of the RNA sequence to be base-modified, or only specific chosen nucleotides of the RNA sequence. If all the nucleotides of the RNA sequence are to be base-modified, then 100% of the "base- modifiable nucleotides" of the RNA sequence are all the nucleotides of the RNA sequence used.
- the chosen nucleotides are, for example, adenosine, cytidine, guanosine or uridine.
- an adenosine of the native sequence can be replaced by a base- modified adenosine
- a cytidine can be replaced by a base-modified cytidine
- a uridine by a base-modified uridine
- a guanosine by a base-modified guanosine.
- 100% of the "base-modifiable nucleotides" of the RNA sequence are 100% of the adenosines, cytidines, guanosines or uridines contained in the RNA sequence used.
- Preferred embodiments of the base-modified RNA of the present invention may e.g. contain at least 10% of all RNA cytidine-5'-triphosphate nucleotides (or all cytidine-5 '-triphosphate nucleotides of the coding region) modified to base-modified cytidine nucleotides, e.g.
- RNA cytidine-5'-triphosphate nucleotides or all cytidine-5 '-triphosphate nucleotides of the coding region modified to base-modified cytidine nucleotides, e.g. 5- methylcytidine-5 '-triphosphate and/or 5-bromocytidine-5'-triphosphate nucleotides, and/or at least 25% of all guanosine-5 '-triphosphate nucleotides (or all guanosine-5 '-triphosphate nucleotides of the coding region) modified to base-modified guanosine nucleotides, e.g.
- RNA cytidine-5'-triphosphate nucleotides or all cytidine-5 '-triphosphate nucleotides of the coding region modified to base-modified cytidine nucleotides, e.g. 5- methylcytidine-5 '-triphosphate and/or 5-bromocytidine-5'-triphosphate nucleotides, and/or at least 50% of all guanosine-5'-triphosphate nucleotides (or all guanosine-5 '-triphosphate nucleotides of the coding region) modified to base-modified guanosine nucleotides, e.g.
- RNA cytidine-5'-triphosphate nucleotides or all cytidine-5 '-triphosphate nucleotides of the coding region modified to base-modified cytidine nucleotides, e.g. 5- methylcytidine-5'-triphosphate and/or 5-bromocytidine-5'-triphosphate nucleotides, and/or at least 75% of all guanosine-5 '-triphosphate nucleotides (or all guanosine-5'-triphosphate nucleotides of the coding region) modified to base-modified guanosine nucleotides, e.g.
- uridine nucleotides are substituted by base-modified uridine nucleotides, e.g. pseudouridine-5 '-triphosphate nucleotides or combinations of pseudouridine- 5 '-triphosphate nucleotides with at least one other type of base-modified uridine nucleotides, or that e.g. at least 75%, 85%, 90%, 95% of all cytidine nucleotides are substituted by base- modified cytidine nucleotides, e.g.
- guanosine nucleotides are substituted by base-modified guanosine nucleotides, e.g. 7- deazaguanosine-5 '-triphosphate nucleotides or combinations of deazaguanosine-5'- triphosphate nucleotides with at least one other type of base-modified guanosine nucleotides.
- Base-modified RNA sequences used according to the invention can further also contain backbone modifications.
- a backbone modification in connection with the present invention is a modification in which phosphates of the backbone of the nucleotides contained in the RNA are chemically modified.
- Such backbone modifications typically include, without implying any limitation, modifications from the group consisting of methylphosphonates, phosphoramidates and phosphorothioates (e.g. cytidine-5'-O-(l-thiophosphate)).
- Base-modified RNA sequences used according to the invention can likewise also contain sugar modifications.
- a sugar modification in connection with the present invention is a chemical modification of the sugar of the nucleotides present and typically includes, without implying any limitation, sugar modifications selected from the group consisting of 2'-deoxy- 2'-fluoro-oligoribonucleotide (2'-fluoro-2'-deoxycytidine-5'-triphosphate, 2'-fluoro-2'- deoxyuridine-5 '-triphosphate), 2'-deoxy-2'-deamine oligoribonucleotide (2'-amino-2'- deoxycytidine-5 '-triphosphate, 2'-amino-2'-deoxyuridine-5'-triphosphate), 2'-O-alkyl oligoribonucleotide, 2'-deoxy-2'-C-alkyl oligoribonucleotide (2'-O-methylcytidine-5'- triphosphate, 2'-
- the base-modified RNA sequence used according to the invention preferably does not contain any sugar modifications or backbone modifications, however.
- the reason for this preferred exclusion is that particular backbone modifications and sugar modifications of RNA sequences can on the one hand prevent or at least greatly reduce their in vitro transcription.
- an in vitro transcription of eGFP carried out by way of example functions, for example, only with the sugar modifications 2'-amino-2'-deoxyuridine-5'-phosphate, 2'-fluoro-2'- deoxyuridine-5 '-phosphate and 2'-azido-2'-deoxyuridine-5'-phosphate.
- the translation of the protein is typically considerably reduced by backbone modifications and, independently thereof, by sugar modifications of RNA sequences. It has been possible to demonstrate this, for eGFP, for example, in connection with the backbone modifications and sugar modifications chosen above.
- the base-modified RNA used according to the invention has a GC content that has been changed as compared with the native sequence.
- the G/C content for the coding region of the base-modified RNA is greater than the G/C content for the coding region of the native RNA sequence, the amino acid sequence that is coded for being unchanged as compared with the wild type, that is to say the amino acid sequence coded for by the native RNA sequence.
- the composition and the sequence of the various nucleotides play a large part here. In particular, sequences having an increased G(guanine)/C(cytosine) content are more stable than sequences having an increased A(adenine)/U(uracil) content.
- the codons are varied as compared with the wild type, while retaining the translated amino acid sequence, in such a manner that they contain an increased number of G/C nucleotides. Because several codons code for the same amino acid (degeneracy of the genetic code), the codons advantageous for stability can be determined (alternative codon usage).
- the codons containing A and/or U nucleotides are changed by substitution with different codons that code for the same amino acids but do not contain A and/or U.
- the codons for Pro can be changed from CCU or CCA to CCC or CCG;
- the codons for Arg can be changed from CGU or CGA or AGA or AGG to CGC or CGG;
- the codons for Ala can be changed from GCU or GCA to GCC or GCG;
- the codons for GIy can be changed from GGU or GGA to GGC or GGG.
- the codons for Phe can be changed from UUU to UUC; the codons for Leu can be changed from UUA, CUU or CUA to CUC or CUG; the codons for Ser can be changed from UCU or UCA or AGU to UCC, UCG or AGC; the codon for Tyr can be changed from UAU to UAC; the stop codon UAA can be changed to UAG or UGA; the codon for Cys can be changed from UGU to UGC; the codon His can be changed from CAU to CAC; the codon for GIn can be changed from CAA to CAG; the codons for He can be changed from AUU or AUA to AUC; the codons for Thr can be changed from ACU or ACA to ACC or ACG; the codon for As
- substitutions listed above can, of course, be used individually or in all possible combinations for increasing the G/C content of the base-modified RNA used according to the invention as compared with the native RNA sequence (or nucleic acid sequence). For example, all the codons for Thr occurring in the native RNA sequence can be changed to ACC (or ACG).
- the G/C content of the coding region of the base-modified RNA used according to the invention is preferably increased as compared with the G/C content of the coding region of the native RNA in such a manner that at least 5%, at least 10%, at least 15%, at least 20%, at least 25% or more preferably at least 30%, at least 35%, at least 40%, at least 45%, at least
- the G/C modified RNA may preferably be provided such that at least 10 %, preferably at least 20%, more preferably at least 59%, more preferably at least 75% and more preferably at least 90% of the substituted G/C nucleotides introduced according to this modification are base-modified G and/or C nucleotides, e.g. 7- deazaguanosine-5'-triphosphate nucleotides and/or 5-methylcytidine-5'-triphosphate and/or 5- bromocytidine-5'-triphosphate nucleotides.
- a second alternative of the base-modified RNA used according to the invention is based on the finding that the translation efficiency of the RNA is also determined by a varying frequency in the occurrence of tRNAs in cells. If, therefore, so-called "rare" codons are present in an increased number in a RNA sequence, then the corresponding RNA is translated markedly more poorly than in the case where codons coding for relative "frequent" tRNAs are present.
- the coding region of the base-modified RNA used according to the invention is changed as compared with the coding region of the native RNA in such a manner that at least one codon of the native RNA coding for a tRNA that is relatively rare in the cell is replaced by a codon coding for a tRNA that is relatively frequent in the cell and that carries the same amino acid as the relatively rare tRNA.
- the base-modified RNA sequence used according to the invention is modified in such a manner that codons for which frequently occurring tRNAs are available are inserted. Which tRNAs occur relatively frequently in the cell and which, by contrast, are relatively rare is known to a person skilled in the art; see, for example, Akashi, Curr. Opin. Genet. Dev. 2001, 11(6): 660-666.
- all the codons of the base-modified RNA sequence used according to the invention that code for a tRNA that is relatively rare in the cell can be replaced according to the invention by a codon that codes for a tRNA that is relatively frequent in the cell and that carries the same amino acid as the relatively rare tRNA. It is particularly preferred to link the increased, especially maximum, sequential G/C content in the base-modified RNA used according to the invention with the "frequent" codons, without changing the amino acid sequence coded for by the base-modified RNA used according to the invention.
- This preferred embodiment represents a particularly efficient translated and stabilised base-modified RNA used according to the invention (for example for a pharmaceutical composition according to the invention).
- RNA sequences can thereby be carried out with the additional different optimisation aims described above: On the one hand with maximum G/C content, on the other hand while taking the best possible account of the frequency of the tRNAs according to codon usage.
- a virtual translation of any desired RNA (or DNA) sequence is carried out in order to generate the corresponding amino acid sequence.
- RNA sequence is prepared and can be given out by means of a suitable display device, for example, and compared with the original (wild-type) sequence. The same is also true of the frequency of the individual nucleotides.
- the changes as compared with the original nucleotide sequence are preferably emphasised.
- stable sequences known in nature are read in, which sequences can form the basis for a RNA stabilised according to native sequence motifs. It is likewise possible to provide a secondary structural analysis, which is able to analyse stabilising and destabilising properties or regions of the RNA on the basis of structural calculations.
- DSEs destabilising sequence elements
- the base-modified RNA used according to the invention optionally in the region coding for the protein, one or more changes are preferably made as compared with the corresponding region of the native RNA, so that no destabilising sequence elements are present.
- DSEs optionally present in the untranslated regions (3'- and/or 5'-UTR) from the
- AURES AU-rich sequences
- the base-modified RNA used according to the invention is therefore preferably changed as compared with the native RNA in such a manner that it does not contain any such destabilising sequences.
- sequence motifs that are recognised by possible endonucleases, for example the sequence GAACAAG, which is contained in the 3'-UTR segment of the gene coding for the transferrin receptor (Binder et al., EMBO J. 1994, 13: 1969 to 1980).
- sequence motifs are preferably also eliminated from the base-modified RNA used according to the invention.
- RNA DNA
- This DNA matrix optionally possesses a suitable promoter, for example a T3, T7 or SP6 promoter, for in vitro transcription, followed by the desired nucleotide sequence for the base-modified RNA to be prepared and a termination signal for the in vitro transcription.
- the DNA molecule that forms the matrix of the base-modified RNA construct to be produced can then be prepared by fermentative propagation and subsequent isolation as part of a plasmid replicable in bacteria.
- plasmids suitable therefor there may be mentioned, for example, the plasmids pT7Ts (GenBank accession number U26404; Lai et al, Development 1995, 121: 2349 to 2360), pGEM ® series, for example pGEM ® -l (GenBank accession number X65300; from Promega) and pSP64 (GenBank accession number X65327); see also Mezei and Storts, Purification of PCR Products, in: Griffin and Griffin (eds.), PCR Technology: Current Innovation, CRC Press, Boca Raton, FL, 2001.
- the base-modified RNA used according to the invention can additionally have a 5'-cap structure (a modified guanosine nucleotide).
- a 5'-cap structure a modified guanosine nucleotide
- cap structures there may be mentioned, without being limited thereto, m7G(5')ppp (5'(A,G(5')ppp(5')A and G(5')ppp(5')G.
- the base-modified RNA used according to the invention contains a poly-A tail of at least about 50 nucleotides, preferably of at least about 70 nucleotides, more preferably of at least about 100 nucleotides and yet more preferably of at least about 200 nucleotides.
- the base-modified RNA used according to the invention contains a poly-C tail of at least about 20 nucleotides, preferably of at least about 30 nucleotides, more preferably of at least about 40 nucleotides and yet more preferably of at least about 50 nucleotides.
- the base-modified RNA used according to the invention can further contain a nucleic acid section that codes for a tag for purification.
- tags include, without implying any limitation, for example a hexahistidine tag (HIS tag, polyhistidine tag), a streptavidin tag (strep tag), a SBP tag (streptavidin binding tag), a GST (glutathione S-transferase) tag, etc.
- the base-modified RNA can further code for a tag for purification via an antibody epitope (antibody binding tag), for example a Myc tag, a Swal 1 epitope, FLAG tag, a Ha tag, etc., that is to say by recognition of the epitope via the (immobilised) antibody.
- antibody epitope antibody binding tag
- Myc tag for example a Myc tag, a Swal 1 epitope, FLAG tag, a Ha tag, etc.
- the base- modified RNA used according to the invention can have an increased A/U content around the ribosome binding site, preferably an A/U content increased by from 5 to 50%, more preferably by from 25 to 50% or more, as compared with the native RNA.
- RNA used according to the invention it is possible according to an embodiment of the base-modified RNA used according to the invention to introduce one or more so-called IRESs (internal ribosomal entry side) into the RNA.
- IRES can thus function as the only ribosomal binding site, but it can also serve to provide a base-modified RNA used according to the invention that codes for a plurality of proteins which are to be translated independently of one another by the ribosomes ("multicistronic RNA").
- IRES sequences which can be used according to the invention are those from picorna viruses (e.g.
- FMDV plague viruses
- CFFV plague viruses
- PV polio viruses
- ECMV encephalo-myocarditis viruses
- FMDV foot-and-mouth viruses
- HCV hepatitis C viruses
- CSFV conventional swine fever viruses
- MMV murine leukoma virus
- SIV simean immune deficiency virus
- CrPV cricket paralysis viruses
- the base-modified RNA used according to the invention contains in its 5'- and/or 3 '-untranslated regions stabilising sequences that are capable of increasing the half-life of the RNA in the cytosol.
- stabilising sequences can exhibit 100% sequence homology with naturally occurring sequences that occur in viruses, bacteria and eukaryotes, but they can also be partially or wholly of synthetic nature.
- stabilising sequences which can be used in the present invention there may be mentioned the untranslated sequences (UTR) of the ⁇ -globin gene, for example of Homo sapiens or Xenopus laevis.
- stabilising sequence has the general formula (C/U)CCAN x CCC(U/A)Py x UC(C/U)CC (SEQ ID NO: 2), which is contained in the 3'-UTR of the very stable RNA that codes for ⁇ -globin, ⁇ -(I)- collagen, 15 -lipoxygenase or for tyrosine-hydroxylase (see Holcik et al., Proc. Natl. Acad. Sci. USA 1997, 94: 2410 to 2414).
- stabilising sequences can be used individually or in combination with one another as well as in combination with other stabilising sequences known to a person skilled in the art.
- the effective transfer of the base-modified RNA used according to the invention into the cells to be treated or the organism to be treated can be improved by associating the base-modified RNA used according to the invention with a cationic peptide or protein or binding it thereto.
- a cationic peptide or protein or binding it thereto In particular the use of protamine, histone, spermin or nucleoline or derivatives of those sequences containing the basic nucleic acid binding sequence as the polycationic, nucleic-acid-binding protein is particularly effective.
- other cationic peptides or proteins, such as poly-L-lysine or histones is likewise possible. This procedure for stabilising the modified RNA is described, for example, in EP-A- 1083232, the disclosure of which is incorporated by reference into the present invention in its entirety.
- the protein coded for by the base-modified RNA used according to the invention can be selected preferably from all therapeutically useful proteins, for example from all proteins known to a person skilled in the art that are produced by recombinant methods or occur naturally and that are used for therapeutic purposes, for diagnostic purposes.
- the present invention provides a system by the base-modified RNA which allows to express protein with an increase expression rate which is useful for almost any purpose, e.g. for diagnostic or for research purposes.
- the inventive base-modified RNA may encode almost any protein, which shall be expressed with a higher expression rate in an in vitro or in vivo expression system than the corresponding naturally occurring RNA (without base-modified nucleotides).
- the protein to be encoded by the base-modified inventive RNA may e.g. be selected from any of the proteins given in the following: 0ATL3, 0FC3, OP A3, 0PD2, 4- IBBL, 5T4, 6Ckine, 707-AP, 9D7, A2M, AA, AAAS, AACT, AASS, ABAT, ABCAl, ABCA4, ABCBl, ABCBl 1, ABCB2, ABCB4, ABCB7, ABCC2, ABCC6, ABCC8, ABCDl, ABCD3, ABCG5, ABCG8, ABLl, ABO, ABR ACAAl, ACACA, ACADL, ACADM, ACADS, ACADVL, ACATl, ACCPN, ACE, ACHE, ACHM3, ACHMl, ACLS, ACPI, ACTAl, ACTC, ACTN4, ACVRLl, AD2, ADA, ADAMTS13, ADAMTS2, ADFN, ADHlB, ADHlC, ADLDH3A
- IFNa/b IFNa/b,.
- the protein encoded by the inventive RNA is selected (without implying any limitation) from e.g. growth hormones or growth factors, for example for promoting growth in a (transgenic) living being, such as, for example, TGF ⁇ and the IGFs (insulin- like growth factors), proteins that influence the metabolism and/or haematopoiesis, such as, for example, ⁇ -anti-trypsin, LDL receptor, erythropoietin (EPO), insulin, GATA-I, etc., or proteins such as, for example, factors VIII and XI of the blood coagulation system, etc.
- growth hormones or growth factors for example for promoting growth in a (transgenic) living being, such as, for example, TGF ⁇ and the IGFs (insulin- like growth factors), proteins that influence the metabolism and/or haematopoiesis, such as, for example, ⁇ -anti-trypsin, LDL receptor, erythropoietin (EPO), insulin, GATA
- Such proteins further include enzymes, such as, for example, ⁇ -galactosidase (lacZ), DNA restriction enzymes (e.g. EcoRI, Hindlll, etc.), lysozymes, etc., or proteases, such as, for example, papain, bromelain, keratinases, trypsin, chymotrypsin, pepsin, renin (chymosin), suizyme, nortase, etc..
- enzymes such as, for example, ⁇ -galactosidase (lacZ), DNA restriction enzymes (e.g. EcoRI, Hindlll, etc.), lysozymes, etc.
- proteases such as, for example, papain, bromelain, keratinases, trypsin, chymotrypsin, pepsin, renin (chymosin), suizyme, nortase, etc.
- the invention provides a technology which allows to substitute proteins
- the present invention may also provide therapeutic proteins, e.g. antibodies or proteases etc. which allow to cure a specific disease due to e.g. (over)expression of a dysfunctional or exogenous proteins causing disorders or diseases.
- the invention may be used to therapeutically introduce the inventive RNA into the organism, which attacks a pathogenic organism (virus, bacteria etc).
- RNA encoding therapeutic proteases may be used to cleave viral proteins which are essential to the viral assembly or other essential steps of virus production.
- the proteins coded for by the base-modified RNA used according to the invention may be used to stimulate an adaptive immune response by providing efficiently expressed antigens which elicit an adaptive immune response, whereas the underlying base- modified RNA does not provoke any immune reaction as such.
- the invention may allow to provide vaccines based on the base-modified RNA, which expresses increased levels of the antigenic protein or peptide. These vaccines may be used for the provision of tumour vaccines providing tumour antigens or antigens derived from pathogenic microorganisms causing e.g. infectious diseases.
- Specifically preferred proteins coded for by the base- modified RNA used according to the invention can be selected from the following antigens: tumour-specific surface antigens (TSSAs), for example 5T4, ⁇ 5 ⁇ l -integral, 707-AP, AFP, ART-4, B7H4, BAGE, ⁇ -catenin/m, Bcr-abl, MN/C EX antigen, CA125, CAMEL, CAP-I, CASP-8, ⁇ -catenin/m, CD4, CD19, CD20, CD22, CD25, CDC27/m, CD 30, CD33, CD52, CD56, CD80, CDK4/m, CEA, CT, Cyp-B, DAM, EGFR, ErbB3, ELF2M, EMMPRIN, EpCam, ETV6-AML1, G250, GAGE, GnT-V, GpIOO, HAGE, HER-2/new, HLA-A*0201- R170I, HPV-E7, HSP70
- RNA may include proteins which modulate various intracellular pathways by e.g. signal transmission modulation (inhibition or stimulation) which may influence pivotal intracellular processes like apoptosis, cell growth etc, in particular with respect to the organism's immune system.
- signal transmission modulation inhibition or stimulation
- immune modulators e.g. cytokines, lymphokines, monokines, interferones etc. may be expressed efficiently by the base-modified RNA.
- these proteins therefore also include, for example, cytokines of class I of the cytokine family that contain 4 position-specific conserved cysteine residues (CCCC) and a conserved sequence motif Trp-Ser-X-Trp- Ser (WSXWS), wherein X represents an unconserved amino acid.
- cytokines of class I of the cytokine family that contain 4 position- specific conserved cysteine residues (CCCC) and a conserved sequence motif Trp-Ser-X-Trp- Ser (WSXWS), wherein X represents an unconserved amino acid.
- Cytokines of class I of the cytokine family include the GM-CSF sub-family, for example IL-3, IL-5, GM-CSF, the IL-6 sub-family, for example IL-6, IL-I l, IL- 12, or the IL-2 sub-family, for example IL-2, IL-4, IL-7, IL-9, IL-15, etc., or the cytokines IL-l ⁇ , IL-l ⁇ , IL-IO etc.
- such proteins can also include cytokines of class II of the cytokine family (interferon receptor family), which likewise contain 4 position-specific conserved cysteine residues (CCCC) but no conserved sequence motif Trp-Ser-X-Trp-Ser (WSXWS).
- Cytokines of class II of the cytokine family include, for example, IFN- ⁇ , IFN- ⁇ , IFN- ⁇ , etc.
- Proteins coded for by the base-modified RNA used according to the invention can further include also cytokines of the tumour necrosis family, for example TNF- ⁇ , TNF- ⁇ , TNF-RI, TNF-RII, CD40, Fas, etc., or cytokines of the chemokine family, which contain 7 transmembrane helices and interact with G-protein, for example IL-8, MIP-I, RANTES, CCR5, CXR4, etc.
- cytokines of the tumour necrosis family for example TNF- ⁇ , TNF- ⁇ , TNF-RI, TNF-RII, CD40, Fas, etc.
- cytokines of the chemokine family which contain 7 transmembrane helices and interact with G-protein, for example IL-8, MIP-I, RANTES, CCR5, CXR4, etc.
- Such proteins can also be selected from apoptosis factors or apoptosis-related or -linked proteins, including AIF, Apaf, for example Apaf-1, Apaf-2, Apaf-3, or APO-2 (L), APO-3 (L), apopain, Bad, Bak, Bax, BcI- 2, BCI-X L , Bcl-xs, bik, CAD, calpain, caspases, for example caspase-1, caspase-2, caspase-3, caspase-4, caspase-5, caspase-6, caspase-7, caspase-8, caspase-9, caspase-10, caspase-11, ced-3, ced-9, c-Jun, c-Myc, crm A, cytochrome C, CdRl, DcRl, DD, DED, DISC, DNA- PKcs, DR3, DR4, DR5, FADD/MORT-1, FAK, Fas (Fas
- the base-modified RNA may also code for antigen specific T cell receptors.
- the T cell receptor or TCR is a molecule found on the surface of T lymphocytes (or T cells) that is generally responsible for recognizing antigens bound to major histocompatibility complex (MHC) molecules. It is a heterodimer consisting of an alpha and beta chain in 95% of T cells, while 5% of T cells have TCRs consisting of gamma and delta chains.Engagement of the TCR with antigen and MHC results in activation of its T lymphocyte through a series of biochemical events mediated by associated enzymes, co-receptors and specialized accessory molecules.
- MHC major histocompatibility complex
- these proteins allow to specifically target specific antigen and may support the functionality of the immune system due to their targeting properties. Accordingly, transfection of cells in vivo by administering base-modified RNA coding for these receptors or, preferably, an ex vivo cell transfection approach (e.g. by transfecting specifically certain immune cells), may be pursued.
- the T cell receptor molecules introduced recognize specific antigens on MHC molecule and may thereby support the immune system's awareness of antigens to be attacked.
- Proteins that can be coded for by the base-modified RNA used according to the invention further include also those proteins or protein sequences that have a sequence identity of at least 80% or 85%, preferably at least 90%, more preferably at least 95% and most preferably at least 99%, with one of the proteins described above, e.g. their native sequence.
- the base- modified nucleotides and their native (non base-modified) analog are considered to be "identical" herein.
- identity in the present application means that the sequences are compared with one another, as hereinbelow.
- the sequences can first be arranged relative to one another (alignment) in order to permit subsequent comparison of the sequences.
- gaps can be introduced into the sequence of the first nucleic acid sequence and the nucleotides can be compared with the corresponding position of the second nucleic acid sequence.
- the percentage identity between two sequences is a function of the number of identical positions divided by the number of all compared positions of the studied sequences. If, for example, a specific sequence identity is assumed for a particular nucleic acid (e.g. a nucleic acid coding for a protein as described above) in comparison with a reference nucleic acid (e.g. a nucleic acid of the prior art) having a defined length, then this percentage identity is indicated relatively in relation to the reference nucleic acid.
- a specific sequence identity is assumed for a particular nucleic acid (e.g. a nucleic acid coding for a protein as described above) in comparison with a reference nucleic acid (e.g. a nucleic acid of the prior art) having a defined length, then this percentage identity is indicated relatively in relation to the reference nucleic acid.
- nucleic acid can represent a nucleic acid having a length of 50 nucleotides that is wholly identical with a section of the reference nucleic acid having a length of 50 nucleotides. It can, however, also represent a nucleic acid having a length of 100 nucleotides that has 50% identity, that is to say in this case 50% identical nucleic acids, with the reference nucleic acid over its entire length.
- nucleic acid can be a nucleic acid having a length of 200 nucleotides that, in a section of the nucleic acid having a length of 100 nucleotides, is wholly identical with the reference nucleic acid having a length of 100 nucleotides.
- Other nucleic acids naturally fulfil these criteria equally. The comments made regarding the identity of nucleic acids apply equally to proteins or peptide sequences.
- the determination of the percentage identity of two sequences can be carried out by means of a mathematical algorithm.
- a preferred but non-limiting example of a mathematical algorithm which can be used for comparing two sequences is the algorithm of Karlin et al. (1993), PNAS USA, 90:5873-5877. Such an algorithm is integrated into the NBLAST program, with which sequences having a desired identity with the sequences of the present invention can be identified.
- the "Gapped BLAST" program can be used, as described in Altschul et al. (1997), Nucleic Acids Res, 25:3389- 3402.
- the default parameters of the particular program e.g. NBLAST
- the sequences can further be aligned using version 9 of GAP (global alignment program) from "Genetic Computing Group”, using the default (BLOSUM62) matrix (values -4 to +11) with a gap open penalty of -12 (for the first zero of a gap) and a gap extension penalty of -4 (for each additional successive zero in the gap).
- GAP global alignment program
- BLOSUM62 default matrix
- the percentage identity is calculated by expressing the number of correspondences as a percentage of the nucleic acids in the claimed sequence.
- the described methods for determining the percentage identity of two nucleic acid sequences can also be applied correspondingly to amino acid sequences, if required.
- the base-modified RNA used according to the invention can additionally contain at least one further functional section on the RNA sequence that codes for another therapeutic component.
- This other therapeutic component may be selected according to the disease to be treated. While this other component may have e.g. immunosuppressive properties when treating e.g. autoimmune diseases (e.g. coding for an immunosuppressant), it may alternatively have immunostimulating properties (enhancing the adaptive immune response elicited by the immunogenic tumour or pathogenic antigen), if the base-modified RNA is used for vaccination purposes (for example for treating infectious or tumour diseases).
- the immunostimulating component additionally being encoded on the base- modified RNA may be selected, for example from a cytokine (monokine, lymphokine, interleukin or chemokine) that promotes the immune response, such as IL-I, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, 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, INF- ⁇ , IFN- ⁇ , INF- ⁇ , GM-CSF, G-CSF, M-CSF, LT- ⁇ or TNF- ⁇ , growth factors, such as hGH.
- the base-modified RNA used according to the invention can code for a secretory signal peptide in addition to the protein as described above.
- signal peptides are (signal) sequences that conventionally comprise a length of from 15 to 30 amino acids and are located preferably at the N-terminus of the (polypeptide that is coded for.
- Signal peptides typically allow the transport of a protein fused thereto (in this case, for example, a therapeutically active protein) into a defined cellular compartment, preferably the cell surface, the endoplasmic reticulum or the endosomal-lysosomal compartment.
- signal sequences which can be used according to the invention are, for example, signal sequences of conventional and non-conventional MHC molecules, cytokines, immunoglobulins, of the invariant chain, Lampl, tapasin, Erp57, calreticulin and calnexin, and all further membrane-located endosomal-lysosomal- or endoplasmatic-reticulum- associated proteins. Preference is given to the use of the signal peptide of the human MHC class I molecule HLA-A*0201.
- the base-modified RNA used according to the invention can contain a lipid modification.
- a lipid-modified RNA typically consists of a base-modified RNA used according to the invention, as described above, at least one linker covalently linked with that RNA, and at least one lipid covalently linked with the respective linker.
- the lipid-modified base-modified RNA used according to the invention consists of (at least) one base-modified RNA used according to the invention, as described above, and at least one (bifunctional) lipid covalently linked with that RNA.
- the lipid-modified base-modified RNA used according to the invention consists of a base-modified RNA used according to the invention, as described above, at least one linker linked with that RNA, and at least one lipid linked covalently with the respective linker and at least one (bifunctional) lipid covalently linked (without a linker) with the base- modified RNA used according to the invention.
- the lipid used for the lipid modification of the base-modified RNA used according to the invention is typically a lipid or a lipophilic radical that preferably is itself biologically active.
- lipids preferably include natural substances or compounds such as, for example, vitamins, e.g. ⁇ -tocopherol (vitamin E), including RRR- ⁇ -tocopherol (formerly D- ⁇ - tocopherol), L- ⁇ -tocopherol, the racemate D,L- ⁇ -tocopherol, vitamin E succinate (VES), or vitamin A and its derivatives, e.g. retinoic acid, retinol, vitamin D and its derivatives, e.g.
- vitamins e.g. ⁇ -tocopherol (vitamin E), including RRR- ⁇ -tocopherol (formerly D- ⁇ - tocopherol), L- ⁇ -tocopherol, the racemate D,L- ⁇ -tocopherol, vitamin E succinate (VES), or vitamin A and its derivatives, e.g
- lipids or lipophilic radicals within the scope of the present invention include, without implying any limitation, polyalkylene glycols (Oberhauser et al, Nucl.
- aliphatic groups such as, for example, Ci-C 20 -alkanes, Q-Qo-alkenes or Ci-C 2 o-alkanol compounds, etc., such as, for example, dodecanediol, hexadecanol or undecyl radicals (Saison-Behmoaras et al, EMBO J, 1991, 10, 111; Kabanov et al, FEBS Lett., 1990, 259, 327; Svinarchuk et al, Biochimie, 1993, 75, 49), phospholipids such as, for example, phosphatidylglycerol, diacylphosphatidylglycerol, phosphatidylcholine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, phosphatidylserine, phosphatidylethanolamine, di-hexadecyl-
- polyamines or polyalkylene glycols such as, for example, polyethylene glycol (PEG) (Manoharan et al., Nucleosides & Nucleotides, 1995, 14, 969), hexaethylene glycol (HEG), palmitin or palmityl radicals (Mishra et al., Biochim. Biophys. Acta, 1995, 1264, 229), octadecylamines or hexylaminocarbonyloxycholesterol radicals (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277, 923), and also waxes, terpenes, alicyclic hydrocarbons, saturated and mono- or polyunsaturated fatty acid radicals, etc.
- PEG polyethylene glycol
- HEG hexaethylene glycol
- HOG hexaethylene glycol
- palmitin or palmityl radicals Mishra et al., Bio
- Linking between the lipid and the base-modified RNA used according to the invention can in principle take place at any nucleotide, at the base or the sugar radical of any nucleotide, at the 3' and/or 5' end, and/or at the phosphate backbone of the base-modified RNA used according to the invention.
- Particular preference is given according to the invention to a terminal lipid modification of the base-modified RNA at the 3' and/or 5' end thereof.
- a terminal modification has a number of advantages over modifications within the sequence. On the one hand, modifications within the sequence can influence the hybridisation behaviour, which may have an adverse effect in the case of sterically demanding radicals.
- linking between the base-modified RNA used according to the invention and at least one lipid that is used is effected via a "linker" (covalently linked with the base-modified RNA).
- Linkers within the scope of the present invention typically have at least two and optionally 3, 4, 5, 6, 7, 8, 9, 10, 10-20, 20-30 or more reactive groups, in each case selected from, for example, a hydroxy group, an amino group, an alkoxy group, etc.
- One reactive group preferably serves to bind the above-described base- modified RNA used according to the invention.
- This reactive group can be present in protected form, for example as a DMT group (dimethoxytrityl chloride), as a Fmoc group, as a MMT (monomethoxytrityl) group, as a TFA (trifluoroacetic acid) group, etc.
- sulfur groups can be protected by disulfides, for example alkylthiols such as, for example, 3- thiopropanol, or by activated components such as 2-thiopyridine.
- One or more further reactive groups serve according to the invention for the covalent binding of one or more lipids.
- a base-modified RNA used according to the invention can bind via the covalently bound linker preferably at least one lipid, for example 1, 2, 3, 4, 5, 5-10, 10-20, 20-30 or more lipid(s), particularly preferably at least 3-8 or more lipid(s) per base-modified RNA.
- the bound lipids can thereby be bound separately from one another at different positions of the base-modified RNA used according to the invention, or they can be present in the form of a complex at one or more positions of the base-modified RNA.
- An additional reactive group of the linker can be used for direct or indirect (cleavable) binding to a carrier material, for example a solid phase.
- Preferred linkers according to the present invention are, for example, glycol, glycerol and glycerol derivatives, 2-aminobutyl- 1,3-propanediol and 2-aminobutyl- 1,3 -propanediol derivatives/skeleton, pyrrolidine linkers or pyrrolidine-containing organic molecules (in particular for a modification at the 3' end), etc.
- Glycerol or glycerol derivatives (C 3 anchor) or a 2-aminobutyl-l,3-propanediol derivative/skeleton (C 7 anchor) are particularly preferably used according to the invention as linkers.
- a glycerol derivative (C 3 anchor) as linker is particularly preferred when the lipid modification can be introduced via an ether bond. If the lipid modification is to be introduced via an amide or a urethane bond, for example, a 2-aminobutyl- 1,3-propanediol skeleton (C 7 anchor), for example, is preferred.
- the nature of the bond formed between the linker and the base-modified RNA used according to the invention is preferably such that it is compatible with the conditions and chemicals of amidite chemistry, that is to say it is preferably neither acid- nor base-labile.
- bonds are in principle all correspondingly suitable bonds, preferably ester bonds, amide bonds, urethane and ether bonds.
- ether bond owing to its relatively high biological stability towards enzymatic hydrolysis.
- the (at least one) base-modified RNA used according to the invention is linked directly with at least one (bifunctional) lipid as described above, that is to say without the use of a linker as described above.
- the (bifunctional) lipid used according to the invention preferably contains at least two reactive groups or optionally 3, 4, 5, 6, 7, 8, 9, 10 or more reactive groups, a first reactive group serving to bind the lipid directly or indirectly to a carrier material described herein and at least one further reactive group serving to bind the base-modified RNA.
- a base-modified RNA used according to the invention can therefore preferably bind at least one lipid (directly without a linker), for example 1, 2, 3, 4, 5, 5-10, 10-20, 20-30 or more lipid(s), particularly preferably at least 3-8 or more lipid(s) per base-modified RNA.
- the bound lipids can be bound separately from one another at different positions of the base- modified RNA, or they can be present in the form of a complex at one or more positions of the base-modified RNA.
- At least one base-modified RNA used according to the invention can be bound according to the second embodiment to a lipid as described above via its reactive groups.
- Lipids that can be used for this second embodiment particularly preferably include those (bifunctional) lipids that permit coupling (preferably at their termini or optionally intramolecularly), such as, for example, polyethylene glycol (PEG) and derivatives thereof, hexaethylene glycol (HEG) and derivatives thereof, alkanediols, aminoalkane, thioalkanols, etc.
- PEG polyethylene glycol
- HEG hexaethylene glycol
- alkanediols aminoalkane
- thioalkanols etc.
- the nature of the bond between a (bifunctional) lipid and a base-modified RNA as described above is preferably as described for the first preferred embodiment.
- linking between the base-modified RNA used according to the invention and at least one lipid as described above can take place via both of the above- mentioned embodiments simultaneously.
- the base-modified RNA used according to the invention can be linked at one position of the RNA with at least one lipid via a linker (analogously to the first embodiment) and at a different position of the base-modified RNA directly with at least one lipid without the use of a linker (analogously to the second embodiment).
- At the 3' end of the base-modified RNA at least one lipid as described above can be covalently linked with the RNA via a linker, and at the 5' end of the base-modified RNA, a lipid as described above can be covalently linked with the RNA without a linker.
- at the 5' end of a base-modified RNA used according to the invention at least one lipid as described above can be covalently linked with the base- modified RNA via a linker, and at the 3' end of the base-modified RNA, a lipid as described above can be covalently linked with the base-modified RNA without a linker.
- covalent linking can take place not only at the termini of the base-modified RNA used according to the invention but also intramolecularly, as described above, for example at the 3' end and intramolecularly, at the 5' end and intramolecularly, at the 3' and 5' end and intramolecularly, only intramolecularly, etc.
- RNA used according to the invention can be prepared by preparation processes known in the prior art, for example automatically or manually via known synthetic nucleic acid syntheses (see e.g. Maniatis et al. (2001) supra).
- the base-modified RNA used according to the invention can be used for the preparation of a pharmaceutical composition for the treatment of tumours and cancer diseases, heart and circulatory diseases, infectious diseases or autoimmune diseases, as well as for the treatment of monogenetic diseases, for example in gene therapy.
- a pharmaceutical composition within the scope of the present invention contains a base- modified RNA as described above and optionally a pharmaceutically acceptable carrier and/or further auxiliary substances and additives and/or adjuvants.
- the pharmaceutical composition used according to the present invention typically comprises a safe and effective amount of a base-modified RNA as described above.
- safe and effective amount means an amount of the base-modified RNA used according to the invention that is sufficient to significantly induce a positive change in a condition to be treated, for example a tumour or cancer disease, a heart or circulatory disease or an infectious disease, as described hereinbelow.
- a "safe and effective amount” is small enough to avoid serious side-effects in the therapy of these diseases, that is to say to permit a sensible relationship between advantage and risk.
- the determination of these limits typically lies within the scope of sensible medical judgment.
- the concentration of the base-modified RNA used according to the invention in such pharmaceutical compositions can therefore vary, for example, without implying any limitation, within a wide range of, for example, from 0.1 ⁇ g to 100 mg/ml.
- Such a "safe and effective amount" of a base-modified RNA used according to the invention can vary in connection with the particular condition to be treated and also with the age and physical condition of the patient to be treated, the severity of the condition, the duration of the treatment, the nature of the accompanying therapy, of the particular pharmaceutically acceptable carrier used, and similar factors, within the knowledge and experience of the accompanying doctor.
- the pharmaceutical composition described here can be used for human and also for veterinary medical purposes.
- the composition can additionally contain one or more auxiliary substances.
- a synergistic action of the base- modified RNA used according to the invention and of an auxiliary substance optionally additionally contained in the pharmaceutical composition is preferably achieved thereby.
- various mechanisms can come into consideration in this respect. For example, compounds that permit the maturation of dendritic cells (DCs), for example lipopolysaccharides, TNF- ⁇ or CD40 ligand, form a first class of suitable auxiliary substances.
- DCs dendritic cells
- TNF- ⁇ or CD40 ligand form a first class of suitable auxiliary substances.
- auxiliary substance any agent that influences the immune system in the manner of a "danger signal" (LPS, GP96, etc.) or cytokines, such as GM-CSF, which allow an immune response produced by the base-modified RNA used according to the invention to be enhanced and/or influenced in a targeted manner and/or an immune reaction to be initiated at the same time.
- a "danger signal” LPS, GP96, etc.
- cytokines such as GM-CSF
- auxiliary substances are cytokines, such as monokines, lymphokines, interleukins or chemokines, for example IL-I, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-14, IL-15, IL- 16, IL- 17, 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, INF- ⁇ , IFN- ⁇ , INF- ⁇ , GM-CSF, G-CSF, M-CSF, LT- ⁇ or TNF- ⁇ , or interferons, for example IFN- ⁇ , or growth factors, for example hGH.
- cytokines such as monokines, lymphokines, interleukins or chem
- adjuvants known in the prior art include, without implying any limitation, stabilising cationic peptides or polypeptides as described above, such as protamine, nucleoline, spermine or spermidine, and cationic polysaccharides, in particular chitosan, TDM, MDP, muramyl dipeptide, pluronics, alum solution, aluminium hydroxide, ADJUMERTM (polyphosphazene); aluminium phosphate gel; glucans from algae; algammulin; aluminium hydroxide gel (alum); highly protein-adsorbing aluminium hydroxide gel; low viscosity aluminium oxide gel; AF or SPT (emulsion of squalane (5%), Tween 80 (0.2%), Pluronic L121 (1.25%), phosphate-buffered
- TM liposomes
- LOXORIBINETM (7-allyl-8-oxoguanosine); LT oral adjuvant (E.coli labile enterotoxin-protoxin); microspheres and microparticles of any composition; MF59TM; (squalene-water emulsion); MONTANIDE ISA 51TM (purified incomplete Freund's adjuvant); MONTANIDE ISA 720TM (metabolisable oil adjuvant); MPLTM (3-Q-desacyl-4'- monophosphoryl lipid A); MTP-PE and MTP-PE liposomes ((N-acetyl-L-alanyl-D- isoglutaminyl-L-alanine-2-( 1 ,2-dipalmitoyl-sn-glycero-3 -(hydroxyphosphoryloxy))- ethylamide, monosodium salt); MURAMETIDETM (NaC-MuT-L-AIa-D-GIn-OCH
- Theramid ® N-acetylglucosaminyl-N-acetylmuramyl-L- Ala-D-isoGlu-L-Ala-dipalmitoxypropylamide
- Theronyl-MDP (TermurtideTM or [thr I]- MDP; N-acetylmuramyl-L-threonyl-D-isoglutamine); Ty particles (Ty-VLPs or virus-like particles); Walter-Reed liposomes (liposomes containing lipid A adsorbed on aluminium hydroxide), and the like, etc.
- Lipopeptides such as Pam3Cys
- Lipopeptides are likewise particularly suitable for combining with the pharmaceutical composition described herein (see Deres et al., Nature 1989, 342: 561-564).
- the above-described pharmaceutical composition may contain as (additional) adjuvant a nucleic-acid-based adjuvant, for example CpG and RNA oligonucleotides, etc., or Toll-like receptor ligands, for example ligands of TLRl, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLRlO, TLRI l, TLR 12 or TLR 13 or homologues thereof.
- a nucleic-acid-based adjuvant for example CpG and RNA oligonucleotides, etc.
- Toll-like receptor ligands for example ligands of TLRl, TLR2, TLR3, TLR4, TLR5, TLR6,
- the pharmaceutical composition (of whatever therapeutic use) according to the invention described herein can optionally contain a pharmaceutically acceptable carrier.
- pharmaceutically acceptable carrier used here preferably includes one or more compatible solid or liquid fillers or diluents or encapsulating compounds, which are suitable for administration to a person.
- compatible means that the constituents of the composition are capable of being mixed with the base-modified RNA used according to the invention, with the adjuvant that is optionally additionally present, and with one another in such a manner that no interaction occurs which would substantially reduce the pharmaceutical effectiveness of the composition under usual use conditions, such as, for example, reduce the pharmaceutical activity of the encoded pharmaceutically active protein or even inhibit or impair the expression of the pharmaceutically active protein.
- Pharmaceutically acceptable carriers must, of course, have sufficiently high purity and sufficiently low toxicity to make them suitable for administration to a person to be treated.
- Some examples of compounds which can be used as pharmaceutically acceptable carriers or constituents thereof are sugars, such as, for example, lactose, glucose and sucrose; starches, such as, for example, corn starch or potato starch; cellulose and its derivatives, such as, for example, sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; powdered tragacanth; malt; gelatin; tallow; solid glidants, such as, for example, stearic acid, magnesium stearate; calcium sulfate; vegetable oils, such as, for example, groundnut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil from theobroma; polyols, such as, for example, polypropylene glycol, glycerol, sorbitol, mannitol and polyethylene glycol; alginic acid;
- a pharmaceutically acceptable carrier is determined in principle by the manner in which the pharmaceutical composition used according to the invention is administered.
- the pharmaceutical composition used according to the invention can be administered, for example, systemically.
- Routes for administration include, for example, transdermal, oral, parenteral, including subcutaneous or intravenous injections, topical and/or intranasal routes.
- the suitable amount of the pharmaceutical composition to be used can be determined by routine experiments with animal models. Such models include, without implying any limitation, rabbit, sheep, mouse, rat, dog and non-human primate models.
- Preferred unit dose forms for injection include sterile solutions of water, physiological saline or mixtures thereof. The pH of such solutions should be adjusted to about 7.4.
- Suitable carriers for injection include hydrogels, devices for controlled or delayed release, polylactic acid and collagen matrices.
- Pharmaceutically acceptable carriers for topical application which can be used here include those which are suitable for use in lotions, creams, gels and the like. If the compound is to be administered perorally, tablets, capsules and the like are the preferred unit dose form.
- the pharmaceutically acceptable carriers for the preparation of unit dose forms which can be used for oral administration are well known in the prior art. The choice thereof will depend on secondary considerations such as taste, costs and storability, which are not critical for the purposes of the present invention, and can be made without difficulty by a person skilled in the art.
- the pharmaceutical composition used here can also be in the form of a vaccine.
- vaccination is based on the introduction of an antigen, in the present case the base-modified RNA used according to the invention and coding for (a therapeutically active) protein(s), into the organism, in particular into the cell.
- the base-modified RNA contained in the pharmaceutical composition used here is translated into the protein that is coded for, i.e. the protein coded for by the base-modified RNA used according to the invention is expressed, resulting in the stimulation of an immune response directed against that protein.
- the adaptive immune response is achieved, for example, by introduction of the genetic information for a tumour or a pathogenic antigen.
- the cancer antigen(s) is/are expressed in the organism, resulting in the triggering of an immune response that is effectively directed against the cancer or tumour cells.
- Vaccines in connection with the present invention typically comprise a composition as described above for a pharmaceutical composition, the composition of such vaccines being determined in particular by the manner in which they are administered. Vaccines are preferably administered systemically, as described here.
- Vaccines as described herein are therefore preferably formulated in liquid or solid form.
- Further auxiliary substances that can further increase the immunogenicity of the vaccine can optionally also be incorporated into vaccines as described herein above.
- one or more further such auxiliary substances, as defined hereinbefore, are to be chosen for the vaccines described herein, depending on other properties of the base-modified RNA used according to the invention.
- the base-modified RNA described herein or a pharmaceutical composition as described herein, particularly preferably the vaccine described herein is used for the treatment of indications mentioned by way of example hereinbelow.
- AML acute myeloid leukaemia
- ALL acute lymphoid leukaemia
- CML chronic myeloid leukaemia
- CLL
- cervical carcinoma cervical cancer
- Another group of diseases to be treated with the base-modified RNA compositions containing the base-modified RNA of the invention relates to heart and circulatory diseases selected from coronary heart disease, arterioscelerosis, apoplexia, hypertonia, and neuronal diseases selected from Alzheimer's disease, amyotrophic lateral sclerosis, dystonia, epilepsy, multiple sclerosis and Parkinson's disease, and autoimmune diseases selected from type I autoimmune diseases or type II autoimmune diseases or type III autoimmune diseases or type IV autoimmune diseases, such as, for example, multiple sclerosis (MS), rheumatoid arthritis, diabetes, type I diabetes (Diabetes mellitus), systemic lupus erythematosus (SLE), chronic polyarthritis, Basedow's disease, autoimmune forms of chronic hepatitis, colitis ulcerosa, type I allergy diseases, type II allergy diseases, type III allergy diseases, type IV allergy diseases, fibromyalgia, hair loss, Bechterew's
- the base-modified RNA or compositions containing the base-modified RNA may also be used to treat genetic disease, which are caused by genetic defects, e.g. due to gene mutations resulting in loss of protein activity or regulatory mutations which do not allow transcribe ot translate the protein. Frequently, these disease lead to metabolic disorders or other symptoms, e.g. muscle dystrophy. Accordingly, the present invention allows to treat these diseases by providing the dysfunctional protein via the base-modified RNA, which allows sufficient level of the protein to be translated due to the increased expression rate.
- 3-beta-hydroxysteroid dehydrogenase deficiency type II
- 3- ketothiolase deficiency 6-mercaptopurine sensitivity
- Aarskog-Scott syndrome Abetalipoproteinemia; Acatalasemia; Achondrogenesis; Achondrogenesis- hypochondrogenesis; Achondroplasia; Achromatopsia; Acromesomelic dysplasia (Hunter- Thompson type); ACTH deficiency; Acyl-CoA dehydrogenase deficiency (short-chain, medium chain, long chain); Adenomatous polyposis coli; Adenosin-deaminase deficiency; Adenylosuccinase deficiency; Adhalinopathy; Adrenal hyperplasia, congenital (due to 11- beta-hydroxylase deficiency; due to 17-alpha-hydroxylase deficiency; due to 21 -hydroxylase deficiency); Ad
- Pseudohypoparathyroidism Pseudovaginal perineoscrotal hypospadias; Pseudovitamin D deficiency rickets; Pseudoxanthoma elasticum (autosomal dominant; autosomal recessive); Pulmonary alveolar proteinosis; Pulmonary hypertension; Purpura fulminans; Pycnodysostosis; Pyropoikilocytosis; Pyruvate carboxylase deficiency; Pyruvate dehydrogenase deficiency; Rabson-Mendenhall syndrome; Refsum disease; Renal cell carcinoma; Renal tubular acidosis; Renal tubular acidosis with deafness; Renal tubular acidosis-osteopetrosis syndrome; Reticulosis (familial histiocytic); Retinal degeneration; Retinal dystrophy; Retinitis pigmentosa; Retinit
- Preferred diseases to be treated which have a genetic inherited background and which are typically caused by a single gene defect and are inherited according to Mendel's laws are preferably selected from the group consisting of autosomal-recessive inherited diseases, such as, for example, adenosine deaminase deficiency, familial hypercholesterolemia, Canavan's syndrome, Gaucher's disease, Fanconi anaemia, neuronal ceroid lipofuscinoses, mucoviscidosis (cystic fibrosis), sickle cell anaemia, phenylketonuria, alcaptonuria, albinism, hypothyreosis, galactosaemia, alpha- 1 -anti-trypsin deficiency, Xeroderma pigmentosum, Ribbing's syndrome, mucopolysaccharidoses, cleft lip, jaw, palate, Laurence Moon Biedl Bardet sydrome, short rib polydactylia syndrome
- the present invention may also provide therapeutic approaches to treat autoimmune diseases.
- the base-modified RNA or a composition containing a base-modified RNA may be used for the treatment of of for the preparation of a medicamrnt for the treatment of autoimmune diseases.
- Autoimmune diseases can be broadly divided into systemic and organ- specific or localised autoimmune disorders, depending on the principal clinico-pathologic features of each disease.
- Autoimmune disease may be divided into the categories of systemic syndromes, including systemic lupus erythematosus (SLE), Sjogren's syndrome, Scleroderma, Rheumatoid Arthritis and polymyositis or local syndromes which may be endocrinologic (type I diabetes (Diabetes mellitus Type 1), Hashimoto's thyroiditis, Addison's disease etc.), dermatologic (pemphigus vulgaris), haematologic (autoimmune haemolytic anaemia), neural (multiple sclerosis) or can involve virtually any circumscribed mass of body tissue.
- SLE systemic lupus erythematosus
- Sjogren's syndrome Sjogren's syndrome
- Scleroderma atoid Arthritis
- Rheumatoid Arthritis and polymyositis or local syndromes
- endocrinologic type I diabetes (Diabetes mellitus Type 1), Hashimoto's thyroidit
- the autoimmune diseases to be treated may be selected from the group consisting of type I autoimmune diseases or type II autoimmune diseases or type III autoimmune diseases or type IV autoimmune diseases, such as, for example, multiple sclerosis (MS), rheumatoid arthritis, diabetes, type I diabetes (Diabetes mellitus Type 1), chronic polyarthritis, Basedow's disease, autoimmune forms of chronic hepatitis, colitis ulcerosa, type I allergy diseases, type II allergy diseases, type III allergy diseases, type IV allergy diseases, fibromyalgia, hair loss, Bechterew's disease, Crohn's disease, Myasthenia gravis, neurodermitis, Polymyalgia rheumatica, progressive systemic sclerosis (PSS), Reiter's syndrome, rheumatic arthritis, psoriasis, vasculitis, etc, or type II diabetes.
- MS multiple sclerosis
- rheumatoid arthritis diabetes
- type I diabetes Diabetes mellit
- the autoreaction may be due to a T-CeIl bypass.
- a normal immune system requires the activation of B-cells by T-cells before the former can produce antibodies in large quantities.
- This requirement of a T-cell can be bypassed in rare instances, such as infection by organisms producing super-antigens, which are capable of initiating polyclonal activation of B-cells, or even of T-cells, by directly binding to the ⁇ -subunit of T-cell receptors in a non-specific fashion.
- Another explanation deduces autoimmune diseases from a Molecular Mimicry.
- An exogenous antigen may share structural similarities with certain host antigens; thus, any antibody produced against this antigen (which mimics the self-antigens) can also, in theory, bind to the host antigens and amplify the immune response.
- the most striking form of molecular mimicry is observed in Group A beta- haemolytic streptococci, which shares antigens with human myocardium, and is responsible for the cardiac manifestations of Rheumatic Fever.
- the present invention allows therefore to provide an inventive composition containing containing an base-modified RNA coding for an autoantigen, which typically allows the immune system to be desensitized, or may also provide an (immunostimulatory) composition according to the invention (which does not contain an autoantigen).
- the invention therefore relates also to the use of a base-modified RNA as described herein, or of a pharmaceutical composition as described herein, particularly preferably the vaccine described herein, for the treatment of indications or diseases mentioned above. It also includes in particular the use of the base-modified RNA described herein for inoculation or the use of the described pharmaceutical composition as an inoculant.
- a method for treating the above- mentioned diseases, or an inoculation method for preventing the above-mentioned diseases comprises administering the described pharmaceutical composition to a patient, in particular to a human being.
- the present invention relates also to an in vitro transcription method for the preparation of base-modified RNA, comprising the following steps: a) preparation/provision of a nucleic acid coding for a protein of interest, in particular as described above; b) addition of the (desoxy)ribonucleic acid to an in vitro transcription medium comprising a RNA polymerase, a suitable buffer, a nucleic acid mix, comprising one or more base-modified nucleotides as described above as replacement for one or more of the naturally occurring nucleotides A, G, C and/or U, and optionally one or more naturally occurring nucleotides A, G, C or U if not all of the naturally occurring nucleotides A, G, C or U are to be replaced, and optionally a RNase inhibitor; c) incubation of the nucleic acid in the in vitro transcription medium and in vitro transcription of the nucleic acid; d) optional purification and removal of the unincorporated nucleotides from the in vitro
- a nucleic acid as described in step a) of the in vitro transcription method according to the invention can be any nucleic acid as described above that codes for a protein of interest, in particular as mentioned herein, preferably a diagnostically relevant protein, a therapeutically active protein, or any other protein used or usable for laboratory or research purposes.
- a nucleic acid as described above codes for a protein of interest, in particular as mentioned herein, preferably a diagnostically relevant protein, a therapeutically active protein, or any other protein used or usable for laboratory or research purposes.
- There are used for this purpose typically DNA sequences, for example genomic DNA or fragments thereof, or plasmids, coding for a protein as described above, or RNA sequences (corresponding thereto), for example mRNA sequences, preferably in linearised form.
- the in vitro transcription can usually be carried out using a vector having a RNA polymerase binding site. To this end there can be used any vectors known in the art, for example commercially available vectors (see above).
- nucleic acid sequences used can be transcribed later, as desired, depending on the chosen RNA polymerase.
- a nucleic acid sequence used for in vitro transcription and coding for a protein as defined above is typically cloned into a vector, for example via a multiple cloning site of the vector used. Before the transcription, the clone is typically cleaved with restriction enzymes at the site at which the future 3' end of the RNA is to be located, using a suitable restriction enzyme, and the fragment is purified.
- RNA from containing vector sequences a RNA of defined length is obtained. It is preferred not to use any restriction enzymes that produce 3 '-protruding ends (such as, for example, Aat II, Apa I, Ban II, BgI I, Bsp 1286, BstX I, Cfo I, Hae II, HgiA I, Hha I, Kpn I, Pst I, Pvu I, Sac I, Sac II, Sfi I, Sph I, etc.). If such restriction enzymes are nevertheless to be used, the 3'-protruding end is preferably filled, for example with Klenow or T4-DNA polymerase.
- restriction enzymes such as, for example, Aat II, Apa I, Ban II, BgI I, Bsp 1286, BstX I, Cfo I, Hae II, HgiA I, Hha I, Kpn I, Pst I, Pvu I, Sac I, Sac II, Sfi I, Sph I, etc
- the nucleic acid as transcription template by polymerase chain reaction (PCR).
- PCR polymerase chain reaction
- one of the primers used typically contains the sequence of a RNA polymerase binding site. It is further preferred for the 5' end of the primer used to have a length of approximately from 10 to 50 further nucleotides, more preferably from 15 to 30 further nucleotides and most preferably of approximately 20 nucleotides.
- the nucleic acid for example the nucleic acid, e.g. the DNA or RNA template, is typically purified and freed of RNase in order to ensure a high yield. Purification can be carried out by any process known in the art, for example with a caesium chloride gradient or ion-exchange process.
- the nucleic acid is added to an in vitro transcription medium.
- a suitable in vitro transcription medium first contains a nucleic acid as prepared under step a), for example approximately from 0.1 to 10 ⁇ g, preferably approximately from 1 to 5 ⁇ g, more preferably 2.5 ⁇ g and most preferably approximately 1 ⁇ g, of such a nucleic acid.
- a suitable in vitro transcription medium further optionally contains a reducing agent, e.g. DTT, more preferably approximately from 1 to 20 ⁇ l of 50 mM DTT, yet more preferably approximately 5 ⁇ l of 50 mM DTT.
- the in vitro transcription medium further contains nucleotides, for example a nucleotide mix, in the case of the present invention consisting of base-modified nucleotides as defined above (typically approximately from 0.1 to 1O mM per nucleotide, preferably from 0.1 to 1 mM per nucleotide, preferably approximately 4 mM in total), and optionally unmodified nucleotides.
- base-modified nucleotides as described above typically approximately from 0.1 to 1O mM per nucleotide, preferably from 0.1 to 1 mM per nucleotide, preferably approximately 4 mM in total
- Base-modified nucleotides as described above approximately 1 mM per nucleotide, preferably approximately 4 mM in total
- base-modified nucleotides as described above (approximately 1 mM per nucleotide, preferably approximately 4 mM in total), e.g.
- pseudouridine-5'-triphosphate, 5-methylcytidine-5'-triphosphate, etc. are typically added in such an amount that the base-modified nucleotide is replaced completely by the native nucleotide. It is, however, also possible to use mixtures of one or more base-modified nucleotides and one or more naturally occurring nucleotides instead of a particular nucleotide, that is to say one or more base-modified nucleotides as described above can occur as a replacement for one or more of the naturally occurring nucleotides A, G, C or U and optionally additionally one or more naturally occurring nucleotides A, G, C or U, if not all the naturally occurring nucleotides A, G, C or U are to be replaced.
- a suitable in vitro transcription medium likewise contains a RNA polymerase, e.g. T7-RNA polymerase (e.g. T7-Opti mRNA Kit, Cure Vac, Tubingen, Germany), T3-RNA polymerase or SP6, typically approximately from 10 to 500 U, preferably approximately from 25 to 250 U, more preferably approximately from 50 to 150 U, and most preferably approximately 100 U of RNA polymerase.
- T7-RNA polymerase e.g. T7-Opti mRNA Kit, Cure Vac, Tubingen, Germany
- T3-RNA polymerase or SP6 typically approximately from 10 to 500 U, preferably approximately from 25 to 250 U, more preferably approximately from 50 to 150 U, and most preferably approximately 100 U of RNA polymerase.
- the in vitro transcription medium is further preferably kept free of RNase in order to avoid degradation of the transcribed RNA.
- a suitable in vitro transcription medium therefore optionally contains in addition a RNase inhibitor.
- the nucleic acid is incubated and transcribed in the in vitro transcription medium, typically for approximately from 30 to 120 minutes, preferably for approximately from 40 to 90 minutes and most preferably for approximately 60 minutes, at approximately from 30 to 45°C, preferably at from 37 to 42°C.
- the incubation temperature is governed by the RNA polymerase that is used, for example in the case of T7 RNA polymerase it is approximately 37 0 C.
- the nucleic acid obtained by the transcription is preferably a RNA, more preferably a mRNA. After the incubation, purification of the reaction can optionally take place in step d) of the in vitro transcription method according to the invention.
- any suitable process known in the art can be used, for example chromatographic purification processes, e.g. affinity chromatography, gel filtration, etc.
- chromatographic purification processes e.g. affinity chromatography, gel filtration, etc.
- non-incorporated, i.e. excess, nucleotides can be removed from the in vitro transcription medium.
- the present invention relates also to an in vitro transcription and translation method for increasing the expression of a protein, comprising the following steps: a) preparation/provision of a nucleic acid coding for a protein of interest, in particular as described above; b) addition of the nucleic acid to an in vitro transcription medium comprising a RNA polymerase, a suitable buffer, a nucleic acid mix, comprising one or more base- modified nucleotides as described above as replacement for one or more of the naturally occurring nucleotides A, G, C and/or U, and optionally one or more naturally occurring nucleotides A, G, C or U if not all the naturally occurring nucleotides A, G, C or U are to be replaced, and optionally a RNase inhibitor; c) incubation of the nucleic acid in the in vitro transcription medium and in vitro transcription of the nucleic acid; d) optional purification and removal of the unincorporated nucleotides from the in vitro transcription medium; e) addition of
- Steps a), b), c) and d) of the in vitro transcription and translation method according to the invention for increasing the expression of a protein are identical with steps a), b), c) and d) of the above-described in vitro transcription method according to the invention.
- step e) of the in vitro transcription and translation method according to the invention for increasing the expression of a protein the base-modified nucleic acid obtained in step c) (and optionally in step d)) is added to a suitable in vitro translation medium.
- a suitable in vitro translation medium comprises, for example, reticulocyte lysate, wheatgerm extract, etc. Such a medium conventionally further comprises an amino acid mix.
- the amino acid mix typically comprises (all) naturally occurring amino acids and, optionally, modified amino acids, e.g. 35 S-methionine (e.g. for controlling the translation efficiency via autoradiography).
- a suitable in vitro translation medium further comprises a reaction buffer.
- In vitro translation media are described, for example, by Krieg and Melton (1987) (P. A. Krieg and D. A. Melton (1987) In vitro RNA synthesis with SP6 RNA polymerase Methods Enzymol 155:397-415), the disclosure of which is incorporated into the present invention by reference in its entirety.
- a step f) of the in vitro transcription and translation method according to the invention for increasing the expression of a protein the base-modified nucleic acid is incubated in the in vitro translation medium, and the protein coded for by the base-modified nucleic acid is translated in vitro.
- the incubation time is typically approximately from 30 to 120 minutes, preferably approximately from 40 to 90 minutes and most preferably approximately 60 minutes.
- the incubation temperature is typically in a range of approximately from 20 to 40°C, preferably approximately from 25 to 35°C and most preferably approximately 3O 0 C.
- Steps b) to f) of the in vitro transcription and translation method according to the invention for increasing the expression of a protein, or individual steps of steps b) to f), can be combined with one another, that is to say can be carried out together. It is preferred to add all the necessary components together at the beginning or to add them to the reaction medium in succession during the reaction according to the sequence of the described steps b) to f).
- the translated protein obtained in step f) can be purified.
- Purification can be carried out by processes known to a person skilled in the art from the art, for example chromatography, such as, for example, affinity chromatography (HPLC, FPLC, etc.), ion- exchange chromatography, gel chromatography, size exclusion chromatography, gas chromatography, or antibody detection, or biophysical processes, such as, for example, NMR analyses, etc. (see e.g. Maniatis et al. (2001) supra).
- Chromatography processes can suitably use tags for purification, as described above, for example a hexahistidine tag (HIS tag, polyhistidine tag), a streptavidin tag (strep tag), a SBP tag (streptavidin binding tag), a GST (glutathione S-transferase) tag, etc.).
- the purification can further take place via an antibody epitope, (antibody binding tag), for example a Myc tag, a Swal 1 epitope, a FLAG tag, a HA tag, etc., that is to say by recognition of the epitope via the (immobilised) antibody.
- the present invention relates also to an in vitro transcription and translation method for increasing the expression of a protein in a host cell, comprising the following steps: a) preparation/procision of a (desoxy)ribonucleic acid coding for a protein of interest, in particular as described above; b) addition of the nucleic acid to an in vitro transcription medium comprising a RNA polymerase, a suitable buffer, one or more base-modified nucleotides as described above as replacement for one or more of the naturally occurring nucleotides A, G, C and/or U, and optionally one or more naturally occurring nucleotides A, G, C or U if not all the naturally occurring nucleotides A, G, C or U are to be replaced; c) incubation of the nucleic acid in the in vitro transcription medium and in vitro transcription of the nucleic acid; d) optional purification and removal of the unincorporated nucleotides from the in vitro transcription medium; e') transfection of the base-modified
- Steps a), b), c) and d) of the in vitro transcription and translation method for increasing the expression of a protein in a host cell are identical with steps a), b), c) and d) of the above- described in vitro transcription method according to the invention and of the above-described in vitro transcription and translation method according to the invention for increasing the expression of a protein.
- step e') of the in vitro transcription and translation method the transfection of the base-modified nucleic acid obtained in step c) (and optionally d)) into a host cell takes place.
- the transfection is generally carried out by transfection methods known in the art (see e.g. Maniatis et al. (2001) Molecular Cloning: A laboratory manual, Cold Spring Harbor Laboratory Press, Cold Spring Habor, NY).
- Suitable transfection methods include, without implying any limitation, for example electroporation methods, including modified electroporation methods (e.g. nucleofection), calcium phosphate methods, e.g.
- the lipofection method e.g. the transferrin-mediated lipofection method, polyprene transfection, particle bombardment, nanoplexes, e.g. PLGA, polyplexes, e.g. PEI, protoplast fusion and the microinjection method, the lipofection method in particular having been found to be a suitable method.
- a (suitable) host cell includes any cell that permits expression of the base-modified RNA used according to the invention, preferably any cultivated eukaryotic cell (e.g. yeast cells, plant cells, animal cells and human cells) or prokaryotic cell (bacterial cells).
- cultivated eukaryotic cell e.g. yeast cells, plant cells, animal cells and human cells
- prokaryotic cell bacterial cells.
- Cells of multicellular organisms are preferably chosen for the expression of the protein coded for by the base-modified RNA used according to the invention, if posttranslational modifications, e.g. glycosylation of the encoded protein, are required (N- and/or O-coupled).
- eukaryotic cells permit the posttranslational modification of the synthesised protein.
- the person skilled in the art knows a large number of such higher eukaryotic cells or cell lines, e.g. 293T (embryonic liver cell line), HeLa (human cervical carcinoma cells), CHO (cells from the ovaries of Chinese hamsters) and further cell lines, including cells and cell lines developed for laboratory purposes, such as, for example, hTERT-MSC, HEK293, Sf9 or COS cells.
- Suitable eukaryotic cells further include cells or cell lines that are impaired by diseases or infections, for example cancer cells, in particular cancer cells of any of the cancer types mentioned herein in the description, cells impaired by HIV and/or cells of the immune system or of the central nervous system (CNS).
- cancer cells in particular cancer cells of any of the cancer types mentioned herein in the description, cells impaired by HIV and/or cells of the immune system or of the central nervous system (CNS).
- Particularly preferred erkaryotic cells are human cells or animal cells.
- Suitable host cells can likewise be derived from eukaryotic microorganisms such as yeast, e.g. Saccharomyces cerevisiae (Stinchcomb et al, Nature, 282:39, (1997)), Schizosaccharomyces pombe, Candida, Pichia, and filamentous fungi of the genera Aspergillus, Penicillium, etc.
- Suitable host cells likewise include prokaryotic cells, such as, for example, bacterial cells, for example from Escherichia coli or from bacteria of the genera Bacillus, Lactococcus, Lactobacillus, Pseudomonas, Streptomyces, Streptococcus, Staphylococcus, preferably E. coli, etc.
- prokaryotic cells such as, for example, bacterial cells, for example from Escherichia coli or from bacteria of the genera Bacillus, Lactococcus, Lactobacillus, Pseudomonas, Streptomyces, Streptococcus, Staphylococcus, preferably E. coli, etc.
- step f of the in vitro transcription and translation method according to the invention for increasing the expression of a protein in a host cell, incubation of the base-modified nucleic acid in the host cell and translation of the protein coded for the by base-modified nucleic acid in the host cell take place.
- expression mechanisms inherent in the host cell are preferably used, e.g. by translation of the (m)RNA in the host cell via ribosomes and tRNAs.
- the incubation temperatures used thereby are governed by the host cell systems used in a particular case.
- the translated protein obtained in step f) can be isolated and/or purified.
- Isolation of the translated (expressed) protein typically comprises separating the protein from reaction constituents and can be carried out by processes known to a person skilled in the art, for example by cell lysis, ultrasonic decomposition, or similar methods. Purification can be carried out by methods as described for step e) of the in vitro transcription and translation method according to the invention for increasing the expression of a protein.
- the nucleic acid used according to the invention can also be expressed by an in vitro translation method of steps (e 1 ) to (g 1 ), which, as such, also forms part of the present invention.
- the present invention relates also to an in vitro transcription and in vivo translation method for increasing the expression of a (therapeutically active) protein in an organism, comprising the following steps: a) preparation/provision of a (desoxy)ribonucleic acid coding for a protein of interest, in particular as described above; b) addition of the nucleic acid to an in vitro transcription medium comprising a RNA polymerase, a suitable buffer, a nucleic acid mix, comprising one or more base- modified nucleotides as described above as replacement for one or more of the naturally occurring nucleotides A, G, C and/or U, and optionally one or more naturally occurring nucleotides A, G, C or U if not all the naturally occurring nucleotides A, G, C or U
- Steps a), b), c) and d) of the in vitro transcription and in vivo translation method according to the invention for increasing the expression of a protein in an organism are identical with steps a), b), c) and d) of the above-described in vitro transcription method according to the invention, of the above-described in vitro transcription and translation method according to the invention for increasing the expression of a protein, and of the above-described in vitro transcription and translation method according to the invention for increasing the expression of a protein in a host cell.
- Host cells in step e") can here also include autologous cells, i.e. cells that are removed from a patient and returned again (cells belonging to the body).
- autologous cells reduce the risk of rejection by the immune system in in vivo applications.
- (healthy or diseased) cells from the affected body regions/organs of the patient are preferably used.
- Transfection methods are preferably those as described above for step e).
- step e" transplantation of the host cell into an organism is carried out in addition to step e).
- An organism or a living being in connection with the present invention is typically an animal, including cattle, pigs, mice, dogs, cats, rodents, hamsters, rabbits, etc., as well as humans.
- steps e") and f ') the isolation and/or purification according to steps f)/f) and/or g)/g') and subsequent administration of the translated (therapeutically active) protein to the living being can be carried out.
- the administration can be carried out as described for pharmaceutical compositions.
- step f ' the translation of the protein coded for by the base-modified nucleic acid is carried out in the organism.
- the translation takes place by host-cell-specific systems in dependence on the host cell used.
- the nucleic acid used according to the invention can also be expressed by an in vitro translation method of steps (e") to (g"), which, as such, also forms part of the present invention.
- Another embodiment of the present invention refers to cell-based approaches for therapeutic purposes. Accordingly, cells explanted from the body of the organism, in particular humans, are cultured in vitro. These cells are transfected by an base-modified RNA as disclosed herein.
- the base-modified RNA is provided as described herein elsewhere.
- transfection of the cells or tissues in vitro or in vivo is in general carried out by adding the base-modified RNA provided and/or prepared according to step a) to the cells or tissue.
- the complexed RNA then enters the cells by using cellular mechanisms, e.g. endocytosis. Addition of the complexed RNA to the cells or tissues may occur directly without any further additional components.
- addition of the base-modified RNA provided and/or prepared according to step a) id added to the cells or tissues may occur as a composition as defined herein, (optionally containing further additional components).
- Cells (or host cells) in this context for transfection of the base-modified RNA (provided and/or prepared according to step a)) in vitro includes any cell, and preferably, with out being restricted thereto, cells, which allow expression of a protein encoded by the base-modified RNA.
- Cells in this context preferably include cultured eukaryotic cells (e.g. yeast cells, plant cells, animal cells and human cells) or prokaryotic cells (e.g. bacteria cells etc.).
- Cells of multicellular organisms are preferably chosen if posttranslational modifications, e.g. glycosylation of the encoded protein, are necessary (N- and/or O-coupled).
- eukaryotic cells render possible posttranslational modification of the protein synthesized.
- the person skilled in the art knows a large number of such higher eukaryotic cells or cell lines, e.g. 293T (embryonal kidney cell line), HeLa (human cervix carcinoma cells), CHO (cells from the ovaries of the Chinese hamster) and further cell lines, including such cells and cell lines developed for laboratory purposes, such as, for example, hTERT-MSC, HEK293, Sf9 or COS cells.
- Suitable eukaryotic cells furthermore include cells or cell lines which are impaired by diseases or infections, e.g.
- cancer cells in particular cancer cells of any of the types of cancer mentioned here in the description, cells impaired by HFV, and/or cells of the immune system or of the central nervous system (CNS).
- Suitable cells can likewise be derived from eukaryotic microorganisms, such as yeast, e.g. Saccharomyces cerevisiae (Stinchcomb et al, Nature, 282:39, (1997)), Schizosaccharomyces pombe, Candida, Pichia, and filamentous fungi of the genera Aspergillus, Penicillium, etc.
- yeast e.g. Saccharomyces cerevisiae (Stinchcomb et al, Nature, 282:39, (1997)
- Schizosaccharomyces pombe e.g. Saccharomyces cerevisiae (Stinchcomb et al, Nature, 282:39, (1997)
- Schizosaccharomyces pombe e.g. Saccharomyces cere
- antigen presenting cells may be used for ex vivo transfection of the bas-modified RNA according to the present invention.
- dendritic cells which may be used for ex vivo transfection of the complexed RNA according to the present invention.
- APCs in particular dendritic cells are particularly useful, if the base-modified RNA codes for an antigen of a pathogenic organism or a tumor antigen.
- the retransplanted APCs are able to express the antigen in vivo and to provoke an adequate, adaptive immune response in vivo.
- the retransplanted, preferably in to the blood, APCs trigger an adequate immune response which allows the organism to immunologically attack the tumor or the pathogenic organism.
- This method may also allow to treat autoimmune diseases, since the autoantigen presented after transfection on the APCs may desensitize the organism (if an adequate administration protocol is followed) and thereby suppresses the Organism's immune response.
- Suitable cells likewise include prokaryotic cells, such as e.g. bacteria cells, e.g. from Escherichia coli or from bacteria of the general Bacillus, Lactococcus, Lactobacillus, Pseudomonas, Streptomyces, Streptococcus, Staphylococcus, preferably E. coli, etc.
- prokaryotic cells such as e.g. bacteria cells, e.g. from Escherichia coli or from bacteria of the general Bacillus, Lactococcus, Lactobacillus, Pseudomonas, Streptomyces, Streptococcus, Staphylococcus, preferably E. coli, etc.
- this embodiment allows to pursue a cell-based gene therapeutic approach, whereby (a) base-modified RNA or a composition containing a base-modified RNA is provided, (b) cells are explanted from a multicellular organism (if required), (c) cells are transfected by a base-modified RNA of the invention and (d) cells are retransplanted into the organism.
- This approach holds, if autologous cells are used. If there is no need to use autologous cells, also allogenic cells may be used (e.g. established cell lines), which are then transfected and re-implanted. Accordingly, the allogenic cells may allow to skip step (b).
- the ex vivo method is one embodiment, the invention encompasses also the use of a base-modified RNA for extracellular transfection of cells or tissues as disclosed above.
- the present invention also provides a process for the preparation of a RNA library or compositions containing an RNA library, comprising the steps:
- preparation/provision of a cDNA library, or a part thereof, from any cell or tissue, in particular a tumour tissue of a patient (b) preparation/provision of a matrix for in vitro transcription of a base-modified RNA according to the invention with the aid of the cDNA library or a part thereof and (c) in vitro transcribing of the matrix.
- the any tissue of the patient can be obtained e.g. by a simple biopsy (e.g. a tumoue tissue). However, it can also be provided by surgical removal of e.g. tumour-invaded tissue.
- the preparation/provision of the cDNA library or a part thereof according to step (a) of the preparation process of the present invention can moreover be carried out after the corresponding tissue has been deep-frozen for storage, preferably at temperatures below -70 0 C.
- isolation of the total RNA e.g. from a tumour tissue biopsy, is first carried out. Processes for this are described e.g. in Maniatis et al., supra.
- Corresponding kits are furthermore commercially obtainable for this, e.g. from Roche AG (e.g. the product "High Pure RNA Isolation Kit”).
- the corresponding poly(A + ) RNA is isolated from the total RNA in accordance with processes known to a person skilled in the art (cf. e.g. Maniatis et al., supra).
- Appropriate kits are also commercially obtainable for this.
- An example is the "High Pure RNA Tissue Kit” from Roche AG.
- the cDNA library is then prepared (in this context cf. also e.g. Maniatis et al., supra).
- kits are available to a person skilled in the art, e.g. the "SMART PCR cDNA Synthesis Kit” from Clontech Inc.
- the individual sub-steps from the poly(A + ) RNA to the double-stranded cDNA may be carried out in accordance with the "SMART PCR cDNA Synthesis Kit” from Clontech Inc.
- a matrix is synthesized for the in vitro transcription.
- this is effected in particular by cloning the cDNA fragments obtained into a suitable RNA production vector, e.g. a plasmid.
- a suitable RNA production vector e.g. a plasmid.
- these are first linearized with a corresponding restriction enzyme, if they are present as circular plasmid (c)DNA.
- the construct cleaved in this way is purified once more, e.g.
- RNA matrix is in a protein-free form.
- the enzymatic synthesis of the RNA is then carried out starting from the purified matrix.
- RNA library may be prepared which contains exclusively a specific base modified form of rATP, rCTP, rUTP or rGTP. Also any combination of base-modified nucleotides may be obtained, e.g.
- the library may also contain only a certain amount of a base-modified nucleotides of one or more types of the 4 types of nucleotides, which may be influenced by the initial ratio of base-modified/unmodified nucleotides added to the transcription reaction medium (e.g. 20% 7-Deazaguanosine-TP and 80% native Guanosin-TP).
- the reaction mixture is present here in RNase-free water.
- a CAP analogue is also added during the actual enzymatic synthesis of the RNA.
- the DNA matrix is degraded by addition of RNase-free DNase, incubation preferably being carried out again at 37 0 C.
- the RNA prepared in this way is precipitated by means of ammonium acetate/ethanol and, where appropriate, washed once or several times with RNase-free ethanol. Finally, the RNA purified in this way is dried and, according to a preferred embodiment, is taken up in RNase-free water.
- the RNA prepared in this way can moreover be subjected to several extractions with phenol/chloroform or phenol/chloroform/isoamyl alcohol.
- a so-called subtraction library can therefore also be used as part of the total cDNA library in order to provide the mRNA molecules according to the invention.
- a preferred part of the cDNA library of any tissue e.g. a tumour tissue
- codes for specific proteins of particular interest while other proteins may be less relevant.
- the corresponding antigens are known.
- the part of the cDNA library which codes for the (tumour)specific antigens can first be defined (i.e. before step (a) of the process defined above). This is preferably effected by determining the sequences of the (tumour)-specific antigens by an alignment with a corresponding cDNA library from healthy tissue. Similar methods may be used to establish RNA libraries containing base-modified RNA sequences, if certain antigens derived from pathogens shall be presented by an inventive RNA library. These antigens may be isolated similarly, subtracting the normal proteins of an infected tissue.
- the alignment according to the invention comprises in particular a comparison of the expression pattern of the healthy tissue with that of the (tumour) tissue in question.
- Corresponding expression patterns can be determined at the nucleic acid level e.g. with the aid of suitable hybridization experiments.
- the corresponding (m)RNA or cDNA libraries of the tissue can in each case be separated in suitable agarose or polyacrylamide gels, transferred to membranes and hybridized with corresponding nucleic acid probes, preferably oligonucleotide probes, which represent the particular genes (northern and southern blots, respectively).
- corresponding nucleic acid probes preferably oligonucleotide probes, which represent the particular genes (northern and southern blots, respectively).
- a comparison of the corresponding hybridizations thus provides those genes which are expressed either exclusively by the tumour tissue or to a greater extent therein.
- the hybridization experiments mentioned are carried out with the aid of a diagnosis by microarrays (one or more microarrays).
- a corresponding DNA microarray comprises a defined arrangement, in particular in a small or very small space, of nucleic acid, in particular oligonucleotide, probes, each probe representing e.g. in each case a gene, the presence or absence of which is to be investigated in the corresponding (m)RNA or cDNA library.
- m mRNA or cDNA library
- the corresponding cDNA is then marked with a suitable marker, in particular fluorescence markers are used for this purpose, and brought into contact with the microarray under suitable hybridization conditions.
- a suitable marker in particular fluorescence markers are used for this purpose, and brought into contact with the microarray under suitable hybridization conditions.
- fluorescence markers are used for this purpose, and brought into contact with the microarray under suitable hybridization conditions.
- a cDNA species binds to a probe molecule present on the microarray, in particular an oligonucleotide probe molecule, a more or less pronounced fluorescence signal, which can be measured with a suitable detection apparatus, e.g. an appropriately designed fluorescence spectrometer, is accordingly observed.
- a suitable detection apparatus e.g. an appropriately designed fluorescence spectrometer
- the corresponding microarray hybridization experiment (or several or many of these) is (are) carried out separately for the tumour tissue and the healthy tissue.
- the genes expressed exclusively or to an increased extent by the tumour tissue can therefore be concluded from the difference between the signals read from the microarray experiments.
- DNA microarray analyses are described e.g. in Schena (2002), Microarray Analysis, ISBN 0-471-41443-3, John Wiley & Sons, Inc., New York, the disclosure content in this respect of this document being included in its full scope in the present invention.
- the establishing of (tumour) tissue-specific expression patterns is in no way limited to analyses at the nucleic acid level.
- RNA library containing base-modified nucleotides is encompassed by the present invention.
- An inventive RNA library may also represent only part of the transcriptom (all transcribed mRNA molecule of a cell/tissue) by subtracting the certain mRNA molecules from the original number of RNA molecules.
- any RNA library obtainable according to the above method of the invention is also encompassed by the present invention.
- Figure 1 shows the results of the base modification of luciferase RNA with pseudouridine-5 '-triphosphate and subsequent transfection in HeLa cells (see Example 2A).
- the overexpression of luciferase was substantially improved (960 amol (attomol) real quantity of the unmodified mRNA sequence compared with 94015 amol real quantity of the base-modified
- FIG. 2 shows the results of the base modifications of luciferase RNA with 5- methylcytidine-5 '-triphosphate and subsequent transfection into HeLa cells (see Example 2B). As will be seen in Figure 2, the overexpression of luciferase was likewise substantially improved (960 amol real quantity of the unmodified mRNA sequence compared with 3087 amol real quantity of the base-modified mRNA sequence).
- Figure 3 shows the results of the base modifications of luciferase RNA with pseudouridine-5 '-triphosphate and in parallel with 5-methylcytidine-5'- triphosphate and subsequent transfection into hPBMC cells (see Example 3B).
- Figure 4A shows the mRNA sequence of luciferase (SEQ ID NO: 3) with the following further modifications (see Example IA): • stabilising sequences from alpha-globin gene
- Figure 4B shows the natural coding mRNA sequence of luciferase (SEQ ID NO: 4) (see Example IA)
- Figure 4C shows the mRNA sequence of luciferase modified with pseudouridine (SEQ ID NO: 5) with the following further modifications (see Example IB):
- Figure 4D shows the methylcytidine-modified mRNA sequence of luciferase (SEQ ID NO: 1
- Figure 5 is a bar graph showing the results of a transfection experiment. hPBMCs were transfected with non-modified or modified mRNA coding for luciferase and luciferase activity was measured 16h after transfection. The data show that substitution of CTP with 5-Bromo-CTP or 5-Methyl-CTP, substitution of GTP with 7-Deaza-GTP or substitution of UTP with Pseudo-UTP increases the activity of luciferase encoded by modified mRNA compared with luciferase activity in cells which were transfected with non-modified mRNA.
- Figure 6 is a bar graph showing the results of a transfection experiment. HeLa cells were transfected with non-modified or modified mRNA coding for luciferase and luciferase activity was measured 16h after transfection. The data show that substitution of CTP with 5-Bromo-CTP or 5-Methyl-CTP, substitution of GTP with 7-Deaza-GTP or substitution of UTP with Pseudo-UTP increases the activity of luciferase encoded by modified mRNA compared with luciferase activity in cells which were transfected with non-modified mRNA.
- A) mRNA constructs A luciferase construct (CAP-Ppluc(wt)-muag-A70-C30) was first produced as template for the base modification (see Figure 4A, SEQ ID NO: 3), which contained the following modifications in addition to the native coding sequence (SEQ ID NO: 4, see Figure 4B):
- the luciferase construct (CAP-Ppluc(wt)-muag-A70-C30, see Figure 4A, SEQ ID NO: 3) was transcribed by means of T7 polymerase (T7-Opti mRNA Kit, CureVac, Tubingen,
- modified nucleotides were acquired from TriLink (San Diego, Calif.
- All mRNA transcripts contained a poly-A tail about 70 bases long and a 5'-cap structure.
- the cap structure was obtained by addition of an excess of N7- methylguanosme-5'-triphosphate-5'-guanosine.
- Pseudouridine-5'-triphosphate-modified mRNA was obtained by adding pseudouridine-5 '-triphosphate to the in vitro transcription reaction instead of uridine triphosphate (SEQ ID NO: 5, Fig. 4C) (see below).
- Methylcytidine-5'-triphosphate-modified RNA was obtained by adding 5- methylcytidine-5'-triphosphate to the in vitro transcription reaction instead of cytidine triphosphate (SEQ ID NO: 6, Fig. 4D) (see below).
- luciferase In order to study the effect of various base modifications on the expression of the protein coded for by the mRNA, a plasmid coding for luciferase was subjected to an in vitro transcription using a medium containing pseudouridine-5 '-triphosphate instead of uridine-5 '-triphosphate. The transcribed mRNA was then transfected into HeLa cells (see above). The expression of luciferase was measured by means of a luminometer after lysis of the cells. The overexpression of luciferase was substantially improved (960 amol real quantity of the unmodified mRNA sequence compared with 94015 amol real quantity of the base-modified mRNA sequence) (see Fig. 1).
- Example 1 HeLa cells and hPBMCs were transfected with 10 ⁇ g of unmodified or base-modified RNA by means of the EasyjecT Plus (Peqlab, Er Weg, Germany). 16 hours after the transfection, the cells were lysed with lysis buffer (25 mM
- Tris-PO 4 2 mM EDTA, 10% glycerol, 1% Triton-X 100, 2 mM DTT.
- the supernatants were mixed with luciferin buffer (25 mM glycylglycine, 15 mM MgSO 4 , 5 mM ATP, 62.5 ⁇ M luciferin) and the luminescence was determined by means of a luminometer (Lumat LB 9507 (Berthold Technologies, Bad Wildbad, Germany)).
- luciferase was substantially improved (260 amol real quantity of the unmodified mRNA sequence compared with 3351 amol real quantity of the mRNA sequence modified with pseudouridine-5'- triphosphate and 1274 amol real quantity of the mRNA sequence modified with 5- methylcytidine-5 '-triphosphate) (see Fig. 3).
- luciferase is expressed about 3 times more in HeLa cells and 5 times more in hPBMCs with methylcytidine as base modification of the mRNA in comparison with the unmodified mRNA.
- the modification of the mRNA with pseudouridine has an even greaeter effect on the expression of the encoded luciferase.
- hi HeLa cells for example, luciferase is expressed about 100 times more and in hPBMCs about 13 times more compared with the unmodified mRNA.
- the effect of the increased overexpression of the protein coded for by a base-modified RNA used according to the invention is accordingly also independent of the chosen host cell.
Abstract
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