US20140010861A1 - Modified polynucleotides for the production of proteins associated with human disease - Google Patents

Modified polynucleotides for the production of proteins associated with human disease Download PDF

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Publication number
US20140010861A1
US20140010861A1 US13/791,910 US201313791910A US2014010861A1 US 20140010861 A1 US20140010861 A1 US 20140010861A1 US 201313791910 A US201313791910 A US 201313791910A US 2014010861 A1 US2014010861 A1 US 2014010861A1
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US
United States
Prior art keywords
optionally substituted
independently
alkyl
polynucleotide
isolated polynucleotide
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US13/791,910
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English (en)
Inventor
Stephane Bancel
Tirtha Chakraborty
Antonin de Fougerolles
Sayda M. Elbashir
Matthias John
Atanu Roy
Susan Whoriskey
Kristy M. Wood
Paul Hatala
Jason P. Schrum
Kenechi Ejebe
Jeff Lynn Ellsworth
Justin Guild
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Moderna Inc
Original Assignee
Moderna Therapeutics Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=49235350&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20140010861(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to US13/791,910 priority Critical patent/US20140010861A1/en
Application filed by Moderna Therapeutics Inc filed Critical Moderna Therapeutics Inc
Assigned to modeRNA Therapeutics reassignment modeRNA Therapeutics ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: SCHRUM, Jason P.
Assigned to modeRNA Therapeutics reassignment modeRNA Therapeutics ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: EJEBE, KENECHI G.
Assigned to modeRNA Therapeutics reassignment modeRNA Therapeutics ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DE FOUGEROLLES, ANTONIN, ELBASHIR, Sayda M., ELLSWORTH, JEFF LYNN, GUILD, JUSTIN, HATALA, PAUL, JOHN, MATTHIAS, ROY, ATANU, WHORISKEY, SUSAN, WOOD, Kristy M., CHAKRABORTY, TIRTHA
Assigned to modeRNA Therapeutics reassignment modeRNA Therapeutics ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BANCEL, STEPHANE
Priority to US14/105,224 priority patent/US9220755B2/en
Priority to US14/105,217 priority patent/US20140255467A1/en
Priority to US14/105,214 priority patent/US20140171485A1/en
Priority to US14/105,210 priority patent/US20150044277A1/en
Priority to US14/105,221 priority patent/US20140255468A1/en
Publication of US20140010861A1 publication Critical patent/US20140010861A1/en
Priority to US14/171,242 priority patent/US20140200264A1/en
Priority to US14/171,249 priority patent/US9089604B2/en
Priority to US14/171,226 priority patent/US9061059B2/en
Priority to US14/171,235 priority patent/US20140206755A1/en
Assigned to MODERNA THERAPEUTICS, INC. reassignment MODERNA THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: EJEBE, KENECHI, DR.
Priority to US14/508,631 priority patent/US20150050354A1/en
Assigned to MODERNA THERAPEUTICS, INC. reassignment MODERNA THERAPEUTICS, INC. CORRECTIVE ASSIGNMENT TO CORRECT THE RECEIVING PARTY NAME PREVIOUSLY RECORDED AT REEL: 030187 FRAME: 0748. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Assignors: BANCEL, STEPHANE
Assigned to MODERNA THERAPEUTICS, INC. reassignment MODERNA THERAPEUTICS, INC. CORRECTIVE ASSIGNMENT TO CORRECT THE RECEIVING PARTY NAME FROM MODERNA THERAPEUTICS TO MODERNA THERAPEUTICS, INC. PREVIOUSLY RECORDED AT REEL: 030043 FRAME: 0160. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Assignors: DE FOUGEROLLES, ANTONIN, ELBASHIR, Sayda M., ELLSWORTH, JEFF LYNN, GUILD, JUSTIN, HATALA, PAUL, JOHN, MATTHIAS, ROY, ATANU, WHORISKEY, SUSAN, WOOD, Kristy M., CHAKRABORTY, TIRTHA
Assigned to MODERNA THERAPEUTICS, INC. reassignment MODERNA THERAPEUTICS, INC. CORRECTIVE ASSIGNMENT TO CORRECT THE RECEIVING PARTY'S NAME PREVIOUSLY RECORDED AT REEL: 030026 FRAME: 0313. ASSIGNOR(S) HEREBY CONFIRMS THE ASSIGNMENT. Assignors: SCHRUM, Jason P.
Priority to US15/060,707 priority patent/US9782462B2/en
Priority to US15/440,523 priority patent/US20180086807A1/en
Priority to US16/665,985 priority patent/US20210115101A1/en
Priority to US18/634,220 priority patent/US20240327476A1/en
Abandoned legal-status Critical Current

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Definitions

  • the invention relates to compositions, methods, processes, kits and devices for the design, preparation, manufacture and/or formulation of polynucleotides, primary constructs and modified mRNA molecules (mmRNA).
  • mmRNA modified mRNA molecules
  • introduced DNA can integrate into host cell genomic DNA at some frequency, resulting in alterations and/or damage to the host cell genomic DNA.
  • the heterologous deoxyribonucleic acid (DNA) introduced into a cell can be inherited by daughter cells (whether or not the heterologous DNA has integrated into the chromosome) or by offspring.
  • nucleic acid based compounds or polynucleotides which encode a polypeptide of interest (e.g., modified mRNA or mmRNA) and which have structural and/or chemical features that avoid one or more of the problems in the art, for example, features which are useful for optimizing formulation and delivery of nucleic acid-based therapeutics while retaining structural and functional integrity, overcoming the threshold of expression, improving expression rates, half life and/or protein concentrations, optimizing protein localization, and avoiding deleterious bio-responses such as the immune response and/or degradation pathways.
  • a polypeptide of interest e.g., modified mRNA or mmRNA
  • compositions, methods, processes, kits and devices for the design, preparation, manufacture and/or formulation of modified mRNA (mmRNA) molecules are described herein.
  • FIG. 1 is a schematic of a primary construct of the present invention.
  • FIG. 2 illustrates lipid structures in the prior art useful in the present invention. Shown are the structures for 98N12-5 (TETA5-LAP), DLin-DMA, DLin-K-DMA (2,2-Dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane), DLin-KC2-DMA, DLin-MC3-DMA and C12-200.
  • TETA5-LAP TETA5-LAP
  • DLin-DMA DLin-K-DMA (2,2-Dilinoleyl-4-dimethylaminomethyl-[1,3]-dioxolane)
  • DLin-KC2-DMA DLin-MC3-DMA
  • C12-200 C12-200.
  • FIG. 3 is a representative plasmid useful in the IVT reactions taught herein.
  • the plasmid contains Insert 64818, designed by the instant inventors.
  • FIG. 4 is a gel profile of modified mRNA encapsulated in PLGA microspheres.
  • FIG. 5 is a histogram of Factor IX protein production PLGA formulation Factor IX modified mRNA.
  • FIG. 6 is a histogram showing VEGF protein production in human keratinocyte cells after transfection of modified mRNA at a range of doses.
  • FIG. 6A shows protein production after transfection of modified mRNA comprising natural nucleoside triphosphate (NTP).
  • FIG. 6B shows protein production after transfection of modified mRNA fully modified with pseudouridine (Pseudo-U) and 5-methylcytosine (5mC).
  • FIG. 6C shows protein production after transfection of modified mRNA fully modified with N1-methyl-pseudouridine (N1-methyl-Pseudo-U) and 5-methylcytosine (5mC).
  • FIG. 7 is a histogram of VEGF protein production in HEK293 cells.
  • FIG. 8 is a histogram of VEGF expression and IFN-alpha induction after transfection of VEGF modified mRNA in peripheral blood mononuclear cells (PBMC).
  • FIG. 8A shows VEGF expression.
  • FIG. 8B shows IFN-alpha induction.
  • FIG. 9 is a histogram of VEGF protein production in HeLa cells from VEGF modified mRNA.
  • FIG. 10 is a histogram of VEGF protein production from lipoplexed VEGF modified mRNA in mice.
  • FIG. 11 is a histogram of G-CSF protein production in HeLa cells from G-CSF modified mRNA.
  • FIG. 12 is a histogram of Factor IX protein production in HeLa cell supernatant from Factor IX modified mRNA.
  • RNA ribonucleic acid
  • RNA ribonucleic acid
  • compositions including pharmaceutical compositions
  • methods for the design, preparation, manufacture and/or formulation of polynucleotides encoding one or more polypeptides of interest are also provided.
  • these polynucleotides are preferably modified as to avoid the deficiencies of other polypeptide-encoding molecules of the art. Hence these polynucleotides are referred to as modified mRNA or mmRNA.
  • polynucleotides, primary constructs and/or mmRNA encoding polypeptides of interest which have been designed to improve one or more of the stability and/or clearance in tissues, receptor uptake and/or kinetics, cellular access by the compositions, engagement with translational machinery, mRNA half-life, translation efficiency, immune evasion, protein production capacity, secretion efficiency (when applicable), accessibility to circulation, protein half-life and/or modulation of a cell's status, function and/or activity.
  • nucleic acid molecules specifically polynucleotides, primary constructs and/or mmRNA which encode one or more polypeptides of interest.
  • nucleic acid in its broadest sense, includes any compound and/or substance that comprise a polymer of nucleotides. These polymers are often referred to as polynucleotides.
  • nucleic acids or polynucleotides of the invention include, but are not limited to, ribonucleic acids (RNAs), deoxyribonucleic acids (DNAs), threose nucleic acids (TNAs), glycol nucleic acids (GNAs), peptide nucleic acids (PNAs), locked nucleic acids (LNAs, including LNA having a ⁇ -D-ribo configuration, ⁇ -LNA having an ⁇ -L-ribo configuration (a diastereomer of LNA), 2′-amino-LNA having a 2′-amino functionalization, and 2′-amino- ⁇ -LNA having a 2′-amino functionalization) or hybrids thereof.
  • RNAs ribonucleic acids
  • DNAs deoxyribonucleic acids
  • TAAs threose nucleic acids
  • GNAs glycol nucleic acids
  • PNAs peptide nucleic acids
  • LNAs locked nu
  • the nucleic acid molecule is a messenger RNA (mRNA).
  • mRNA messenger RNA
  • the term “messenger RNA” (mRNA) refers to any polynucleotide which encodes a polypeptide of interest and which is capable of being translated to produce the encoded polypeptide of interest in vitro, in vivo, in situ or ex vivo.
  • the basic components of an mRNA molecule include at least a coding region, a 5′UTR, a 3′UTR, a 5′ cap and a poly-A tail.
  • the present invention expands the scope of functionality of traditional mRNA molecules by providing polynucleotides or primary RNA constructs which maintain a modular organization, but which comprise one or more structural and/or chemical modifications or alterations which impart useful properties to the polynucleotide including, in some embodiments, the lack of a substantial induction of the innate immune response of a cell into which the polynucleotide is introduced.
  • modified mRNA molecules of the present invention are termed “mmRNA.”
  • a “structural” feature or modification is one in which two or more linked nucleotides are inserted, deleted, duplicated, inverted or randomized in a polynucleotide, primary construct or mmRNA without significant chemical modification to the nucleotides themselves. Because chemical bonds will necessarily be broken and reformed to effect a structural modification, structural modifications are of a chemical nature and hence are chemical modifications. However, structural modifications will result in a different sequence of nucleotides. For example, the polynucleotide “ATCG” may be chemically modified to “AT-5meC-G”. The same polynucleotide may be structurally modified from “ATCG” to “ATCCCG”. Here, the dinucleotide “CC” has been inserted, resulting in a structural modification to the polynucleotide.
  • the mmRNA of the present invention are distinguished from wild type mRNA in their functional and/or structural design features which serve to, as evidenced herein, overcome existing problems of effective polypeptide production using nucleic acid-based therapeutics.
  • FIG. 1 shows a representative polynucleotide primary construct 100 of the present invention.
  • the term “primary construct” or “primary mRNA construct” refers to a polynucleotide transcript which encodes one or more polypeptides of interest and which retains sufficient structural and/or chemical features to allow the polypeptide of interest encoded therein to be translated.
  • Primary constructs may be polynucleotides of the invention. When structurally or chemically modified, the primary construct may be referred to as an mmRNA.
  • the primary construct 100 here contains a first region of linked nucleotides 102 that is flanked by a first flanking region 104 and a second flaking region 106 .
  • the “first region” may be referred to as a “coding region” or “region encoding” or simply the “first region.”
  • This first region may include, but is not limited to, the encoded polypeptide of interest.
  • the polypeptide of interest may comprise at its 5 ′ terminus one or more signal sequences encoded by a signal sequence region 103 .
  • the flanking region 104 may comprise a region of linked nucleotides comprising one or more complete or incomplete 5′ UTRs sequences.
  • the flanking region 104 may also comprise a 5′ terminal cap 108 .
  • the second flanking region 106 may comprise a region of linked nucleotides comprising one or more complete or incomplete 3′ UTRs.
  • the flanking region 106 may also comprise a 3′ tailing sequence 110 .
  • first operational region 105 Bridging the 5′ terminus of the first region 102 and the first flanking region 104 is a first operational region 105 .
  • this operational region comprises a Start codon.
  • the operational region may alternatively comprise any translation initiation sequence or signal including a Start codon.
  • this operational region comprises a Stop codon.
  • the operational region may alternatively comprise any translation initiation sequence or signal including a Stop codon. According to the present invention, multiple serial stop codons may also be used.
  • the shortest length of the first region of the primary construct of the present invention can be the length of a nucleic acid sequence that is sufficient to encode for a dipeptide, a tripeptide, a tetrapeptide, a pentapeptide, a hexapeptide, a heptapeptide, an octapeptide, a nonapeptide, or a decapeptide.
  • the length may be sufficient to encode a peptide of 2-30 amino acids, e.g. 5-30, 10-30, 2-25, 5-25, 10-25, or 10-20 amino acids.
  • the length may be sufficient to encode for a peptide of at least 11, 12, 13, 14, 15, 17, 20, 25 or 30 amino acids, or a peptide that is no longer than 40 amino acids, e.g. no longer than 35, 30, 25, 20, 17, 15, 14, 13, 12, 11 or 10 amino acids.
  • the length of the first region encoding the polypeptide of interest of the present invention is greater than about 30 nucleotides in length (e.g., at least or greater than about 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, and 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000, 10,000, 20,000, 30,000, 40,000, 50,000, 60,000, 70,000, 80,000, 90,000 or up to and including 100,000 nucleotides).
  • the “first region” may be referred to as a “coding region” or “region encoding” or simply the “first region.”
  • the polynucleotide, primary construct, or mmRNA includes from about 30 to about 100,000 nucleotides (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 1,000, from 30 to 1,500, from 30 to 3,000, from 30 to 5,000, from 30 to 7,000, from 30 to 10,000, from 30 to 25,000, from 30 to 50,000, from 30 to 70,000, from 100 to 250, from 100 to 500, from 100 to 1,000, from 100 to 1,500, from 100 to 3,000, from 100 to 5,000, from 100 to 7,000, from 100 to 10,000, from 100 to 25,000, from 100 to 50,000, from 100 to 70,000, from 100 to 100,000, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 3,000, from 500 to 5,000, from 500 to 7,000, from 500 to 10,000, from 500 to 25,000, from 500 to 50,000, from 500 to 70,000, from 500 to 100,000, from 1,000 to 1,500, from 1,000, from 500 to 2,000, from 500 to
  • the first and second flanking regions may range independently from 15-1,000 nucleotides in length (e.g., greater than 30, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, and 900 nucleotides or at least 30, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, and 1,000 nucleotides).
  • 15-1,000 nucleotides in length e.g., greater than 30, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, and 1,000 nucleotides.
  • the tailing sequence may range from absent to 500 nucleotides in length (e.g., at least 60, 70, 80, 90, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, or 500 nucleotides).
  • the length may be determined in units of or as a function of polyA Binding Protein binding.
  • the polyA tail is long enough to bind at least 4 monomers of PolyA Binding Protein.
  • PolyA Binding Protein monomers bind to stretches of approximately 38 nucleotides. As such, it has been observed that polyA tails of about 80 nucleotides and 160 nucleotides are functional.
  • the capping region may comprise a single cap or a series of nucleotides forming the cap.
  • the capping region may be from 1 to 10, e.g. 2-9, 3-8, 4-7, 1-5, 5-10, or at least 2, or 10 or fewer nucleotides in length.
  • the cap is absent.
  • the first and second operational regions may range from 3 to 40, e.g., 5-30, 10-20, 15, or at least 4, or 30 or fewer nucleotides in length and may comprise, in addition to a Start and/or Stop codon, one or more signal and/or restriction sequences.
  • a primary construct or mmRNA may be cyclized, or concatemerized, to generate a translation competent molecule to assist interactions between poly-A binding proteins and 5′-end binding proteins.
  • the mechanism of cyclization or concatemerization may occur through at least 3 different routes: 1) chemical, 2) enzymatic, and 3) ribozyme catalyzed.
  • the newly formed 5′-/3′-linkage may be intramolecular or intermolecular.
  • the 5′-end and the 3′-end of the nucleic acid contain chemically reactive groups that, when close together, form a new covalent linkage between the 5′-end and the 3′-end of the molecule.
  • the 5′-end may contain an NHS-ester reactive group and the 3′-end may contain a 3′-amino-terminated nucleotide such that in an organic solvent the 3′-amino-terminated nucleotide on the 3′-end of a synthetic mRNA molecule will undergo a nucleophilic attack on the 5′—NHS-ester moiety forming a new 5′-/3′-amide bond.
  • T4 RNA ligase may be used to enzymatically link a 5′-phosphorylated nucleic acid molecule to the 3′-hydroxyl group of a nucleic acid forming a new phosphorodiester linkage.
  • 1 ⁇ g of a nucleic acid molecule is incubated at 37° C. for 1 hour with 1-10 units of T4 RNA ligase (New England Biolabs, Ipswich, Mass.) according to the manufacturer's protocol.
  • the ligation reaction may occur in the presence of a split oligonucleotide capable of base-pairing with both the 5′- and 3′-region in juxtaposition to assist the enzymatic ligation reaction.
  • either the 5′- or 3′-end of the cDNA template encodes a ligase ribozyme sequence such that during in vitro transcription, the resultant nucleic acid molecule can contain an active ribozyme sequence capable of ligating the 5′-end of a nucleic acid molecule to the 3′-end of a nucleic acid molecule.
  • the ligase ribozyme may be derived from the Group I Intron, Group I Intron, Hepatitis Delta Virus, Hairpin ribozyme or may be selected by SELEX (systematic evolution of ligands by exponential enrichment).
  • the ribozyme ligase reaction may take 1 to 24 hours at temperatures between 0 and 37° C.
  • multiple distinct polynucleotides, primary constructs or mmRNA may be linked together through the 3′-end using nucleotides which are modified at the 3′-terminus.
  • Chemical conjugation may be used to control the stoichiometry of delivery into cells.
  • the glyoxylate cycle enzymes, isocitrate lyase and malate synthase may be supplied into HepG2 cells at a 1:1 ratio to alter cellular fatty acid metabolism.
  • This ratio may be controlled by chemically linking polynucleotides, primary constructs or mmRNA using a 3′-azido terminated nucleotide on one polynucleotide, primary construct or mmRNA species and a C5-ethynyl or alkynyl-containing nucleotide on the opposite polynucleotide, primary construct or mmRNA species.
  • the modified nucleotide is added post-transcriptionally using terminal transferase (New England Biolabs, Ipswich, Mass.) according to the manufacturer's protocol.
  • the two polynucleotide, primary construct or mmRNA species may be combined in an aqueous solution, in the presence or absence of copper, to form a new covalent linkage via a click chemistry mechanism as described in the literature.
  • more than two polynucleotides may be linked together using a functionalized linker molecule.
  • a functionalized saccharide molecule may be chemically modified to contain multiple chemical reactive groups (SH—, NH 2 —, N 3 , etc. . . . ) to react with the cognate moiety on a 3′-functionalized mRNA molecule (i.e., a 3′-maleimide ester, 3′—NHS-ester, alkynyl).
  • the number of reactive groups on the modified saccharide can be controlled in a stoichiometric fashion to directly control the stoichiometric ratio of conjugated polynucleotide, primary construct or mmRNA.
  • primary constructs or mmRNA of the present invention can be designed to be conjugated to other polynucleotides, dyes, intercalating agents (e.g. acridines), cross-linkers (e.g. psoralene, mitomycin C), porphyrins (TPPC4, texaphyrin, Sapphyrin), polycyclic aromatic hydrocarbons (e.g., phenazine, dihydrophenazine), artificial endonucleases (e.g.
  • intercalating agents e.g. acridines
  • cross-linkers e.g. psoralene, mitomycin C
  • porphyrins TPPC4, texaphyrin, Sapphyrin
  • polycyclic aromatic hydrocarbons e.g., phenazine, dihydrophenazine
  • artificial endonucleases e.g.
  • alkylating agents phosphate, amino, mercapto, PEG (e.g., PEG-40K), MPEG, [MPEG] 2 , polyamino, alkyl, substituted alkyl, radiolabeled markers, enzymes, haptens (e.g.
  • biotin e.g., aspirin, vitamin E, folic acid
  • transport/absorption facilitators e.g., aspirin, vitamin E, folic acid
  • synthetic ribonucleases proteins, e.g., glycoproteins, or peptides, e.g., molecules having a specific affinity for a co-ligand, or antibodies e.g., an antibody, that binds to a specified cell type such as a cancer cell, endothelial cell, or bone cell, hormones and hormone receptors, non-peptidic species, such as lipids, lectins, carbohydrates, vitamins, cofactors, or a drug.
  • a specified cell type such as a cancer cell, endothelial cell, or bone cell
  • hormones and hormone receptors non-peptidic species, such as lipids, lectins, carbohydrates, vitamins, cofactors, or a drug.
  • Conjugation may result in increased stability and/or half life and may be particularly useful in targeting the polynucleotides, primary constructs or mmRNA to specific sites in the cell, tissue or organism.
  • the mmRNA or primary constructs may be administered with, or further encode one or more of RNAi agents, siRNAs, shRNAs, miRNAs, miRNA binding sites, antisense RNAs, ribozymes, catalytic DNA, tRNA, RNAs that induce triple helix formation, aptamers or vectors, and the like.
  • RNAi agents siRNAs, shRNAs, miRNAs, miRNA binding sites, antisense RNAs, ribozymes, catalytic DNA, tRNA, RNAs that induce triple helix formation, aptamers or vectors, and the like.
  • bifunctional polynucleotides e.g., bifunctional primary constructs or bifunctional mmRNA.
  • bifunctional polynucleotides are those having or capable of at least two functions. These molecules may also by convention be referred to as multi-functional.
  • bifunctional polynucleotides may be encoded by the RNA (the function may not manifest until the encoded product is translated) or may be a property of the polynucleotide itself. It may be structural or chemical.
  • Bifunctional modified polynucleotides may comprise a function that is covalently or electrostatically associated with the polynucleotides. Further, the two functions may be provided in the context of a complex of a mmRNA and another molecule.
  • Bifunctional polynucleotides may encode peptides which are anti-proliferative. These peptides may be linear, cyclic, constrained or random coil. They may function as aptamers, signaling molecules, ligands or mimics or mimetics thereof. Anti-proliferative peptides may, as translated, be from 3 to 50 amino acids in length. They may be 5-40, 10-30, or approximately 15 amino acids long. They may be single chain, multichain or branched and may form complexes, aggregates or any multi-unit structure once translated.
  • noncoding region may be the “first region” of the primary construct.
  • the noncoding region may be a region other than the first region.
  • Such molecules are generally not translated, but can exert an effect on protein production by one or more of binding to and sequestering one or more translational machinery components such as a ribosomal protein or a transfer RNA (tRNA), thereby effectively reducing protein expression in the cell or modulating one or more pathways or cascades in a cell which in turn alters protein levels.
  • translational machinery components such as a ribosomal protein or a transfer RNA (tRNA)
  • the polynucleotide or primary construct may contain or encode one or more long noncoding RNA (1ncRNA, or lincRNA) or portion thereof, a small nucleolar RNA (sno-RNA), micro RNA (miRNA), small interfering RNA (siRNA) or Piwi-interacting RNA (piRNA).
  • RNA long noncoding RNA
  • miRNA micro RNA
  • siRNA small interfering RNA
  • piRNA Piwi-interacting RNA
  • the primary construct is designed to encode one or more polypeptides of interest or fragments thereof.
  • a polypeptide of interest may include, but is not limited to, whole polypeptides, a plurality of polypeptides or fragments of polypeptides, which independently may be encoded by one or more nucleic acids, a plurality of nucleic acids, fragments of nucleic acids or variants of any of the aforementioned.
  • the term “polypeptides of interest” refer to any polypeptide which is selected to be encoded in the primary construct of the present invention.
  • polypeptide means a polymer of amino acid residues (natural or unnatural) linked together most often by peptide bonds.
  • polypeptides refers to proteins, polypeptides, and peptides of any size, structure, or function.
  • polypeptide encoded is smaller than about 50 amino acids and the polypeptide is then termed a peptide. If the polypeptide is a peptide, it will be at least about 2, 3, 4, or at least 5 amino acid residues long.
  • polypeptides include gene products, naturally occurring polypeptides, synthetic polypeptides, homologs, orthologs, paralogs, fragments and other equivalents, variants, and analogs of the foregoing.
  • a polypeptide may be a single molecule or may be a multi-molecular complex such as a dimer, trimer or tetramer.
  • polypeptides may also comprise single chain or multichain polypeptides such as antibodies or insulin and may be associated or linked. Most commonly disulfide linkages are found in multichain polypeptides.
  • polypeptide may also apply to amino acid polymers in which one or more amino acid residues are an artificial chemical analogue of a corresponding naturally occurring amino acid.
  • polypeptide variant refers to molecules which differ in their amino acid sequence from a native or reference sequence.
  • the amino acid sequence variants may possess substitutions, deletions, and/or insertions at certain positions within the amino acid sequence, as compared to a native or reference sequence.
  • variants will possess at least about 50% identity (homology) to a native or reference sequence, and preferably, they will be at least about 80%, more preferably at least about 90% identical (homologous) to a native or reference sequence.
  • variant mimics are provided.
  • the term “variant mimic” is one which contains one or more amino acids which would mimic an activated sequence.
  • glutamate may serve as a mimic for phosphoro-threonine and/or phosphoro-serine.
  • variant mimics may result in deactivation or in an inactivated product containing the mimic, e.g., phenylalanine may act as an inactivating substitution for tyrosine; or alanine may act as an inactivating substitution for serine.
  • “Homology” as it applies to amino acid sequences is defined as the percentage of residues in the candidate amino acid sequence that are identical with the residues in the amino acid sequence of a second sequence after aligning the sequences and introducing gaps, if necessary, to achieve the maximum percent homology. Methods and computer programs for the alignment are well known in the art. It is understood that homology depends on a calculation of percent identity but may differ in value due to gaps and penalties introduced in the calculation.
  • homologs as it applies to polypeptide sequences means the corresponding sequence of other species having substantial identity to a second sequence of a second species.
  • Analogs is meant to include polypeptide variants which differ by one or more amino acid alterations, e.g., substitutions, additions or deletions of amino acid residues that still maintain one or more of the properties of the parent or starting polypeptide.
  • compositions which are polypeptide based including variants and derivatives. These include substitutional, insertional, deletion and covalent variants and derivatives.
  • derivative is used synonymously with the term “variant” but generally refers to a molecule that has been modified and/or changed in any way relative to a reference molecule or starting molecule.
  • mmRNA encoding polypeptides containing substitutions, insertions and/or additions, deletions and covalent modifications with respect to reference sequences, in particular the polypeptide sequences disclosed herein are included within the scope of this invention.
  • sequence tags or amino acids such as one or more lysines
  • Sequence tags can be used for peptide purification or localization.
  • Lysines can be used to increase peptide solubility or to allow for biotinylation.
  • amino acid residues located at the carboxy and amino terminal regions of the amino acid sequence of a peptide or protein may optionally be deleted providing for truncated sequences.
  • Certain amino acids e.g., C-terminal or N-terminal residues
  • substitutional variants when referring to polypeptides are those that have at least one amino acid residue in a native or starting sequence removed and a different amino acid inserted in its place at the same position. The substitutions may be single, where only one amino acid in the molecule has been substituted, or they may be multiple, where two or more amino acids have been substituted in the same molecule.
  • conservative amino acid substitution refers to the substitution of an amino acid that is normally present in the sequence with a different amino acid of similar size, charge, or polarity.
  • conservative substitutions include the substitution of a non-polar (hydrophobic) residue such as isoleucine, valine and leucine for another non-polar residue.
  • conservative substitutions include the substitution of one polar (hydrophilic) residue for another such as between arginine and lysine, between glutamine and asparagine, and between glycine and serine.
  • substitution of a basic residue such as lysine, arginine or histidine for another, or the substitution of one acidic residue such as aspartic acid or glutamic acid for another acidic residue are additional examples of conservative substitutions.
  • non-conservative substitutions include the substitution of a non-polar (hydrophobic) amino acid residue such as isoleucine, valine, leucine, alanine, methionine for a polar (hydrophilic) residue such as cysteine, glutamine, glutamic acid or lysine and/or a polar residue for a non-polar residue.
  • “Insertional variants” when referring to polypeptides are those with one or more amino acids inserted immediately adjacent to an amino acid at a particular position in a native or starting sequence. “Immediately adjacent” to an amino acid means connected to either the alpha-carboxy or alpha-amino functional group of the amino acid.
  • “Deletional variants” when referring to polypeptides are those with one or more amino acids in the native or starting amino acid sequence removed. Ordinarily, deletional variants will have one or more amino acids deleted in a particular region of the molecule.
  • Covalent derivatives when referring to polypeptides include modifications of a native or starting protein with an organic proteinaceous or non-proteinaceous derivatizing agent, and/or post-translational modifications. Covalent modifications are traditionally introduced by reacting targeted amino acid residues of the protein with an organic derivatizing agent that is capable of reacting with selected side-chains or terminal residues, or by harnessing mechanisms of post-translational modifications that function in selected recombinant host cells. The resultant covalent derivatives are useful in programs directed at identifying residues important for biological activity, for immunoassays, or for the preparation of anti-protein antibodies for immunoaffinity purification of the recombinant glycoprotein. Such modifications are within the ordinary skill in the art and are performed without undue experimentation.
  • Certain post-translational modifications are the result of the action of recombinant host cells on the expressed polypeptide.
  • Glutaminyl and asparaginyl residues are frequently post-translationally deamidated to the corresponding glutamyl and aspartyl residues. Alternatively, these residues are deamidated under mildly acidic conditions. Either form of these residues may be present in the polypeptides produced in accordance with the present invention.
  • post-translational modifications include hydroxylation of proline and lysine, phosphorylation of hydroxyl groups of seryl or threonyl residues, methylation of the alpha-amino groups of lysine, arginine, and histidine side chains (T. E. Creighton, Proteins: Structure and Molecular Properties, W.H. Freeman & Co., San Francisco, pp. 79-86 (1983)).
  • Features when referring to polypeptides are defined as distinct amino acid sequence-based components of a molecule.
  • Features of the polypeptides encoded by the mmRNA of the present invention include surface manifestations, local conformational shape, folds, loops, half-loops, domains, half-domains, sites, termini or any combination thereof.
  • surface manifestation refers to a polypeptide based component of a protein appearing on an outermost surface.
  • local conformational shape means a polypeptide based structural manifestation of a protein which is located within a definable space of the protein.
  • fold refers to the resultant conformation of an amino acid sequence upon energy minimization.
  • a fold may occur at the secondary or tertiary level of the folding process.
  • secondary level folds include beta sheets and alpha helices.
  • tertiary folds include domains and regions formed due to aggregation or separation of energetic forces. Regions formed in this way include hydrophobic and hydrophilic pockets, and the like.
  • turn as it relates to protein conformation means a bend which alters the direction of the backbone of a peptide or polypeptide and may involve one, two, three or more amino acid residues.
  • loop refers to a structural feature of a polypeptide which may serve to reverse the direction of the backbone of a peptide or polypeptide. Where the loop is found in a polypeptide and only alters the direction of the backbone, it may comprise four or more amino acid residues. Oliva et al. have identified at least 5 classes of protein loops (J. Mol. Biol 266 (4): 814-830; 1997). Loops may be open or closed. Closed loops or “cyclic” loops may comprise 2, 3, 4, 5, 6, 7, 8, 9, 10 or more amino acids between the bridging moieties.
  • Such bridging moieties may comprise a cysteine-cysteine bridge (Cys-Cys) typical in polypeptides having disulfide bridges or alternatively bridging moieties may be non-protein based such as the dibromozylyl agents used herein.
  • Cys-Cys cysteine-cysteine bridge
  • bridging moieties may be non-protein based such as the dibromozylyl agents used herein.
  • domain refers to a motif of a polypeptide having one or more identifiable structural or functional characteristics or properties (e.g., binding capacity, serving as a site for protein-protein interactions).
  • sub-domains may be identified within domains or half-domains, these subdomains possessing less than all of the structural or functional properties identified in the domains or half domains from which they were derived. It is also understood that the amino acids that comprise any of the domain types herein need not be contiguous along the backbone of the polypeptide (i.e., nonadjacent amino acids may fold structurally to produce a domain, half-domain or subdomain).
  • site As used herein when referring to polypeptides the terms “site” as it pertains to amino acid based embodiments is used synonymously with “amino acid residue” and “amino acid side chain.”
  • a site represents a position within a peptide or polypeptide that may be modified, manipulated, altered, derivatized or varied within the polypeptide based molecules of the present invention.
  • terminal refers to an extremity of a peptide or polypeptide. Such extremity is not limited only to the first or final site of the peptide or polypeptide but may include additional amino acids in the terminal regions.
  • the polypeptide based molecules of the present invention may be characterized as having both an N-terminus (terminated by an amino acid with a free amino group (NH2)) and a C-terminus (terminated by an amino acid with a free carboxyl group (COOH)).
  • Proteins of the invention are in some cases made up of multiple polypeptide chains brought together by disulfide bonds or by non-covalent forces (multimers, oligomers). These sorts of proteins will have multiple N- and C-termini.
  • the termini of the polypeptides may be modified such that they begin or end, as the case may be, with a non-polypeptide based moiety such as an organic conjugate.
  • any of the features have been identified or defined as a desired component of a polypeptide to be encoded by the primary construct or mmRNA of the invention, any of several manipulations and/or modifications of these features may be performed by moving, swapping, inverting, deleting, randomizing or duplicating. Furthermore, it is understood that manipulation of features may result in the same outcome as a modification to the molecules of the invention. For example, a manipulation which involved deleting a domain would result in the alteration of the length of a molecule just as modification of a nucleic acid to encode less than a full length molecule would.
  • Modifications and manipulations can be accomplished by methods known in the art such as, but not limited to, site directed mutagenesis.
  • the resulting modified molecules may then be tested for activity using in vitro or in vivo assays such as those described herein or any other suitable screening assay known in the art.
  • the polypeptides may comprise a consensus sequence which is discovered through rounds of experimentation.
  • a “consensus” sequence is a single sequence which represents a collective population of sequences allowing for variability at one or more sites.
  • protein fragments, functional protein domains, and homologous proteins are also considered to be within the scope of polypeptides of interest of this invention.
  • any protein fragment meaning a polypeptide sequence at least one amino acid residue shorter than a reference polypeptide sequence but otherwise identical
  • a reference protein 10 20, 30, 40, 50, 60, 70, 80, 90, 100 or greater than 100 amino acids in length.
  • any protein that includes a stretch of about 20, about 30, about 40, about 50, or about 100 amino acids which are about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, or about 100% identical to any of the sequences described herein can be utilized in accordance with the invention.
  • a polypeptide to be utilized in accordance with the invention includes 2, 3, 4, 5, 6, 7, 8, 9, 10, or more mutations as shown in any of the sequences provided or referenced herein.
  • the primary constructs or mmRNA of the present invention may be designed to encode polypeptides of interest selected from any of several target categories including, but not limited to, biologics, antibodies, vaccines, therapeutic proteins or peptides, cell penetrating peptides, secreted proteins, plasma membrane proteins, cytoplasmic or cytoskeletal proteins, intracellular membrane bound proteins, nuclear proteins, proteins associated with human disease, targeting moieties or those proteins encoded by the human genome for which no therapeutic indication has been identified but which nonetheless have utility in areas of research and discovery.
  • target categories including, but not limited to, biologics, antibodies, vaccines, therapeutic proteins or peptides, cell penetrating peptides, secreted proteins, plasma membrane proteins, cytoplasmic or cytoskeletal proteins, intracellular membrane bound proteins, nuclear proteins, proteins associated with human disease, targeting moieties or those proteins encoded by the human genome for which no therapeutic indication has been identified but which nonetheless have utility in areas of research and discovery.
  • primary constructs or mmRNA may encode variant polypeptides which have a certain identity with a reference polypeptide sequence.
  • a “reference polypeptide sequence” refers to a starting polypeptide sequence. Reference sequences may be wild type sequences or any sequence to which reference is made in the design of another sequence.
  • a “reference polypeptide sequence” may, e.g., be any one of SEQ ID NOs: 35608-71005 as disclosed herein, e.g., any of SEQ ID NOs 35608, 35609, 35610, 35611, 35612, 35613, 35614, 35615, 35616, 35617, 35618, 35619, 35620, 35621, 35622, 35623, 35624, 35625, 35626, 35627, 35628, 35629, 35630, 35631, 35632, 35633, 35634, 35635, 35636, 35637, 35638, 35639, 35640, 35641, 35642, 35643, 35644, 35645, 35646, 35647, 35648, 35649, 35650, 35651, 35652, 35653, 35654, 35655, 35656, 35657, 35658, 35659, 35660, 35661, 35662, 35663, 35664, 35665, 35666, 35667, 3566
  • identity refers to a relationship between the sequences of two or more peptides, as determined by comparing the sequences. In the art, identity also means the degree of sequence relatedness between peptides, as determined by the number of matches between strings of two or more amino acid residues. Identity measures the percent of identical matches between the smaller of two or more sequences with gap alignments (if any) addressed by a particular mathematical model or computer program (i.e., “algorithms”). Identity of related peptides can be readily calculated by known methods. Such methods include, but are not limited to, those described in Computational Molecular Biology, Lesk, A.
  • the polypeptide variant may have the same or a similar activity as the reference polypeptide.
  • the variant may have an altered activity (e.g., increased or decreased) relative to a reference polypeptide.
  • variants of a particular polynucleotide or polypeptide of the invention will have at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% but less than 100% sequence identity to that particular reference polynucleotide or polypeptide as determined by sequence alignment programs and parameters described herein and known to those skilled in the art.
  • Such tools for alignment include those of the BLAST suite (Stephen F. Altschul, Thomas L. Madden, Alejandro A. Schulffer, Jinghui Zhang, Zheng Zhang, Webb Miller, and David J. Lipman (1997), “Gapped BLAST and PSI-BLAST: a new generation of protein database search programs”, Nucleic Acids Res. 25:3389-3402.) Other tools are described herein, specifically in the definition of “Identity.”
  • BLAST algorithm Default parameters in the BLAST algorithm include, for example, an expect threshold of 10, Word size of 28, Match/Mismatch Scores 1, -2, Gap costs Linear. Any filter can be applied as well as a selection for species specific repeats, e.g., Homo sapiens.
  • the polynucleotides, primary constructs or mmRNA disclosed herein may encode one or more biologics.
  • a “biologic” is a polypeptide-based molecule produced by the methods provided herein and which may be used to treat, cure, mitigate, prevent, or diagnose a serious or life-threatening disease or medical condition.
  • Biologics include, but are not limited to, allergenic extracts (e.g. for allergy shots and tests), blood components, gene therapy products, human tissue or cellular products used in transplantation, vaccines, monoclonal antibodies, cytokines, growth factors, enzymes, thrombolytics, and immunomodulators, among others.
  • one or more biologics currently being marketed or in development may be encoded by the polynucleotides, primary constructs or mmRNA of the present invention. While not wishing to be bound by theory, it is believed that incorporation of the encoding polynucleotides of a known biologic into the primary constructs or mmRNA of the invention will result in improved therapeutic efficacy due at least in part to the specificity, purity and/or selectivity of the construct designs.
  • the primary constructs or mmRNA disclosed herein may encode one or more antibodies or fragments thereof.
  • antibody includes monoclonal antibodies (including full length antibodies which have an immunoglobulin Fc region), antibody compositions with polyepitopic specificity, multispecific antibodies (e.g., bispecific antibodies, diabodies, and single-chain molecules), as well as antibody fragments.
  • immunoglobulin Ig is used interchangeably with “antibody” herein.
  • the term “monoclonal antibody” refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are identical except for possible naturally occurring mutations and/or post-translation modifications (e.g., isomerizations, amidations) that may be present in minor amounts. Monoclonal antibodies are highly specific, being directed against a single antigenic site.
  • the monoclonal antibodies herein specifically include “chimeric” antibodies (immunoglobulins) in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is(are) identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.
  • chimeric antibodies immunoglobulins in which a portion of the heavy and/or light chain is identical with or homologous to corresponding sequences in antibodies derived from a particular species or belonging to a particular antibody class or subclass, while the remainder of the chain(s) is(are) identical with or homologous to corresponding sequences in antibodies derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.
  • Chimeric antibodies of interest herein include, but are not limited to, “primatized” antibodies comprising variable domain antigen-binding sequences derived from a non-human primate (e.g., Old World Monkey, Ape etc.) and human constant region sequences.
  • a non-human primate e.g., Old World Monkey, Ape etc.
  • antibody fragment comprises a portion of an intact antibody, preferably the antigen binding and/or the variable region of the intact antibody.
  • antibody fragments include Fab, Fab′, F(ab′) 2 and Fv fragments; diabodies; linear antibodies; nanobodies; single-chain antibody molecules and multispecific antibodies formed from antibody fragments.
  • any of the five classes of immunoglobulins, IgA, IgD, IgE, IgG and IgM, may be encoded by the mmRNA of the invention, including the heavy chains designated alpha, delta, epsilon, gamma and mu, respectively. Also included are polynucleotide sequences encoding the subclasses, gamma and mu. Hence any of the subclasses of antibodies may be encoded in part or in whole and include the following subclasses: IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2.
  • one or more antibodies or fragments currently being marketed or in development may be encoded by the polynucleotides, primary constructs or mmRNA of the present invention. While not wishing to be bound by theory, it is believed that incorporation into the primary constructs of the invention will result in improved therapeutic efficacy due at least in part to the specificity, purity and selectivity of the mmRNA designs.
  • Antibodies encoded in the polynucleotides, primary constructs or mmRNA of the invention may be utilized to treat conditions or diseases in many therapeutic areas such as, but not limited to, blood, cardiovascular, CNS, poisoning (including antivenoms), dermatology, endocrinology, gastrointestinal, medical imaging, musculoskeletal, oncology, immunology, respiratory, sensory and anti-infective.
  • primary constructs or mmRNA disclosed herein may encode monoclonal antibodies and/or variants thereof. Variants of antibodies may also include, but are not limited to, substitutional variants, conservative amino acid substitution, insertional variants, deletional variants and/or covalent derivatives.
  • the primary construct and/or mmRNA disclosed herein may encode an immunoglobulin Fc region.
  • the primary constructs and/or mmRNA may encode a variant immunoglobulin Fc region.
  • the primary constructs and/or mmRNA may encode an antibody having a variant immunoglobulin Fc region as described in U.S. Pat. No. 8,217,147 herein incorporated by reference in its entirety.
  • the primary constructs or mmRNA disclosed herein may encode one or more vaccines.
  • a “vaccine” is a biological preparation that improves immunity to a particular disease or infectious agent.
  • one or more vaccines currently being marketed or in development may be encoded by the polynucleotides, primary constructs or mmRNA of the present invention. While not wishing to be bound by theory, it is believed that incorporation into the primary constructs or mmRNA of the invention will result in improved therapeutic efficacy due at least in part to the specificity, purity and selectivity of the construct designs.
  • Vaccines encoded in the polynucleotides, primary constructs or mmRNA of the invention may be utilized to treat conditions or diseases in many therapeutic areas such as, but not limited to, cardiovascular, CNS, dermatology, endocrinology, oncology, immunology, respiratory, and anti-infective.
  • the primary constructs or mmRNA disclosed herein may encode one or more validated or “in testing” therapeutic proteins or peptides.
  • one or more therapeutic proteins or peptides currently being marketed or in development may be encoded by the polynucleotides, primary constructs or mmRNA of the present invention. While not wishing to be bound by theory, it is believed that incorporation into the primary constructs or mmRNA of the invention will result in improved therapeutic efficacy due at least in part to the specificity, purity and selectivity of the construct designs.
  • Therapeutic proteins and peptides encoded in the polynucleotides, primary constructs or mmRNA of the invention may be utilized to treat conditions or diseases in many therapeutic areas such as, but not limited to, blood, cardiovascular, CNS, poisoning (including antivenoms), dermatology, endocrinology, genetic, genitourinary, gastrointestinal, musculoskeletal, oncology, and immunology, respiratory, sensory and anti-infective.
  • the primary constructs or mmRNA disclosed herein may encode one or more cell-penetrating polypeptides.
  • “cell-penetrating polypeptide” or CPP refers to a polypeptide which may facilitate the cellular uptake of molecules.
  • a cell-penetrating polypeptide of the present invention may contain one or more detectable labels.
  • the polypeptides may be partially labeled or completely labeled throughout.
  • the polynucleotide, primary construct or mmRNA may encode the detectable label completely, partially or not at all.
  • the cell-penetrating peptide may also include a signal sequence.
  • a “signal sequence” refers to a sequence of amino acid residues bound at the amino terminus of a nascent protein during protein translation.
  • the signal sequence may be used to signal the secretion of the cell-penetrating polypeptide.
  • the polynucleotides, primary constructs or mmRNA may also encode a fusion protein.
  • the fusion protein may be created by operably linking a charged protein to a therapeutic protein.
  • “operably linked” refers to the therapeutic protein and the charged protein being connected in such a way to permit the expression of the complex when introduced into the cell.
  • “charged protein” refers to a protein that carries a positive, negative or overall neutral electrical charge.
  • the therapeutic protein may be covalently linked to the charged protein in the formation of the fusion protein.
  • the ratio of surface charge to total or surface amino acids may be approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8 or 0.9.
  • the cell-penetrating polypeptide encoded by the polynucleotides, primary constructs or mmRNA may form a complex after being translated.
  • the complex may comprise a charged protein linked, e.g. covalently linked, to the cell-penetrating polypeptide.
  • “Therapeutic protein” refers to a protein that, when administered to a cell has a therapeutic, diagnostic, and/or prophylactic effect and/or elicits a desired biological and/or pharmacological effect.
  • the cell-penetrating polypeptide may comprise a first domain and a second domain.
  • the first domain may comprise a supercharged polypeptide.
  • the second domain may comprise a protein-binding partner.
  • protein-binding partner includes, but is not limited to, antibodies and functional fragments thereof, scaffold proteins, or peptides.
  • the cell-penetrating polypeptide may further comprise an intracellular binding partner for the protein-binding partner.
  • the cell-penetrating polypeptide may be capable of being secreted from a cell where the polynucleotide, primary construct or mmRNA may be introduced.
  • the cell-penetrating polypeptide may also be capable of penetrating the first cell.
  • the cell-penetrating polypeptide is capable of penetrating a second cell.
  • the second cell may be from the same area as the first cell, or it may be from a different area.
  • the area may include, but is not limited to, tissues and organs.
  • the second cell may also be proximal or distal to the first cell.
  • the polynucleotides, primary constructs or mmRNA may encode a cell-penetrating polypeptide which may comprise a protein-binding partner.
  • the protein binding partner may include, but is not limited to, an antibody, a supercharged antibody or a functional fragment.
  • the polynucleotides, primary constructs or mmRNA may be introduced into the cell where a cell-penetrating polypeptide comprising the protein-binding partner is introduced.
  • Each membrane-bounded compartment, or organelle contains different proteins essential for the function of the organelle.
  • the cell uses “sorting signals,” which are amino acid motifs located within the protein, to target proteins to particular cellular organelles.
  • sorting signal One type of sorting signal, called a signal sequence, a signal peptide, or a leader sequence, directs a class of proteins to an organelle called the endoplasmic reticulum (ER).
  • ER endoplasmic reticulum
  • Proteins targeted to the ER by a signal sequence can be released into the extracellular space as a secreted protein.
  • proteins residing on the cell membrane can also be secreted into the extracellular space by proteolytic cleavage of a “linker” holding the protein to the membrane.
  • the molecules of the present invention may be used to exploit the cellular trafficking described above.
  • polynucleotides, primary constructs or mmRNA are provided to express a secreted protein.
  • the secreted proteins may be selected from those described herein or those in US Patent Publication, 20100255574, the contents of which are incorporated herein by reference in their entirety.
  • these may be used in the manufacture of large quantities of valuable human gene products.
  • polynucleotides, primary constructs or mmRNA are provided to express a protein of the plasma membrane.
  • polynucleotides, primary constructs or mmRNA are provided to express a cytoplasmic or cytoskeletal protein.
  • polynucleotides, primary constructs or mmRNA are provided to express an intracellular membrane bound protein.
  • polynucleotides, primary constructs or mmRNA are provided to express a nuclear protein.
  • polynucleotides, primary constructs or mmRNA are provided to express a protein associated with human disease.
  • polynucleotides, primary constructs or mmRNA are provided to express a protein with a presently unknown therapeutic function.
  • polynucleotides, primary constructs or mmRNA are provided to express a targeting moiety.
  • a targeting moiety include a protein-binding partner or a receptor on the surface of the cell, which functions to target the cell to a specific tissue space or to interact with a specific moiety, either in vivo or in vitro.
  • Suitable protein-binding partners include, but are not limited to, antibodies and functional fragments thereof, scaffold proteins, or peptides.
  • polynucleotide, primary construct or mmRNA can be employed to direct the synthesis and extracellular localization of lipids, carbohydrates, or other biological moieties or biomolecules.
  • the polynucleotides, primary constructs or mmRNA may be used to produce polypeptide libraries. These libraries may arise from the production of a population of polynucleotides, primary constructs or mmRNA, each containing various structural or chemical modification designs.
  • a population of polynucleotides, primary constructs or mmRNA may comprise a plurality of encoded polypeptides, including but not limited to, an antibody or antibody fragment, protein binding partner, scaffold protein, and other polypeptides taught herein or known in the art.
  • the polynucleotides are primary constructs of the present invention, including mmRNA which may be suitable for direct introduction into a target cell or culture which in turn may synthesize the encoded polypeptides.
  • multiple variants of a protein may be produced and tested to determine the best variant in terms of pharmacokinetics, stability, biocompatibility, and/or biological activity, or a biophysical property such as expression level.
  • a library may contain 10, 10 2 , 10 3 , 10 4 , 10 5 , 10 6 , 10 7 , 10 8 , 10 9 , or over 10 9 possible variants (including, but not limited to, substitutions, deletions of one or more residues, and insertion of one or more residues).
  • the polynucleotides, primary constructs and mmRNA of the present invention may be designed to encode on or more antimicrobial peptides (AMP) or antiviral peptides (AVP).
  • AMPs and AVPs have been isolated and described from a wide range of animals such as, but not limited to, microorganisms, invertebrates, plants, amphibians, birds, fish, and mammals (Wang et al., Nucleic Acids Res. 2009; 37 (Database issue):D933-7).
  • anti-microbial polypeptides are described in Antimicrobial Peptide Database (http://aps.unmc.edu/AP/main.php; Wang et al., Nucleic Acids Res.
  • the anti-microbial polypeptides described herein may block cell fusion and/or viral entry by one or more enveloped viruses (e.g., HIV, HCV).
  • the anti-microbial polypeptide can comprise or consist of a synthetic peptide corresponding to a region, e.g., a consecutive sequence of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 amino acids of the transmembrane subunit of a viral envelope protein, e.g., HIV-1 gp120 or gp41.
  • the amino acid and nucleotide sequences of HIV-1 gp120 or gp41 are described in, e.g., Kuiken et al., (2008). “HIV Sequence Compendium,” Los Alamos National Laboratory.
  • the anti-microbial polypeptide may have at least about 75%, 80%, 85%, 90%, 95%, 100% sequence homology to the corresponding viral protein sequence. In some embodiments, the anti-microbial polypeptide may have at least about 75%, 80%, 85%, 90%, 95%, or 100% sequence homology to the corresponding viral protein sequence.
  • the anti-microbial polypeptide may comprise or consist of a synthetic peptide corresponding to a region, e.g., a consecutive sequence of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 amino acids of the binding domain of a capsid binding protein.
  • the anti-microbial polypeptide may have at least about 75%, 80%, 85%, 90%, 95%, or 100% sequence homology to the corresponding sequence of the capsid binding protein.
  • the anti-microbial polypeptides described herein may block protease dimerization and inhibit cleavage of viral proproteins (e.g., HIV Gag-pol processing) into functional proteins thereby preventing release of one or more enveloped viruses (e.g., HIV, HCV).
  • the anti-microbial polypeptide may have at least about 75%, 80%, 85%, 90%, 95%, 100% sequence homology to the corresponding viral protein sequence.
  • the anti-microbial polypeptide can comprise or consist of a synthetic peptide corresponding to a region, e.g., a consecutive sequence of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 amino acids of the binding domain of a protease binding protein.
  • the anti-microbial polypeptide may have at least about 75%, 80%, 85%, 90%, 95%, 100% sequence homology to the corresponding sequence of the protease binding protein.
  • the anti-microbial polypeptides described herein can include an in vitro-evolved polypeptide directed against a viral pathogen.
  • AMPs Anti-microbial polypeptides
  • AMPs are small peptides of variable length, sequence and structure with broad spectrum activity against a wide range of microorganisms including, but not limited to, bacteria, viruses, fungi, protozoa, parasites, prions, and tumor/cancer cells.
  • AMPs have broad-spectrum of rapid onset of killing activities, with potentially low levels of induced resistance and concomitant broad anti-inflammatory effects.
  • the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be under 10 kDa, e.g., under 8 kDa, 6 kDa, 4 kDa, 2 kDa, or 1 kDa.
  • the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) consists of from about 6 to about 100 amino acids, e.g., from about 6 to about 75 amino acids, about 6 to about 50 amino acids, about 6 to about 25 amino acids, about 25 to about 100 amino acids, about 50 to about 100 amino acids, or about 75 to about 100 amino acids.
  • the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may consist of from about 15 to about 45 amino acids. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) is substantially cationic.
  • the anti-microbial polypeptide may be substantially amphipathic. In certain embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be substantially cationic and amphipathic. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be cytostatic to a Gram-positive bacterium. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be cytotoxic to a Gram-positive bacterium.
  • the anti-microbial polypeptide may be cytostatic and cytotoxic to a Gram-positive bacterium. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be cytostatic to a Gram-negative bacterium. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be cytotoxic to a Gram-negative bacterium. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be cytostatic and cytotoxic to a Gram-positive bacterium.
  • the anti-microbial polypeptide may be cytostatic to a virus, fungus, protozoan, parasite, prion, or a combination thereof. In some embodiments, the anti-microbial polypeptide may be cytotoxic to a virus, fungus, protozoan, parasite, prion, or a combination thereof. In certain embodiments, the anti-microbial polypeptide may be cytostatic and cytotoxic to a virus, fungus, protozoan, parasite, prion, or a combination thereof. In some embodiments, the anti-microbial polypeptide may be cytotoxic to a tumor or cancer cell (e.g., a human tumor and/or cancer cell).
  • a tumor or cancer cell e.g., a human tumor and/or cancer cell.
  • the anti-microbial polypeptide may be cytostatic to a tumor or cancer cell (e.g., a human tumor and/or cancer cell). In certain embodiments, the anti-microbial polypeptide may be cytotoxic and cytostatic to a tumor or cancer cell (e.g., a human tumor or cancer cell). In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) may be a secreted polypeptide.
  • the anti-microbial polypeptide comprises or consists of a defensin.
  • defensins include, but are not limited to, ⁇ -defensins (e.g., neutrophil defensin 1, defensin alpha 1, neutrophil defensin 3, neutrophil defensin 4, defensin 5, defensin 6), ⁇ -defensins (e.g., beta-defensin 1, beta-defensin 2, beta-defensin 103, beta-defensin 107, beta-defensin 110, beta-defensin 136), and ⁇ -defensins.
  • the anti-microbial polypeptide comprises or consists of a cathelicidin (e.g., hCAP18).
  • Anti-viral polypeptides are small peptides of variable length, sequence and structure with broad spectrum activity against a wide range of viruses. See, e.g., Zaiou, J Mol Med, 2007; 85:317. It has been shown that AVPs have a broad-spectrum of rapid onset of killing activities, with potentially low levels of induced resistance and concomitant broad anti-inflammatory effects.
  • the anti-viral polypeptide is under 10 kDa, e.g., under 8 kDa, 6 kDa, 4 kDa, 2 kDa, or 1 kDa.
  • the anti-viral polypeptide comprises or consists of from about 6 to about 100 amino acids, e.g., from about 6 to about 75 amino acids, about 6 to about 50 amino acids, about 6 to about 25 amino acids, about 25 to about 100 amino acids, about 50 to about 100 amino acids, or about 75 to about 100 amino acids. In certain embodiments, the anti-viral polypeptide comprises or consists of from about 15 to about 45 amino acids. In some embodiments, the anti-viral polypeptide is substantially cationic. In some embodiments, the anti-viral polypeptide is substantially amphipathic. In certain embodiments, the anti-viral polypeptide is substantially cationic and amphipathic.
  • the anti-viral polypeptide is cytostatic to a virus. In some embodiments, the anti-viral polypeptide is cytotoxic to a virus. In some embodiments, the anti-viral polypeptide is cytostatic and cytotoxic to a virus. In some embodiments, the anti-viral polypeptide is cytostatic to a bacterium, fungus, protozoan, parasite, prion, or a combination thereof. In some embodiments, the anti-viral polypeptide is cytotoxic to a bacterium, fungus, protozoan, parasite, prion or a combination thereof.
  • the anti-viral polypeptide is cytostatic and cytotoxic to a bacterium, fungus, protozoan, parasite, prion, or a combination thereof. In some embodiments, the anti-viral polypeptide is cytotoxic to a tumor or cancer cell (e.g., a human cancer cell). In some embodiments, the anti-viral polypeptide is cytostatic to a tumor or cancer cell (e.g., a human cancer cell). In certain embodiments, the anti-viral polypeptide is cytotoxic and cytostatic to a tumor or cancer cell (e.g., a human cancer cell). In some embodiments, the anti-viral polypeptide is a secreted polypeptide.
  • the polynucleotides, primary constructs or mmRNA of the present invention may incorporate one or more cytotoxic nucleosides.
  • cytotoxic nucleosides may be incorporated into polynucleotides, primary constructs or mmRNA such as bifunctional modified RNAs or mRNAs.
  • Cytotoxic nucleoside anti-cancer agents include, but are not limited to, adenosine arabinoside, cytarabine, cytosine arabinoside, 5-fluorouracil, fludarabine, floxuridine, FTORAFUR® (a combination of tegafur and uracil), tegafur ((RS)-5-fluoro-1-(tetrahydrofuran-2-yl)pyrimidine-2,4(1H,3H)-dione), and 6-mercaptopurine.
  • cytotoxic nucleoside analogues are in clinical use, or have been the subject of clinical trials, as anticancer agents.
  • examples of such analogues include, but are not limited to, cytarabine, gemcitabine, troxacitabine, decitabine, tezacitabine, 2′-deoxy-2′-methylidenecytidine (DMDC), cladribine, clofarabine, 5-azacytidine, 4′-thio-aracytidine, cyclopentenylcytosine and 1-(2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl)-cytosine.
  • Another example of such a compound is fludarabine phosphate.
  • cytotoxic nucleoside analogues examples include, but are not limited to, N4-behenoyl-1-beta-D-arabinofuranosylcytosine, N4-octadecyl-1-beta-D-arabinofuranosylcytosine, N4-palmitoyl-1-(2-C-cyano-2-deoxy-beta-D-arabino-pentofuranosyl) cytosine, and P-4055 (cytarabine 5′-elaidic acid ester).
  • these prodrugs may be converted into the active drugs mainly in the liver and systemic circulation and display little or no selective release of active drug in the tumor tissue.
  • active drug for example, capecitabine, a prodrug of 5′-deoxy-5-fluorocytidine (and eventually of 5-fluorouracil), is metabolized both in the liver and in the tumor tissue.
  • capecitabine analogues containing “an easily hydrolysable radical under physiological conditions” has been claimed by Fujiu et al. (U.S. Pat. No. 4,966,891) and is herein incorporated by reference.
  • Cytotoxic nucleotides which may be chemotherapeutic also include, but are not limited to, pyrazolo[3,4-D]-pyrimidines, allopurinol, azathioprine, capecitabine, cytosine arabinoside, fluorouracil, mercaptopurine, 6-thioguanine, acyclovir, ara-adenosine, ribavirin, 7-deaza-adenosine, 7-deaza-guanosine, 6-aza-uracil, 6-aza-cytidine, thymidine ribonucleotide, 5-bromodeoxyuridine, 2-chloro-purine, and inosine, or combinations thereof.
  • UTRs Untranslated Regions
  • Untranslated regions (UTRs) of a gene are transcribed but not translated.
  • the 5′UTR starts at the transcription start site and continues to the start codon but does not include the start codon; whereas, the 3′UTR starts immediately following the stop codon and continues until the transcriptional termination signal.
  • the regulatory features of a UTR can be incorporated into the polynucleotides, primary constructs and/or mmRNA of the present invention to enhance the stability of the molecule.
  • the specific features can also be incorporated to ensure controlled down-regulation of the transcript in case they are misdirected to undesired organs sites.
  • Natural 5′UTRs bear features which play roles in for translation initiation. They harbor signatures like Kozak sequences which are commonly known to be involved in the process by which the ribosome initiates translation of many genes. Kozak sequences have the consensus CCR(A/G)CCAUGG, where R is a purine (adenine or guanine) three bases upstream of the start codon (AUG), which is followed by another ‘G’. 5′UTR also have been known to form secondary structures which are involved in elongation factor binding.
  • mRNA such as albumin, serum amyloid A, Apolipoprotein A/B/E, transferrin, alpha fetoprotein, erythropoietin, or Factor VIII
  • tissue-specific mRNA to improve expression in that tissue is possible for muscle (MyoD, Myosin, Myoglobin, Myogenin, Herculin), for endothelial cells (Tie-1, CD36), for myeloid cells (C/EBP, AML1, G-CSF, GM-CSF, CD11b, MSR, Fr-1, i-NOS), for leukocytes (CD45, CD18), for adipose tissue (CD36, GLUT4, ACRP30, adiponectin) and for lung epithelial cells (SP-A/B/C/D).
  • non-UTR sequences may be incorporated into the 5′ (or 3′ UTR) UTRs.
  • introns or portions of introns sequences may be incorporated into the flanking regions of the polynucleotides, primary constructs or mmRNA of the invention. Incorporation of intronic sequences may increase protein production as well as mRNA levels.
  • 3′ UTRs are known to have stretches of Adenosines and Uridines embedded in them. These AU rich signatures are particularly prevalent in genes with high rates of turnover. Based on their sequence features and functional properties, the AU rich elements (AREs) can be separated into three classes (Chen et al, 1995): Class I AREs contain several dispersed copies of an AUUUA motif within U-rich regions. C-Myc and MyoD contain class I AREs. Class II AREs possess two or more overlapping UUAUUUA(U/A)(U/A) nonamers. Molecules containing this type of AREs include GM-CSF and TNF-a. Class III ARES are less well defined.
  • AREs 3′ UTR AU rich elements
  • Introduction, removal or modification of 3′ UTR AU rich elements can be used to modulate the stability of polynucleotides, primary constructs or mmRNA of the invention.
  • AREs can be identified and removed or mutated to increase the intracellular stability and thus increase translation and production of the resultant protein.
  • Transfection experiments can be conducted in relevant cell lines, using polynucleotides, primary constructs or mmRNA of the invention and protein production can be assayed at various time points post-transfection.
  • cells can be transfected with different ARE-engineering molecules and by using an ELISA kit to the relevant protein and assaying protein produced at 6 hour, 12 hour, 24 hour, 48 hour, and 7 days post-transfection.
  • microRNAs are 19-25 nucleotide long noncoding RNAs that bind to the 3′UTR of nucleic acid molecules and down-regulate gene expression either by reducing nucleic acid molecule stability or by inhibiting translation.
  • the polynucleotides, primary constructs or mmRNA of the invention may comprise one or more microRNA target sequences, microRNA seqences, or microRNA seeds. Such sequences may correspond to any known microRNA such as those taught in US Publication US2005/0261218 and US Publication US2005/0059005, the contents of which are incorporated herein by reference in their entirety.
  • a microRNA sequence comprises a “seed” region, i.e., a sequence in the region of positions 2-8 of the mature microRNA, which sequence has perfect Watson-Crick complementarity to the miRNA target sequence.
  • a microRNA seed may comprise positions 2-8 or 2-7 of the mature microRNA.
  • a microRNA seed may comprise 7 nucleotides (e.g., nucleotides 2-8 of the mature microRNA), wherein the seed-complementary site in the corresponding miRNA target is flanked by an adenine (A) opposed to microRNA position 1.
  • a microRNA seed may comprise 6 nucleotides (e.g., nucleotides 2-7 of the mature microRNA), wherein the seed-complementary site in the corresponding miRNA target is flanked byan adenine (A) opposed to microRNA position 1.
  • A an adenine
  • the bases of the microRNA seed have complete complementarity with the target sequence.
  • microRNA target sequences By engineering microRNA target sequences into the 3′UTR of polynucleotides, primary constructs or mmRNA of the invention one can target the molecule for degradation or reduced translation, provided the microRNA in question is available. This process will reduce the hazard of off target effects upon nucleic acid molecule delivery. Identification of microRNA, microRNA target regions, and their expression patterns and role in biology have been reported (Bonauer et al., Curr Drug Targets 2010 11:943-949; Anand and Cheresh Curr Opin Hematol 2011 18:171-176; Contreras and Rao Leukemia 2012 26:404-413 (2011 Dec. 20. doi: 10.1038/leu.2011.356); Bartel Cell 2009 136:215-233; Landgraf et al, Cell, 2007 129:1401-1414; each of which is herein incorporated by reference in its entirety).
  • miR-122 a microRNA abundant in liver, can inhibit the expression of the gene of interest if one or multiple target sites of miR-122 are engineered into the 3′ UTR of the polynucleotides, primary constructs or mmRNA.
  • Introduction of one or multiple binding sites for different microRNA can be engineered to further decrease the longevity, stability, and protein translation of a polynucleotides, primary constructs or mmRNA.
  • microRNA site refers to a microRNA target site or a microRNA recognition site, or any nucleotide sequence to which a microRNA binds or associates. It should be understood that “binding” may follow traditional Watson-Crick hybridization rules or may reflect any stable association of the microRNA with the target sequence at or adjacent to the microRNA site.
  • microRNA binding sites can be engineered out of (i.e. removed from) sequences in which they naturally occur in order to increase protein expression in specific tissues.
  • miR-122 binding sites may be removed to improve protein expression in the liver. Regulation of expression in multiple tissues can be accomplished through introduction or removal or one or several microRNA binding sites.
  • tissues where microRNA are known to regulate mRNA, and thereby protein expression include, but are not limited to, liver (miR-122), muscle (miR-133, miR-206, miR-208), endothelial cells (miR-17-92, miR-126), myeloid cells (miR-142-3p, miR-142-5p, miR-16, miR-21, miR-223, miR-24, miR-27), adipose tissue (let-7, miR-30c), heart (miR-id, miR-149), kidney (miR-192, miR-194, miR-204), and lung epithelial cells (let-7, miR-133, miR-126).
  • liver miR-122
  • muscle miR-133, miR-206, miR-208
  • endothelial cells miR-17-92, miR-126
  • myeloid cells miR-142-3p, miR-142-5p, miR-16, miR-21, miR-223, mi
  • MicroRNA can also regulate complex biological processes such as angiogenesis (miR-132) (Anand and Cheresh Curr Opin Hematol 2011 18:171-176; herein incorporated by reference in its entirety).
  • angiogenesis miR-132
  • binding sites for microRNAs that are involved in such processes may be removed or introduced, in order to tailor the expression of the polynucleotides, primary constructs or mmRNA expression to biologically relevant cell types or to the context of relevant biological processes.
  • a listing of MicroRNA, miR sequences and miR binding sites is listed in Table 9 of U.S. Provisional Application No. 61/753,661 filed Jan. 17, 2013, in Table 9 of U.S. Provisional Application No. 61/754,159 filed Jan. 18, 2013, and in Table 7 of U.S. Provisional Application No. 61/758,921 filed Jan. 31, 2013, each of which are herein incorporated by reference in their entireties.
  • microRNA seed sites can be incorporated into mRNA to decrease expression in certain cells which results in a biological improvement.
  • An example of this is incorporation of miR-142 sites into a UGT1A1-expressing lentiviral vector.
  • miR-142 seed sites reduced expression in hematopoietic cells, and as a consequence reduced expression in antigen-presentating cells, leading to the absence of an immune response against the virally expressed UGT1A1 (Schmitt et al., Gastroenterology 2010; 139:999-1007; Gonzalez-Asequinolaza et al. Gastroenterology 2010, 139:726-729; both herein incorporated by reference in its entirety).
  • Incorporation of miR-142 sites into modified mRNA could not only reduce expression of the encoded protein in hematopoietic cells, but could also reduce or abolish immune responses to the mRNA-encoded protein.
  • Incorporation of miR-142 seed sites (one or multiple) into mRNA would be important in the case of treatment of patients with complete protein deficiencies (UGT1A1 type I, LDLR-deficient patients, CRIM-negative Pompe patients, etc.).
  • polynucleotides, primary constructs or mmRNA can be engineered for more targeted expression in specific cell types or only under specific biological conditions.
  • tissue-specific microRNA binding sites polynucleotides, primary constructs or mmRNA could be designed that would be optimal for protein expression in a tissue or in the context of a biological condition.
  • Transfection experiments can be conducted in relevant cell lines, using engineered polynucleotides, primary constructs or mmRNA and protein production can be assayed at various time points post-transfection.
  • cells can be transfected with different microRNA binding site-engineering polynucleotides, primary constructs or mmRNA and by using an ELISA kit to the relevant protein and assaying protein produced at 6 hour, 12 hour, 24 hour, 48 hour, 72 hour and 7 days post-transfection.
  • In vivo experiments can also be conducted using microRNA-binding site-engineered molecules to examine changes in tissue-specific expression of formulated polynucleotides, primary constructs or mmRNA.
  • the 5′ cap structure of an mRNA is involved in nuclear export, increasing mRNA stability and binds the mRNA Cap Binding Protein (CBP), which is responsibile for mRNA stability in the cell and translation competency through the association of CBP with poly(A) binding protein to form the mature cyclic mRNA species.
  • CBP mRNA Cap Binding Protein
  • the cap further assists the removal of 5′ proximal introns removal during mRNA splicing.
  • Endogenous mRNA molecules may be 5′-end capped generating a 5′-ppp-5′-triphosphate linkage between a terminal guanosine cap residue and the 5′-terminal transcribed sense nucleotide of the mRNA molecule.
  • This 5′-guanylate cap may then be methylated to generate an N7-methyl-guanylate residue.
  • the ribose sugars of the terminal and/or anteterminal transcribed nucleotides of the 5′ end of the mRNA may optionally also be 2′-O-methylated.
  • 5′-decapping through hydrolysis and cleavage of the guanylate cap structure may target a nucleic acid molecule, such as an mRNA molecule, for degradation.
  • Modifications to the polynucleotides, primary constructs, and mmRNA of the present invention may generate a non-hydrolyzable cap structure preventing decapping and thus increasing mRNA half-life. Because cap structure hydrolysis requires cleavage of 5′-ppp-5′ phosphorodiester linkages, modified nucleotides may be used during the capping reaction. For example, a Vaccinia Capping Enzyme from New England Biolabs (Ipswich, Mass.) may be used with a-thio-guanosine nucleotides according to the manufacturer's instructions to create a phosphorothioate linkage in the 5′-ppp-5′ cap. Additional modified guanosine nucleotides may be used such as ⁇ -methyl-phosphonate and seleno-phosphate nucleotides.
  • Additional modifications include, but are not limited to, 2′-O-methylation of the ribose sugars of 5′-terminal and/or 5′-anteterminal nucleotides of the mRNA (as mentioned above) on the 2′-hydroxyl group of the sugar ring.
  • Multiple distinct 5′-cap structures can be used to generate the 5′-cap of a nucleic acid molecule, such as an mRNA molecule.
  • Cap analogs which herein are also referred to as synthetic cap analogs, chemical caps, chemical cap analogs, or structural or functional cap analogs, differ from natural (i.e. endogenous, wild-type or physiological) 5′-caps in their chemical structure, while retaining cap function. Cap analogs may be chemically (i.e. non-enzymatically) or enzymatically synthesized and/or linked to a nucleic acid molecule.
  • the Anti-Reverse Cap Analog (ARCA) cap contains two guanines linked by a 5′-5′-triphosphate group, wherein one guanine contains an N7 methyl group as well as a 3′-O-methyl group (i.e., N7,3′-O-dimethyl-guanosine-5′-triphosphate-5′-guanosine (m 7 G-3′mppp-G; which may equivaliently be designated 3′ O-Me-m7G(5′)ppp(5′)G).
  • the 3′-O atom of the other, unmodified, guanine becomes linked to the 5′-terminal nucleotide of the capped nucleic acid molecule (e.g. an mRNA or mmRNA).
  • the N7- and 3′-O-methlyated guanine provides the terminal moiety of the capped nucleic acid molecule (e.g. mRNA or mmRNA).
  • mCAP is similar to ARCA but has a 2′-O-methyl group on guanosine (i.e., N7,2′-O-dimethyl-guanosine-5′-triphosphate-5′-guanosine, m 7 Gm-ppp-G).
  • cap analogs allow for the concomitant capping of a nucleic acid molecule in an in vitro transcription reaction, up to 20% of transcripts can remain uncapped. This, as well as the structural differences of a cap analog from an endogenous 5′-cap structures of nucleic acids produced by the endogenous, cellular transcription machinery, may lead to reduced translational competency and reduced cellular stability.
  • Polynucleotides, primary constructs and mmRNA of the invention may also be capped post-transcriptionally, using enzymes, in order to generate more authentic 5′-cap structures.
  • the phrase “more authentic” refers to a feature that closely mirrors or mimics, either structurally or functionally, an endogenous or wild type feature. That is, a “more authentic” feature is better representative of an endogenous, wild-type, natural or physiological cellular function and/or structure as compared to synthetic features or analogs, etc., of the prior art, or which outperforms the corresponding endogenous, wild-type, natural or physiological feature in one or more respects.
  • Non-limiting examples of more authentic 5′cap structures of the present invention are those which, among other things, have enhanced binding of cap binding proteins, increased half life, reduced susceptibility to 5′ endonucleases and/or reduced 5′decapping, as compared to synthetic 5′cap structures known in the art (or to a wild-type, natural or physiological 5′cap structure).
  • recombinant Vaccinia Virus Capping Enzyme and recombinant 2′-O-methyltransferase enzyme can create a canonical 5′-5′-triphosphate linkage between the 5′-terminal nucleotide of an mRNA and a guanine cap nucleotide wherein the cap guanine contains an N7 methylation and the 5′-terminal nucleotide of the mRNA contains a 2′-O-methyl.
  • Cap1 structure is termed the Cap1 structure.
  • Cap structures include, but are not limited to, 7mG(5′)ppp(5′)N,pN2p (cap 0), 7mG(5′)ppp(5′)N1mpNp (cap 1), and 7mG(5′)-ppp(5′)N1mpN2 mp (cap 2).
  • polynucleotides, primary constructs or mmRNA may be capped post-transcriptionally, and because this process is more efficient, nearly 100% of the polynucleotides, primary constructs or mmRNA may be capped. This is in contrast to ⁇ 80% when a cap analog is linked to an mRNA in the course of an in vitro transcription reaction.
  • 5′ terminal caps may include endogenous caps or cap analogs.
  • a 5′ terminal cap may comprise a guanine analog.
  • Useful guanine analogs include, but are not limited to, inosine, N1-methyl-guanosine, 2′fluoro-guanosine, 7-deaza-guanosine, 8-oxo-guanosine, 2-amino-guanosine, LNA-guanosine, and 2-azido-guanosine.
  • Additional viral sequences such as, but not limited to, the translation enhancer sequence of the barley yellow dwarf virus (BYDV-PAV), the Jaagsiekte sheep retrovirus (JSRV) and/or the Enzootic nasal tumor virus (See e.g., International Pub. No. WO2012129648; herein incorporated by reference in its entirety) can be engineered and inserted in the 3′ UTR of the polynucleotides, primary constructs or mmRNA of the invention and can stimulate the translation of the construct in vitro and in vivo. Transfection experiments can be conducted in relevant cell lines at and protein production can be assayed by ELISA at 12 hr, 24 hr, 48 hr, 72 hr and day 7 post-transfection.
  • BYDV-PAV barley yellow dwarf virus
  • JSRV Jaagsiekte sheep retrovirus
  • Enzootic nasal tumor virus See e.g., International Pub. No. WO2012129648; herein incorporated by reference in its entirety
  • IRES internal ribosome entry site
  • IRES first identified as a feature Picorna virus RNA, IRES plays an important role in initiating protein synthesis in absence of the 5′ cap structure. An IRES may act as the sole ribosome binding site, or may serve as one of multiple ribosome binding sites of an mRNA.
  • Polynucleotides, primary constructs or mmRNA containing more than one functional ribosome binding site may encode several peptides or polypeptides that are translated independently by the ribosomes (“multicistronic nucleic acid molecules”).
  • IRES sequences that can be used according to the invention include without limitation, those from picornaviruses (e.g. FMDV), pest viruses (CFFV), polio viruses (PV), encephalomyocarditis viruses (ECMV), foot-and-mouth disease viruses (FMDV), hepatitis C viruses (HCV), classical swine fever viruses (CSFV), murine leukemia virus (MLV), simian immune deficiency viruses (SIV) or cricket paralysis viruses (CrPV).
  • picornaviruses e.g. FMDV
  • CFFV pest viruses
  • PV polio viruses
  • ECMV encephalomyocarditis viruses
  • FMDV foot-and-mouth disease viruses
  • HCV hepatitis C viruses
  • CSFV classical swine fever viruses
  • MLV murine leukemia virus
  • SIV simian immune deficiency viruses
  • CrPV cricket paralysis viruses
  • a long chain of adenine nucleotides may be added to a polynucleotide such as an mRNA molecules in order to increase stability.
  • a polynucleotide such as an mRNA molecules
  • the 3′ end of the transcript may be cleaved to free a 3′ hydroxyl.
  • poly-A polymerase adds a chain of adenine nucleotides to the RNA.
  • the process called polyadenylation, adds a poly-A tail that can be between, for example, approximately 100 and 250 residues long.
  • the length of a poly-A tail of the present invention is greater than 30 nucleotides in length.
  • the poly-A tail is greater than 35 nucleotides in length (e.g., at least or greater than about 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140, 160, 180, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1,100, 1,200, 1,300, 1,400, 1,500, 1,600, 1,700, 1,800, 1,900, 2,000, 2,500, and 3,000 nucleotides).
  • the polynucleotide, primary construct, or mmRNA includes from about 30 to about 3,000 nucleotides (e.g., from 30 to 50, from 30 to 100, from 30 to 250, from 30 to 500, from 30 to 750, from 30 to 1,000, from 30 to 1,500, from 30 to 2,000, from 30 to 2,500, from 50 to 100, from 50 to 250, from 50 to 500, from 50 to 750, from 50 to 1,000, from 50 to 1,500, from 50 to 2,000, from 50 to 2,500, from 50 to 3,000, from 100 to 500, from 100 to 750, from 100 to 1,000, from 100 to 1,500, from 100 to 2,000, from 100 to 2,500, from 100 to 3,000, from 500 to 750, from 500 to 1,000, from 500 to 1,500, from 500 to 2,000, from 500 to 2,500, from 500 to 3,000, from 1,000 to 1,500, from 1,000 to 2,000, from 1,000 to 2,500, from 1,000 to 3,000, from 1,500 to 2,000, from 1,500 to 2,500, from 1,500 to 2,500,
  • the poly-A tail is designed relative to the length of the overall polynucleotides, primary constructs or mmRNA. This design may be based on the length of the coding region, the length of a particular feature or region (such as the first or flanking regions), or based on the length of the ultimate product expressed from the polynucleotides, primary constructs or mmRNA.
  • the poly-A tail may be 10, 20, 30, 40, 50, 60, 70, 80, 90, or 100% greater in length than the polynucleotides, primary constructs or mmRNA or feature thereof.
  • the poly-A tail may also be designed as a fraction of polynucleotides, primary constructs or mmRNA to which it belongs.
  • the poly-A tail may be 10, 20, 30, 40, 50, 60, 70, 80, or 90% or more of the total length of the construct or the total length of the construct minus the poly-A tail.
  • engineered binding sites and conjugation of polynucleotides, primary constructs or mmRNA for Poly-A binding protein may enhance expression.
  • multiple distinct polynucleotides, primary constructs or mmRNA may be linked together to the PABP (Poly-A binding protein) through the 3′-end using modified nucleotides at the 3′-terminus of the poly-A tail.
  • Transfection experiments can be conducted in relevant cell lines at and protein production can be assayed by ELISA at 12 hr, 24 hr, 48 hr, 72 hr and day 7 post-transfection.
  • the polynucleotide primary constructs of the present invention are designed to include a polyA-G quartet.
  • the G-quartet is a cyclic hydrogen bonded array of four guanine nucleotides that can be formed by G-rich sequences in both DNA and RNA.
  • the G-quartet is incorporated at the end of the poly-A tail.
  • the resultant mmRNA construct is assayed for stability, protein production and other parameters including half-life at various time points. It has been discovered that the polyA-G quartet results in protein production equivalent to at least 75% of that seen using a poly-A tail of 120 nucleotides alone.
  • the polynucleotides, primary constructs or mmRNA of the present invention may be quantified in exosomes derived from one or more bodily fluid.
  • bodily fluids include peripheral blood, serum, plasma, ascites, urine, cerebrospinal fluid (CSF), sputum, saliva, bone marrow, synovial fluid, aqueous humor, amniotic fluid, cerumen, breast milk, broncheoalveolar lavage fluid, semen, prostatic fluid, cowper's fluid or pre-ejaculatory fluid, sweat, fecal matter, hair, tears, cyst fluid, pleural and peritoneal fluid, pericardial fluid, lymph, chyme, chyle, bile, interstitial fluid, menses, pus, sebum, vomit, vaginal secretions, mucosal secretion, stool water, pancreatic juice, lavage fluids from sinus cavities, bronchopulmonary aspirates, blastocyl cavity fluid, and um
  • exosomes may be retrieved from an organ selected from the group consisting of lung, heart, pancreas, stomach, intestine, bladder, kidney, ovary, testis, skin, colon, breast, prostate, brain, esophagus, liver, and placenta.
  • the level or concentration of a polynucleotide, primary construct or mmRNA may be an expression level, presence, absence, truncation or alteration of the administered construct. It is advantageous to correlate the level with one or more clinical phenotypes or with an assay for a human disease biomarker.
  • the assay may be performed using construct specific probes, cytometry, qRT-PCR, real-time PCR, PCR, flow cytometry, electrophoresis, mass spectrometry, or combinations thereof while the exosomes may be isolated using immunohistochemical methods such as enzyme linked immunosorbent assay (ELISA) methods. Exosomes may also be isolated by size exclusion chromatography, density gradient centrifugation, differential centrifugation, nanomembrane ultrafiltration, immunoabsorbent capture, affinity purification, microfluidic separation, or combinations thereof
  • Polynucleotides, primary constructs or mmRNA for use in accordance with the invention may be prepared according to any available technique including, but not limited to chemical synthesis, enzymatic synthesis, which is generally termed in vitro transcription (IVT) or enzymatic or chemical cleavage of a longer precursor, etc.
  • IVT in vitro transcription
  • Methods of synthesizing RNAs are known in the art (see, e.g., Gait, M. J. (ed.) Oligonucleotide synthesis: a practical approach , Oxford [Oxfordshire], Washington, D.C.: IRL Press, 1984; and Herdewijn, P. (ed.) Oligonucleotide synthesis: methods and applications , Methods in Molecular Biology, v. 288 (Clifton, N. J.) Totowa, N. J.: Humana Press, 2005; both of which are incorporated herein by reference).
  • the process of design and synthesis of the primary constructs of the invention generally includes the steps of gene construction, mRNA production (either with or without modifications) and purification.
  • a target polynucleotide sequence encoding the polypeptide of interest is first selected for incorporation into a vector which will be amplified to produce a cDNA template.
  • the target polynucleotide sequence and/or any flanking sequences may be codon optimized.
  • the cDNA template is then used to produce mRNA through in vitro transcription (IVT). After production, the mRNA may undergo purification and clean-up processes. The steps of which are provided in more detail below.
  • the step of gene construction may include, but is not limited to gene synthesis, vector amplification, plasmid purification, plasmid linearization and clean-up, and cDNA template synthesis and clean-up.
  • a primary construct is designed.
  • a first region of linked nucleosides encoding the polypeptide of interest may be constructed using an open reading frame (ORF) of a selected nucleic acid (DNA or RNA) transcript.
  • the ORF may comprise the wild type ORF, an isoform, variant or a fragment thereof.
  • an “open reading frame” or “ORF” is meant to refer to a nucleic acid sequence (DNA or RNA) which is capable of encoding a polypeptide of interest. ORFs often begin with the start codon, ATG and end with a nonsense or termination codon or signal.
  • nucleotide sequence of the first region may be codon optimized. Codon optimization methods are known in the art and may be useful in efforts to achieve one or more of several goals. These goals include to match codon frequencies in target and host organisms to ensure proper folding, bias GC content to increase mRNA stability or reduce secondary structures, minimize tandem repeat codons or base runs that may impair gene construction or expression, customize transcriptional and translational control regions, insert or remove protein trafficking sequences, remove/add post translation modification sites in encoded protein (e.g.
  • Codon optimization tools, algorithms and services are known in the art, non-limiting examples include services from GeneArt (Life Technologies), DNA2.0 (Menlo Park Calif.) and/or proprietary methods.
  • the ORF sequence is optimized using optimization algorithms. Codon options for each amino acid are given in Table 1.
  • flanking regions may be incorporated into the primary construct before and/or after optimization of the ORF. It is not required that a primary construct contain both a 5′ and 3′ flanking region. Examples of such features include, but are not limited to, untranslated regions (UTRs), Kozak sequences, an oligo(dT) sequence, and detectable tags and may include multiple cloning sites which may have XbaI recognition.
  • a 5′ UTR and/or a 3′ UTR may be provided as flanking regions. Multiple 5′ or 3′ UTRs may be included in the flanking regions and may be the same or of different sequences. Any portion of the flanking regions, including none, may be codon optimized and any may independently contain one or more different structural or chemical modifications, before and/or after codon optimization. Combinations of features may be included in the first and second flanking regions and may be contained within other features.
  • the ORF may be flanked by a 5′ UTR which may contain a strong Kozak translational initiation signal and/or a 3′ UTR which may include an oligo(dT) sequence for templated addition of a poly-A tail.
  • 5′UTR may comprise a first polynucleotide fragment and a second polynucleotide fragment from the same and/or different genes such as the 5′UTRs described in US Patent Application Publication No. 20100293625, herein incorporated by reference in its entirety.
  • Tables 2 and 3 provide a listing of exemplary UTRs which may be utilized in the primary construct of the present invention as flanking regions. Shown in Table 2 is a listing of a 5′-untranslated region of the invention. Variants of 5′ UTRs may be utilized wherein one or more nucleotides are added or removed to the termini, including A, T, C or G.
  • Table 3 Shown in Table 3 is a representative listing of 3′-untranslated regions of the invention. Variants of 3′ UTRs may be utilized wherein one or more nucleotides are added or removed to the termini, including A, T, C or G.
  • any UTR from any gene may be incorporated into the respective first or second flanking region of the primary construct.
  • multiple wild-type UTRs of any known gene may be utilized. It is also within the scope of the present invention to provide artificial UTRs which are not variants of wild type genes. These UTRs or portions thereof may be placed in the same orientation as in the transcript from which they were selected or may be altered in orientation or location. Hence a 5′ or 3′ UTR may be inverted, shortened, lengthened, made chimeric with one or more other 5′ UTRs or 3′ UTRs.
  • the term “altered” as it relates to a UTR sequence means that the UTR has been changed in some way in relation to a reference sequence.
  • a 3′ or 5′ UTR may be altered relative to a wild type or native UTR by the change in orientation or location as taught above or may be altered by the inclusion of additional nucleotides, deletion of nucleotides, swapping or transposition of nucleotides. Any of these changes producing an “altered” UTR (whether 3′ or 5′) comprise a variant UTR.
  • a double, triple or quadruple UTR such as a 5′ or 3′ UTR may be used.
  • a “double” UTR is one in which two copies of the same UTR are encoded either in series or substantially in series.
  • a double beta-globin 3′ UTR may be used as described in US Patent publication 20100129877, the contents of which are incorporated herein by reference in its entirety.
  • patterned UTRs are those UTRs which reflect a repeating or alternating pattern, such as ABABAB or AABBAABBAABB or ABCABCABC or variants thereof repeated once, twice, or more than 3 times. In these patterns, each letter, A, B, or C represent a different UTR at the nucleotide level.
  • flanking regions are selected from a family of transcripts whose proteins share a common function, structure, feature of property.
  • polypeptides of interest may belong to a family of proteins which are expressed in a particular cell, tissue or at some time during development.
  • the UTRs from any of these genes may be swapped for any other UTR of the same or different family of proteins to create a new chimeric primary transcript.
  • a “family of proteins” is used in the broadest sense to refer to a group of two or more polypeptides of interest which share at least one function, structure, feature, localization, origin, or expression pattern.
  • the primary construct components are reconstituted and transformed into a vector such as, but not limited to, plasmids, viruses, cosmids, and artificial chromosomes.
  • a vector such as, but not limited to, plasmids, viruses, cosmids, and artificial chromosomes.
  • the optimized construct may be reconstituted and transformed into chemically competent E. coli , yeast, neurospora, maize, drosophila , etc. where high copy plasmid-like or chromosome structures occur by methods described herein.
  • the untranslated region may also include translation enhancer elements (TEE).
  • TEE translation enhancer elements
  • the TEE may include those described in US Application No. 20090226470, herein incorporated by reference in its entirety, and those known in the art.
  • the primary constructs of the present invention may include at least two stop codons before the 3′ untranslated region (UTR).
  • the stop codon may be selected from TGA, TAA and TAG.
  • the primary constructs of the present invention include the stop codon TGA and one additional stop codon.
  • the addition stop codon may be TAA.
  • the primary constructs of the present invention include three stop codons.
  • the vector containing the primary construct is then amplified and the plasmid isolated and purified using methods known in the art such as, but not limited to, a maxi prep using the Invitrogen PURELINKTM HiPure Maxiprep Kit (Carlsbad, Calif.).
  • the plasmid may then be linearized using methods known in the art such as, but not limited to, the use of restriction enzymes and buffers.
  • the linearization reaction may be purified using methods including, for example Invitrogen's PURELINKTM PCR Micro Kit (Carlsbad, Calif.), and HPLC based purification methods such as, but not limited to, strong anion exchange HPLC, weak anion exchange HPLC, reverse phase HPLC (RP-HPLC), and hydrophobic interaction HPLC (HIC-HPLC) and Invitrogen's standard PURELINKTM PCR Kit (Carlsbad, Calif.).
  • the purification method may be modified depending on the size of the linearization reaction which was conducted.
  • the linearized plasmid is then used to generate cDNA for in vitro transcription (IVT) reactions.
  • a cDNA template may be synthesized by having a linearized plasmid undergo polymerase chain reaction (PCR).
  • Table 4 is a listing of primers and probes that may be usefully in the PCR reactions of the present invention. It should be understood that the listing is not exhaustive and that primer-probe design for any amplification is within the skill of those in the art.
  • Probes may also contain chemically modified bases to increase base-pairing fidelity to the target molecule and base-pairing strength. Such modifications may include 5-methyl-Cytidine, 2,6-di-amino-purine, 2′-fluoro, phosphoro-thioate, or locked nucleic acids.
  • the cDNA may be submitted for sequencing analysis before undergoing transcription.
  • the process of mRNA or mmRNA production may include, but is not limited to, in vitro transcription, cDNA template removal and RNA clean-up, and mRNA capping and/or tailing reactions.
  • the cDNA produced in the previous step may be transcribed using an in vitro transcription (IVT) system.
  • the system typically comprises a transcription buffer, nucleotide triphosphates (NTPs), an RNase inhibitor and a polymerase.
  • NTPs may be manufactured in house, may be selected from a supplier, or may be synthesized as described herein.
  • the NTPs may be selected from, but are not limited to, those described herein including natural and unnatural (modified) NTPs.
  • the polymerase may be selected from, but is not limited to, T7 RNA polymerase, T3 RNA polymerase and mutant polymerases such as, but not limited to, polymerases able to incorporate modified nucleic acids.
  • RNA polymerases or variants may be used in the design of the primary constructs of the present invention.
  • RNA polymerases may be modified by inserting or deleting amino acids of the RNA polymerase sequence.
  • the RNA polymerase may be modified to exhibit an increased ability to incorporate a 2′-modified nucleotide triphosphate compared to an unmodified RNA polymerase (see International Publication WO2008078180 and U.S. Pat. No. 8,101,385; herein incorporated by reference in their entireties).
  • Variants may be obtained by evolving an RNA polymerase, optimizing the RNA polymerase amino acid and/or nucleic acid sequence and/or by using other methods known in the art.
  • T7 RNA polymerase variants may be evolved using the continuous directed evolution system set out by Esvelt et al.
  • T7 RNA polymerase may encode at least one mutation such as, but not limited to, lysine at position 93 substituted for threonine (K93T), 14M, A7T, E63V, V64D, A65E, D66Y, T76N, C125R, S128R, A136T, N165S, G175R, H176L, Y178H, F182L, L196F, G198V, D208Y, E222K, S228A, Q239R, T243N, G259D, M267I, G280C, H300R, D351A, A354S, E356D, L360P, A383V, Y385C, D388Y, S397R, M401T, N410S, K450R, P451T, G452V, E484A, H523
  • T7 RNA polymerase variants may encode at least mutation as described in U.S. Pub. Nos. 20100120024 and 20070117112; herein incorporated by reference in their entireties.
  • Variants of RNA polymerase may also include, but are not limited to, substitutional variants, conservative amino acid substitution, insertional variants, deletional variants and/or covalent derivatives.
  • the primary construct may be designed to be recognized by the wild type or variant RNA polymerases. In doing so, the primary construct may be modified to contain sites or regions of sequence changes from the wild type or parent primary construct.
  • the primary construct may be designed to include at least one substitution and/or insertion upstream of an RNA polymerase binding or recognition site, downstream of the RNA polymerase binding or recognition site, upstream of the TATA box sequence, downstream of the TATA box sequence of the primary construct but upstream of the coding region of the primary construct, within the 5′UTR, before the 5′UTR and/or after the 5′UTR.
  • the 5′UTR of the primary construct may be replaced by the insertion of at least one region and/or string of nucleotides of the same base.
  • the region and/or string of nucleotides may include, but is not limited to, at least 3, at least 4, at least 5, at least 6, at least 7 or at least 8 nucleotides and the nucleotides may be natural and/or unnatural.
  • the group of nucleotides may include 5-8 adenine, cytosine, thymine, a string of any of the other nucleotides disclosed herein and/or combinations thereof.
  • the 5′UTR of the primary construct may be replaced by the insertion of at least two regions and/or strings of nucleotides of two different bases such as, but not limited to, adenine, cytosine, thymine, any of the other nucleotides disclosed herein and/or combinations thereof.
  • the 5′UTR may be replaced by inserting 5-8 adenine bases followed by the insertion of 5-8 cytosine bases.
  • the 5′UTR may be replaced by inserting 5-8 cytosine bases followed by the insertion of 5-8 adenine bases.
  • the primary construct may include at least one substitution and/or insertion downstream of the transcription start site which may be recognized by an RNA polymerase.
  • at least one substitution and/or insertion may occur downstream the transcription start site by substituting at least one nucleic acid in the region just downstream of the transcription start site (such as, but not limited to, +1 to +6). Changes to region of nucleotides just downstream of the transcription start site may affect initiation rates, increase apparent nucleotide triphosphate (NTP) reaction constant values, and increase the dissociation of short transcripts from the transcription complex curing initial transcription (Brieba et al, Biochemistry (2002) 41: 5144-5149; herein incorporated by reference in its entirety).
  • the modification, substitution and/or insertion of at least one nucleic acid may cause a silent mutation of the nucleic acid sequence or may cause a mutation in the amino acid sequence.
  • the primary construct may include the substitution of at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12 or at least 13 guanine bases downstream of the transcription start site.
  • the primary construct may include the substitution of at least 1, at least 2, at least 3, at least 4, at least 5 or at least 6 guanine bases in the region just downstream of the transcription start site.
  • the guanine bases may be substituted by at least 1, at least 2, at least 3 or at least 4 adenine nucleotides.
  • the guanine bases may be substituted by at least 1, at least 2, at least 3 or at least 4 cytosine bases.
  • the guanine bases in the region are GGGAGA the guanine bases may be substituted by at least 1, at least 2, at least 3 or at least 4 thymine, and/or any of the nucleotides described herein.
  • the primary construct may include at least one substitution and/or insertion upstream of the start codon.
  • the start codon is the first codon of the protein coding region whereas the transcription start site is the site where transcription begins.
  • the primary construct may include, but is not limited to, at least 1, at least 2, at least 3, at least 4, at least 5, at least 6, at least 7 or at least 8 substitutions and/or insertions of nucleotide bases.
  • the nucleotide bases may be inserted or substituted at 1, at least 1, at least 2, at least 3, at least 4 or at least 5 locations upstream of the start codon.
  • the nucleotides inserted and/or substituted may be the same base (e.g., all A or all C or all T or all G), two different bases (e.g., A and C, A and T, or C and T), three different bases (e.g., A, C and T or A, C and T) or at least four different bases.
  • the guanine base upstream of the coding region in the primary construct may be substituted with adenine, cytosine, thymine, or any of the nucleotides described herein.
  • the substitution of guanine bases in the primary construct may be designed so as to leave one guanine base in the region downstream of the transcription start site and before the start codon (see Esvelt et al. Nature (2011) 472(7344):499-503; herein incorporated by reference in its entirety).
  • at least 5 nucleotides may be inserted at 1 location downstream of the transcription start site but upstream of the start codon and the at least 5 nucleotides may be the same base type.
  • RNA clean-up may also include a purification method such as, but not limited to, AGENCOURT® CLEANSEQ® system from Beckman Coulter (Danvers, Mass.), HPLC based purification methods such as, but not limited to, strong anion exchange HPLC, weak anion exchange HPLC, reverse phase HPLC (RP-HPLC), and hydrophobic interaction HPLC (HIC-HPLC).
  • AGENCOURT® CLEANSEQ® system from Beckman Coulter (Danvers, Mass.
  • HPLC based purification methods such as, but not limited to, strong anion exchange HPLC, weak anion exchange HPLC, reverse phase HPLC (RP-HPLC), and hydrophobic interaction HPLC (HIC-HPLC).
  • the primary construct or mmRNA may also undergo capping and/or tailing reactions.
  • a capping reaction may be performed by methods known in the art to add a 5′ cap to the 5′ end of the primary construct. Methods for capping include, but are not limited to, using a Vaccinia Capping enzyme (New England Biolabs, Ipswich, Mass.).
  • a poly-A tailing reaction may be performed by methods known in the art, such as, but not limited to, 2′ O-methyltransferase and by methods as described herein. If the primary construct generated from cDNA does not include a poly-T, it may be beneficial to perform the poly-A-tailing reaction before the primary construct is cleaned.
  • Primary construct or mmRNA purification may include, but is not limited to, mRNA or mmRNA clean-up, quality assurance and quality control.
  • mRNA or mmRNA clean-up may be performed by methods known in the arts such as, but not limited to, AGENCOURT® beads (Beckman Coulter Genomics, Danvers, Mass.), poly-T beads, LNATM oligo-T capture probes (EXIQON® Inc, Vedbaek, Denmark) or HPLC based purification methods such as, but not limited to, strong anion exchange HPLC, weak anion exchange HPLC, reverse phase HPLC (RP-HPLC), and hydrophobic interaction HPLC (HIC-HPLC).
  • AGENCOURT® beads Beckman Coulter Genomics, Danvers, Mass.
  • poly-T beads poly-T beads
  • LNATM oligo-T capture probes EXIQON® Inc, Vedbaek, Denmark
  • HPLC based purification methods such as, but not limited to, strong anion exchange
  • purified when used in relation to a polynucleotide such as a “purified mRNA or mmRNA” refers to one that is separated from at least one contaminant.
  • a “contaminant” is any substance which makes another unfit, impure or inferior.
  • a purified polynucleotide e.g., DNA and RNA
  • a quality assurance and/or quality control check may be conducted using methods such as, but not limited to, gel electrophoresis, UV absorbance, or analytical HPLC.
  • the mRNA or mmRNA may be sequenced by methods including, but not limited to reverse-transcriptase-PCR.
  • the mRNA or mmRNA may be quantified using methods such as, but not limited to, ultraviolet visible spectroscopy (UV/Vis).
  • UV/Vis ultraviolet visible spectroscopy
  • a non-limiting example of a UV/Vis spectrometer is a NANODROP® spectrometer (ThermoFisher, Waltham, Mass.).
  • the quantified mRNA or mmRNA may be analyzed in order to determine if the mRNA or mmRNA may be of proper size, check that no degradation of the mRNA or mmRNA has occurred.
  • Degradation of the mRNA and/or mmRNA may be checked by methods such as, but not limited to, agarose gel electrophoresis, HPLC based purification methods such as, but not limited to, strong anion exchange HPLC, weak anion exchange HPLC, reverse phase HPLC (RP-HPLC), and hydrophobic interaction HPLC (HIC-HPLC), liquid chromatography-mass spectrometry (LCMS), capillary electrophoresis (CE) and capillary gel electrophoresis (CGE).
  • HPLC based purification methods such as, but not limited to, strong anion exchange HPLC, weak anion exchange HPLC, reverse phase HPLC (RP-HPLC), and hydrophobic interaction HPLC (HIC-HPLC), liquid chromatography-mass spectrometry (LCMS), capillary electrophoresis (CE) and capillary gel electrophoresis (CGE).
  • the primary constructs or mmRNA may also encode additional features which facilitate trafficking of the polypeptides to therapeutically relevant sites.
  • One such feature which aids in protein trafficking is the signal sequence.
  • a “signal sequence” or “signal peptide” is a polynucleotide or polypeptide, respectively, which is from about 9 to 200 nucleotides (3-60 amino acids) in length which is incorporated at the 5′ (or N-terminus) of the coding region or polypeptide encoded, respectively. Addition of these sequences result in trafficking of the encoded polypeptide to the endoplasmic reticulum through one or more secretory pathways. Some signal peptides are cleaved from the protein by signal peptidase after the proteins are transported.
  • Table 5 is a representative listing of protein signal sequences which may be incorporated for encoding by the polynucleotides, primary constructs or mmRNA of the invention.
  • SS secretion signal
  • MLS mitochondrial leader signal.
  • the primary constructs or mmRNA of the present invention may be designed to encode any of the signal sequences of SEQ ID NOs 94-155, or fragments or variants thereof. These sequences may be included at the beginning of the polypeptide coding region, in the middle or at the terminus or alternatively into a flanking region. Further, any of the polynucleotide primary constructs of the present invention may also comprise one or more of the sequences defined by SEQ ID NOs 32-93. These may be in the first region or either flanking region.
  • Additional signal sequences which may be utilized in the present invention include those taught in, for example, databases such as those found at http://www.signalpeptide.de/ or http://proline.bic.nus.edu.sg/spdb/. Those described in U.S. Pat. Nos. 8,124,379; 7,413,875 and 7,385,034 are also within the scope of the invention and the contents of each are incorporated herein by reference in their entirety.
  • the primary constructs comprise at least a first region of linked nucleosides encoding at least one polypeptide of interest.
  • the polypeptides of interest or “Targets” of the present invention are listed in LengthyTable 6. Shown in Lengthy Table 6, in addition to the name and description of the gene encoding the polypeptide of interest (Target Description) are the ENSEMBL Transcript ID (ENST), the ENSEMBL Protein ID (ENSP) and when available the optimized transcript sequence ID (Optimized Trans SEQ ID) or optimized open reading frame sequence ID (Optimized ORF SEQ ID). For any particular gene there may exist one or more variants or isoforms. Where these exist, they are shown in the table as well.
  • flanking regions are encoded in each ENST transcript either to the 5′ (upstream) or 3′ (downstream) of the ORF or coding region.
  • the coding region is definitively and specifically disclosed by teaching the ENSP sequence. Consequently, the sequences taught flanking that encoding the protein are considered flanking regions. It is also possible to further characterize the 5′ and 3′ flanking regions by utilizing one or more available databases or algorithms. Databases have annotated the features contained in the flanking regions of the ENST transcripts and these are available in the art.
  • the polypeptides of the present invention may include at least one protein cleavage signal containing at least one protein cleavage site.
  • the protein cleavage site may be located at the N-terminus, the C-terminus, at any space between the N- and the C-termini such as, but not limited to, half-way between the N- and C-termini, between the N-terminus and the half way point, between the half way point and the C-terminus, and combinations thereof.
  • the polypeptides of the present invention may include, but is not limited to, a proprotein convertase (or prohormone convertase), thrombin or Factor Xa protein cleavage signal.
  • Proprotein convertases are a family of nine proteinases, comprising seven basic amino acid-specific subtilisin-like serine proteinases related to yeast kexin, known as prohormone convertase 1/3 (PC1/3), PC2, furin, PC4, PC5/6, paired basic amino-acid cleaving enzyme 4 (PACE4) and PC7, and two other subtilases that cleave at non-basic residues, called subtilisin kexin isozyme 1 (SKI-1) and proprotein convertase subtilisin kexin 9 (PCSK9).
  • Non-limiting examples of protein cleavage signal amino acid sequences are listing in Table 7.
  • “X” refers to any amino acid
  • “n” may be 0, 2, 4 or 6 amino acids
  • “*” refers to the protein cleavage site.
  • the primary constructs and the mmRNA of the present invention may be engineered such that the primary construct or mmRNA contains at least one encoded protein cleavage signal.
  • the encoded protein cleavage signal may be located before the start codon, after the start codon, before the coding region, within the coding region such as, but not limited to, half way in the coding region, between the start codon and the half way point, between the half way point and the stop codon, after the coding region, before the stop codon, between two stop codons, after the stop codon and combinations thereof
  • the primary constructs or mmRNA of the present invention may include at least one encoded protein cleavage signal containing at least one protein cleavage site.
  • the encoded protein cleavage signal may include, but is not limited to, a proprotein convertase (or prohormone convertase), thrombin and/or Factor Xa protein cleavage signal.
  • a proprotein convertase or prohormone convertase
  • thrombin or Factor Xa protein cleavage signal.
  • Factor Xa protein cleavage signal may be used as Table 1 above or other known methods to determine the appropriate encoded protein cleavage signal to include in the primary constructs or mmRNA of the present invention. For example, starting with the signal of Table 7 and considering the codons of Table 1 one can design a signal for the primary construct which can produce a protein signal in the resulting polypeptide.
  • polypeptides of the present invention include at least one protein cleavage signal and/or site.
  • the polypeptides of the present invention include at least one protein cleavage signal and/or site with the proviso that the polypeptide is not GLP-1.
  • the primary constructs or mmRNA of the present invention includes at least one encoded protein cleavage signal and/or site.
  • the primary constructs or mmRNA of the present invention includes at least one encoded protein cleavage signal and/or site with the proviso that the primary construct or mmRNA does not encode GLP-1.
  • the primary constructs or mmRNA of the present invention may include more than one coding region. Where multiple coding regions are present in the primary construct or mmRNA of the present invention, the multiple coding regions may be separated by encoded protein cleavage sites.
  • the primary construct or mmRNA may be signed in an ordered pattern. On such pattern follows AXBY form where A and B are coding regions which may be the same or different coding regions and/or may encode the same or different polypeptides, and X and Y are encoded protein cleavage signals which may encode the same or different protein cleavage signals.
  • a second such pattern follows the form AXYBZ where A and B are coding regions which may be the same or different coding regions and/or may encode the same or different polypeptides, and X, Y and Z are encoded protein cleavage signals which may encode the same or different protein cleavage signals.
  • a third pattern follows the form ABXCY where A, B and C are coding regions which may be the same or different coding regions and/or may encode the same or different polypeptides, and X and Y are encoded protein cleavage signals which may encode the same or different protein cleavage signals.
  • the polypeptides, primary constructs and mmRNA can also contain sequences that encode protein cleavage sites so that the polypeptides, primary constructs and mmRNA can be released from a carrier region or a fusion partner by treatment with a specific protease for said protein cleavage site.
  • the polypeptides, primary constructs and mmRNA of the present invention may include a sequence encoding the 2A peptide. In one embodiment, this sequence may be used to separate the coding region of two or more polypeptides of interest. As a non-limiting example, the sequence encoding the 2A peptide may be between coding region A and coding region B (A-2Apep-B). The presence of the 2A peptide would result in the cleavage of one long protein into protein A, protein B and the 2A peptide. Protein A and protein B may be the same or different polypeptides of interest. In another embodiment, the 2A peptide may be used in the polynucleotides, primary constructs and/or mmRNA of the present invention to produce two, three, four, five, six, seven, eight, nine, ten or more proteins.
  • the polynucleotides, primary constructs and/or mmRNA of the present invention may include at least one post transcriptional control modulator.
  • post transcriptional control modulators may be, but are not limited to, small molecules, compounds and regulatory sequences.
  • post transcriptional control may be achieved using small molecules identified by PTC Therapeutics Inc. (South Plainfield, N.J.) using their GEMSTM (Gene Expression Modulation by Small-Moleclues) screening technology.
  • the post transcriptional control modulator may be a gene expression modulator which is screened by the method detailed in or a gene expression modulator described in International Publication No. WO2006022712, herein incorporated by reference in its entirety. Methods identifying RNA regulatory sequences involved in translational control are described in International Publication No. WO2004067728, herein incorporated by reference in its entirety; methods identifying compounds that modulate untranslated region dependent expression of a gene are described in International Publication No. WO2004065561, herein incorporated by reference in its entirety.
  • the polynucleotides, primary constructs and/or mmRNA of the present invention may include at least one post transcriptional control modulator is located in the 5′ and/or the 3′ untranslated region of the polynucleotides, primary constructs and/or mmRNA of the present invention
  • the polynucleotides, primary constructs and/or mmRNA of the present invention may include at least one post transcription control modulator to modulate premature translation termination.
  • the post transcription control modulators may be compounds described in or a compound found by methods outlined in International Publication Nso. WO2004010106, WO2006044456, WO2006044682, WO2006044503 and WO2006044505, each of which is herein incorporated by reference in its entirety.
  • the compound may bind to a region of the 28S ribosomal RNA in order to modulate premature translation termination (See e.g., WO2004010106, herein incorporated by reference in its entirety).
  • polynucleotides, primary constructs and/or mmRNA of the present invention may include at least one post transcription control modulator to alter protein expression.
  • the expression of VEGF may be regulated using the compounds described in or a compound found by the methods described in International Publication Nos. WO2005118857, WO2006065480, WO2006065479 and WO2006058088, each of which is herein incorporated by reference in its entirety.
  • the polynucleotides, primary constructs and/or mmRNA of the present invention may include at least one post transcription control modulator to control translation.
  • the post transcription control modulator may be a RNA regulatory sequence.
  • the RNA regulatory sequence may be identified by the methods described in International Publication No. WO2006071903, herein incorporated by reference in its entirety.
  • modify refers to modification with respect to A, G, U or C ribonucleotides. Generally, herein, these terms are not intended to refer to the ribonucleotide modifications in naturally occurring 5′-terminal mRNA cap moieties.
  • modification refers to a modification as compared to the canonical set of 20 amino acids, moiety
  • the modifications may be various distinct modifications.
  • the coding region, the flanking regions and/or the terminal regions may contain one, two, or more (optionally different) nucleoside or nucleotide modifications.
  • a modified polynucleotide, primary construct, or mmRNA introduced to a cell may exhibit reduced degradation in the cell, as compared to an unmodified polynucleotide, primary construct, or mmRNA.
  • the polynucleotides, primary constructs, and mmRNA can include any useful modification, such as to the sugar, the nucleobase, or the internucleoside linkage (e.g. to a linking phosphate/to a phosphodiester linkage/to the phosphodiester backbone).
  • One or more atoms of a pyrimidine nucleobase may be replaced or substituted with optionally substituted amino, optionally substituted thiol, optionally substituted alkyl (e.g., methyl or ethyl), or halo (e.g., chloro or fluoro).
  • modifications e.g., one or more modifications
  • RNAs ribonucleic acids
  • DNAs deoxyribonucleic acids
  • TAAs threose nucleic acids
  • GNAs glycol nucleic acids
  • PNAs peptide nucleic acids
  • LNAs locked nucleic acids
  • the polynucleotides, primary constructs, and mmRNA of the invention do not substantially induce an innate immune response of a cell into which the mRNA is introduced.
  • Featues of an induced innate immune response include 1) increased expression of pro-inflammatory cytokines, 2) activation of intracellular PRRs (RIG-I, MDA5, etc, and/or 3) termination or reduction in protein translation.
  • the invention provides a modified nucleic acid molecule containing a degradation domain, which is capable of being acted on in a directed manner within a cell.
  • the present disclosure provides polynucleotides comprising a nucleoside or nucleotide that can disrupt the binding of a major groove interacting, e.g. binding, partner with the polynucleotide (e.g., where the modified nucleotide has decreased binding affinity to major groove interacting partner, as compared to an unmodified nucleotide).
  • the polynucleotides, primary constructs, and mmRNA can optionally include other agents (e.g., RNAi-inducing agents, RNAi agents, siRNAs, shRNAs, miRNAs, antisense RNAs, ribozymes, catalytic DNA, tRNA, RNAs that induce triple helix formation, aptamers, vectors, etc.).
  • the polynucleotides, primary constructs, or mmRNA may include one or more messenger RNAs (mRNAs) and one or more modified nucleoside or nucleotides (e.g., mmRNA molecules). Details for these polynucleotides, primary constructs, and mmRNA follow.
  • the polynucleotides, primary constructs, and mmRNA of the invention includes a first region of linked nucleosides encoding a polypeptide of interest, a first flanking region located at the 5′ terminus of the first region, and a second flanking region located at the 3′ terminus of the first region.
  • the polynucleotide, primary construct, or mmRNA (e.g., the first region, first flanking region, or second flanking region) includes n number of linked nucleosides having Formula (Ia) or Formula (Ia-1):
  • each R U is, independently, H, halo, or optionally substituted alkyl;
  • — is a single bond or absent
  • each of R 1′ , R 2′ , R 1′′ , R 2′′ , R 1 , R 2 , R 3 , R 4 , and R 5 is independently, if present, H, halo, hydroxy, thiol, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aminoalkoxy, optionally substituted alkoxyalkoxy, optionally substituted hydroxyalkoxy, optionally substituted amino, azido, optionally substituted aryl, optionally substituted aminoalkyl, optionally substituted aminoalkenyl, optionally substituted aminoalkynyl, or absent; wherein the combination of R 3 with one or more of R1′, R1′′, R2′, R2′′, or R5 (e.g., the combination of R1′ and R3, the combination of R1′′ and R3, the combination of R2′ and R3, the combination of R2′′ and R3, or
  • each of Y 1 , Y 2 , and Y 3 is, independently, O, S, Se, —NR N1 —, optionally substituted alkylene, or optionally substituted heteroalkylene, wherein R N1 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or absent;
  • each Y 4 is, independently, H, hydroxy, thiol, boranyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted thioalkoxy, optionally substituted alkoxyalkoxy, or optionally substituted amino;
  • each Y 5 is, independently, O, S, Se, optionally substituted alkylene (e.g., methylene), or optionally substituted heteroalkylene;
  • n is an integer from 1 to 100,000;
  • B is a nucleobase (e.g., a purine, a pyrimidine, or derivatives thereof), wherein the combination of B and R 1′ , the combination of B and R 2′ , the combination of B and
  • R 1′′ , or the combination of B and R 2′′ can, taken together with the carbons to which they are attached, optionally form a bicyclic group (e.g., a bicyclic heterocyclyl) or wherein the combination of B, R 1′ , and R 3 or the combination of B, R 2′′ , and R 3 can optionally form a tricyclic or tetracyclic group (e.g., a tricyclic or tetracyclic heterocyclyl, such as in Formula (IIo)-(IIp) herein).
  • the polynucleotide, primary construct, or mmRNA includes a modified ribose.
  • the polynucleotide, primary construct, or mmRNA (e.g., the first region, the first flanking region, or the second flanking region) includes n number of linked nucleosides having Formula (Ia-2)-(Ia-5) or a pharmaceutically acceptable salt or stereoisomer thereof.
  • the polynucleotide, primary construct, or mmRNA (e.g., the first region, the first flanking region, or the second flanking region) includes n number of linked nucleosides having Formula (Ib) or Formula (Ib-1):
  • each R U is, independently, H, halo, or optionally substituted alkyl;
  • — is a single bond or absent
  • each of R 1 , R 3′ , R 3′′ , and R 4 is, independently, H, halo, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aminoalkoxy, optionally substituted alkoxyalkoxy, optionally substituted hydroxyalkoxy, optionally substituted amino, azido, optionally substituted aryl, optionally substituted aminoalkyl, optionally substituted aminoalkenyl, optionally substituted aminoalkynyl, or absent; and wherein the combination of R 1 and R 3′ or the combination of R 1 and R 3′′ can be taken together to form optionally substituted alkylene or optionally substituted heteroalkylene (e.g., to produce a locked nucleic acid);
  • each R 5 is, independently, H, halo, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aminoalkoxy, optionally substituted alkoxyalkoxy, or absent;
  • each of Y 1 , Y 2 , and Y 3 is, independently, O, S, Se, —NR N1 —, optionally substituted alkylene, or optionally substituted heteroalkylene, wherein R N1 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted aryl;
  • each Y 4 is, independently, H, hydroxy, thiol, boranyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted alkoxyalkoxy, or optionally substituted amino;
  • n is an integer from 1 to 100,000;
  • B is a nucleobase
  • the polynucleotide, primary construct, or mmRNA (e.g., the first region, first flanking region, or second flanking region) includes n number of linked nucleosides having Formula (Ic):
  • each R U is, independently, H, halo, or optionally substituted alkyl;
  • — is a single bond or absent
  • each of B 1 , B 2 , and B 3 is, independently, a nucleobase (e.g., a purine, a pyrimidine, or derivatives thereof, as described herein), H, halo, hydroxy, thiol, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aminoalkoxy, optionally substituted alkoxyalkoxy, optionally substituted hydroxyalkoxy, optionally substituted amino, azido, optionally substituted aryl, optionally substituted aminoalkyl, optionally substituted aminoalkenyl, or optionally substituted aminoalkynyl, wherein one and only one of B 1 , B 2 , and B 3 is a nucleobase;
  • a nucleobase e.g., a purine, a pyrimidine, or derivatives thereof, as described herein
  • H halo, hydroxy, thi
  • each of R b1 , R b2 , R b3 , R 3 , and R 5 is, independently, H, halo, hydroxy, thiol, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aminoalkoxy, optionally substituted alkoxyalkoxy, optionally substituted hydroxyalkoxy, optionally substituted amino, azido, optionally substituted aryl, optionally substituted aminoalkyl, optionally substituted aminoalkenyl or optionally substituted aminoalkynyl;
  • each of Y 1 , Y 2 , and Y 3 is, independently, O, S, Se, —NR N1 —, optionally substituted alkylene, or optionally substituted heteroalkylene, wherein R N1 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted aryl;
  • each Y 4 is, independently, H, hydroxy, thiol, boranyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted thioalkoxy, optionally substituted alkoxyalkoxy, or optionally substituted amino;
  • each Y 5 is, independently, O, S, Se, optionally substituted alkylene (e.g., methylene), or optionally substituted heteroalkylene;
  • n is an integer from 1 to 100,000;
  • ring including U can include one or more double bonds.
  • the ring including U does not have a double bond between U-CB 3 R b3 or between CB3R b3 —C B2 R b2 .
  • the polynucleotide, primary construct, or mmRNA (e.g., the first region, first flanking region, or second flanking region) includes n number of linked nucleosides having Formula (Id):
  • each R U is, independently, H, halo, or optionally substituted alkyl;
  • each R 3 is, independently, H, halo, hydroxy, thiol, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aminoalkoxy, optionally substituted alkoxyalkoxy, optionally substituted hydroxyalkoxy, optionally substituted amino, azido, optionally substituted aryl, optionally substituted aminoalkyl, optionally substituted aminoalkenyl, or optionally substituted aminoalkynyl;
  • each of Y 1 , Y 2 , and Y 3 is, independently, O, S, Se, —NR N1 —, optionally substituted alkylene, or optionally substituted heteroalkylene, wherein R N1 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted aryl;
  • each Y 4 is, independently, H, hydroxy, thiol, boranyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted thioalkoxy, optionally substituted alkoxyalkoxy, or optionally substituted amino;
  • each Y 5 is, independently, O, S, optionally substituted alkylene (e.g., methylene), or optionally substituted heteroalkylene;
  • n is an integer from 1 to 100,000;
  • B is a nucleobase (e.g., a purine, a pyrimidine, or derivatives thereof).
  • the polynucleotide, primary construct, or mmRNA (e.g., the first region, first flanking region, or second flanking region) includes n number of linked nucleosides having Formula (Ie):
  • each of U′ and U′′ is, independently, O, S, N(R U ) nu , or C(R U ) nu , wherein nu is an integer from 0 to 2 and each R U is, independently, H, halo, or optionally substituted alkyl;
  • each R 6 is, independently, H, halo, hydroxy, thiol, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aminoalkoxy, optionally substituted alkoxyalkoxy, optionally substituted hydroxyalkoxy, optionally substituted amino, azido, optionally substituted aryl, optionally substituted aminoalkyl, optionally substituted aminoalkenyl, or optionally substituted aminoalkynyl;
  • each Y 5′ is, independently, O, S, optionally substituted alkylene (e.g., methylene or ethylene), or optionally substituted heteroalkylene;
  • n is an integer from 1 to 100,000;
  • B is a nucleobase (e.g., a purine, a pyrimidine, or derivatives thereof).
  • the polynucleotide, primary construct, or mmRNA (e.g., the first region, first flanking region, or second flanking region) includes n number of linked nucleosides having Formula (If) or (If-1):
  • each of U′ and U′′ is, independently, O, S, N, N(R U ) nu , or C(R U ) nu , wherein nu is an integer from 0 to 2 and each R U is, independently, H, halo, or optionally substituted alkyl (e.g., U′ is 0 and U′′ is N);
  • — is a single bond or absent
  • each of R 1′ , R 2′ , R 1′′ , R 2′′ , R 3 , and R 4 is, independently, H, halo, hydroxy, thiol, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aminoalkoxy, optionally substituted alkoxyalkoxy, optionally substituted hydroxyalkoxy, optionally substituted amino, azido, optionally substituted aryl, optionally substituted aminoalkyl, optionally substituted aminoalkenyl, optionally substituted aminoalkynyl, or absent; and wherein the combination of R 1′ and R 3 , the combination of R 1′′ and R 3 , the combination of R 2′ and R 3 , or the combination of R 2′′ and R 3 can be taken together to form optionally substituted alkylene or optionally substituted heteroalkylene (e.g., to produce a locked nucleic acid);each of m
  • each of Y 1 , Y 2 , and Y 3 is, independently, O, S, Se, —NR N1 —, optionally substituted alkylene, or optionally substituted heteroalkylene, wherein R N1 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or absent;
  • each Y 4 is, independently, H, hydroxy, thiol, boranyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted thioalkoxy, optionally substituted alkoxyalkoxy, or optionally substituted amino;
  • each Y 5 is, independently, O, S, Se, optionally substituted alkylene (e.g., methylene), or optionally substituted heteroalkylene;
  • n is an integer from 1 to 100,000;
  • B is a nucleobase (e.g., a purine, a pyrimidine, or derivatives thereof).
  • the ring including U has one or two double bonds.
  • polynucleotides, primary constructs, or mmRNA e.g., Formulas (Ia)-(Ia-5), (Ib)-(If-1), (IIa)-(IIp), (IIb-1), (IIb-2), (IIc-1)-(IIc-2), (IIn-1), (IIn-2), (IVa)-(IVl), and (IXa)-(IXr)), each of R 1 , R 1′ , and R 1′′ , if present, is H.
  • Formulas (Ia)-(Ia-5), (Ib)-(If-1), (IIa)-(IIp), (IIb-1), (IIb-2), (IIc-1)-(IIc-2), (IIn-1), (IIn-2), (IVa)-(IVl), and (IXa)-(IXr) each of R 1 , R 1′ , and R 1′′ , if present, is H.
  • each of R 2 , R 2′ , and R 2′′ is, independently, H, halo (e.g., fluoro), hydroxy, optionally substituted alkoxy (e.g., methoxy or ethoxy), or optionally substituted alkoxyalkoxy.
  • alkoxyalkoxy is —(CH 2 ) s2 (OCH 2 CH 2 ) s1 (CH 2 ) s3 OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C 1-20 alkyl). In some embodiments, s2 is 0, s1 is 1 or 2, s3 is 0 or 1, and R′ is C 1-6 alkyl.
  • polynucleotides, primary constructs, or mmRNA e.g., Formulas (Ia)-(Ia-5), (Ib)-(If-1), (IIa)-(IIp), (IIb-1), (IIb-2), (IIc-1)-(IIc-2), (IIn-1), (IIn-2), (IVa)-(IVl), and (IXa)-(IXr)), each of R 2 , R 2′ , and R 2′′ , if present, is H.
  • Formulas (Ia)-(Ia-5), (Ib)-(If-1), (IIa)-(IIp), (IIb-1), (IIb-2), (IIc-1)-(IIc-2), (IIn-1), (IIn-2), (IVa)-(IVl), and (IXa)-(IXr) each of R 2 , R 2′ , and R 2′′ , if present, is H.
  • each of R 1 , R 1′ , and R 1′′ is, independently, H, halo (e.g., fluoro), hydroxy, optionally substituted alkoxy (e.g., methoxy or ethoxy), or optionally substituted alkoxyalkoxy.
  • alkoxyalkoxy is —(CH 2 ) s2 (OCH 2 CH 2 ) s1 (CH 2 ) s3 OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C 1-20 alkyl). In some embodiments, s2 is 0, s1 is 1 or 2, s3 is 0 or 1, and R′ is C 1-6 alkyl.
  • each of R 3 , R 4 , and R 5 is, independently, H, halo (e.g., fluoro), hydroxy, optionally substituted alkyl, optionally substituted alkoxy (e.g., methoxy or ethoxy), or optionally substituted alkoxyalkoxy.
  • R 3 is H, R 4 is H, R 5 is H, or R 3 , R 4 , and R 5 are all H.
  • R 3 is C 1-6 alkyl
  • R 4 is C 1-6 alkyl
  • R 5 is C 1-6 alkyl
  • R 3 and R 4 are both H
  • R 5 is C 1-6 alkyl.
  • R 3 and R 5 join together to form optionally substituted alkylene or optionally substituted heteroalkylene and, taken together with the carbons to which they are attached, provide an optionally substituted heterocyclyl (e.g., a bicyclic, tricyclic, or tetracyclic heterocyclyl, such as trans-3′,4′ analogs, wherein R 3 and R 5 join together to form heteroalkylene (e.g., —(CH 2 ) b1 O(CH 2 ) b2 O(CH 2 ) b3
  • R 3 and one or more of R 1′ , R 1′′ , R 2′ , R 2′′ , or R 5 join together to form optionally substituted alkylene or optionally substituted heteroalkylene and, taken together with the carbons to which they are attached, provide an optionally substituted heterocyclyl (e.g., a bicyclic, tricyclic, or tetracyclic heterocyclyl, R 3 and one or more of R 1′ , R 1′′ , R 2′ , R 2′′ , or R 5 join together to form heteroal
  • R 5 and one or more of R 1′ , R 1′′ , R 2′ , or R 2′′ join together to form optionally substituted alkylene or optionally substituted heteroalkylene and, taken together with the carbons to which they are attached, provide an optionally substituted heterocyclyl (e.g., a bicyclic, tricyclic, or tetracyclic heterocyclyl, R 5 and one or more of R 1′ , R 1′′ , R 2′ , or R 2′′ join together to form heteroalkylene (e.g.,
  • each Y 2 is, independently, O, S, or —NR N1 —, wherein R N1 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted aryl.
  • Y 2 is NR N1 —, wherein R N1 is H or optionally substituted alkyl (e.g., C 1-6 alkyl, such as methyl, ethyl, isopropyl, or n-propyl).
  • R N1 is H or optionally substituted alkyl (e.g., C 1-6 alkyl, such as methyl, ethyl, isopropyl, or n-propyl).
  • each Y 3 is, independently, O or S.
  • R 1 is H; each R 2 is, independently, H, halo (e.g., fluoro), hydroxy, optionally substituted alkoxy (e.g., methoxy or ethoxy), or optionally substituted alkoxyalkoxy (e.g., —(CH 2 ) s2 (OCH 2 CH 2 ) s1 (CH 2 ) s3 OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3,
  • R 3 is H, halo (e.g., fluoro), hydroxy, optionally substituted alkyl, optionally substituted alkoxy (e.g., methoxy or ethoxy), or optionally substituted alkoxyalkoxy.
  • halo e.g., fluoro
  • hydroxy optionally substituted alkyl
  • optionally substituted alkoxy e.g., methoxy or ethoxy
  • optionally substituted alkoxyalkoxy optionally substituted alkoxyalkoxy.
  • each Y 1 is, independently, O or —NR N1 —, wherein R N1 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted aryl (e.g., wherein R N1 is H or optionally substituted alkyl (e.g., C 1-6 alkyl, such as methyl, ethyl, isopropyl, or n-propyl)); and each Y 4 is, independently, H, hydroxy, thiol, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted thioalkoxy, optionally substituted alkoxyalkoxy, or optionally substituted amino.
  • R N1 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted aryl (e.g., wherein R N1 is H or optionally substituted alkyl (e.g.
  • each R 1 is, independently, H, halo (e.g., fluoro), hydroxy, optionally substituted alkoxy (e.g., methoxy or ethoxy), or optionally substituted alkoxyalkoxy (e.g., —(CH 2 ) s2 (OCH 2 CH 2 ) s1 (CH 2 ) s3 OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer
  • R 3 is H, halo (e.g., fluoro), hydroxy, optionally substituted alkyl, optionally substituted alkoxy (e.g., methoxy or ethoxy), or optionally substituted alkoxyalkoxy.
  • halo e.g., fluoro
  • hydroxy optionally substituted alkyl
  • optionally substituted alkoxy e.g., methoxy or ethoxy
  • optionally substituted alkoxyalkoxy optionally substituted alkoxyalkoxy.
  • each Y 1 is, independently, O or —NR N1 —, wherein R N1 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted aryl (e.g., wherein R N1 is H or optionally substituted alkyl (e.g., C 1-6 alkyl, such as methyl, ethyl, isopropyl, or n-propyl)); and each Y 4 is, independently, H, hydroxy, thiol, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted thioalkoxy, optionally substituted alkoxyalkoxy, or optionally substituted amino.
  • R N1 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted aryl (e.g., wherein R N1 is H or optionally substituted alkyl (e.g.
  • the ring including U is in the ⁇ -D (e.g., ⁇ -D-ribo) configuration.
  • the ring including U is in the ⁇ -L (e.g., ⁇ -L-ribo) configuration.
  • one or more B is not pseudouridine ( ⁇ ) or 5-methyl-cytidine (m 5 C).
  • about 10% to about 100% of n number of B nucleobases is not ⁇ or m 5 C (e.g., from 10% to 20%, from 10% to 35%, from 10% to 50%, from 10% to 60%, from 10% to 75%, from 10% to 90%, from 10% to 95%, from 10% to 98%, from 10% to 99%, from 20% to 35%, from 20% to 50%, from 20% to 60%, from 20% to 75%, from 20% to 90%, from 20% to 95%, from 20% to 98%, from 20% to 99%, from 20% to 100%, from 50% to 60%, from 50% to 75%, from 50% to 90%, from 50% to 95%, from 50% to 98%, from 50% to 99%, from 50% to 100%, from 75% to 90%, from 75% to 95%, from 75% to 98%, from 75% to 99%, and from 75% to 100% of n number of B is not ⁇ or m 5 C).
  • B is not ⁇ or m 5 C.
  • polynucleotides, primary constructs, or mmRNA e.g., Formulas (Ia)-(Ia-5), (Ib)-(If-1), (IIa)-(IIp), (IIb-1), (IIb-2), (IIc-1)-(IIc-2), (IIn-1), (IIn-2), (IVa)-(IVl), and (IXa)-(IXr)
  • B is an unmodified nucleobase selected from cytosine, guanine, uracil and adenine
  • at least one of Y 1 , Y 2 , or Y 3 is not O.
  • the polynucleotide, primary construct, or mmRNA includes a modified ribose.
  • the polynucleotide, primary construct, or mmRNA e.g., the first region, the first flanking region, or the second flanking region
  • U is O or C(R U ) nu , wherein nu is an integer from 0 to 2 and each R U is, independently, H, halo, or optionally substituted alkyl (e.g., U is —CH 2 — or —CH—).
  • each of R 1 , R 2 , R 3 , R 4 , and R 5 is, independently, H, halo, hydroxy, thiol, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aminoalkoxy, optionally substituted alkoxyalkoxy, optionally substituted hydroxyalkoxy, optionally substituted amino, azido, optionally substituted aryl, optionally substituted aminoalkyl, optionally substituted aminoalkenyl, optionally substituted aminoalkynyl, or absent (e.g., each R 1 and R 2 is, independently, H, halo, hydroxy, optionally substituted alkyl, or optionally substituted alkoxy; each R 3 and R 4 is, independently, H or optionally substituted alkyl; and R 5 is H or hydroxy), and is a single bond or double bond.
  • the polynucleotidesor mmRNA includes n number of linked nucleosides having Formula (IIb-1)-(IIb-2):
  • U is O or C(R U ) nu , wherein nu is an integer from 0 to 2 and each R U is, independently, H, halo, or optionally substituted alkyl (e.g., U is —CH 2 — or —CH—).
  • each of R 1 and R 2 is, independently, H, halo, hydroxy, thiol, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aminoalkoxy, optionally substituted alkoxyalkoxy, optionally substituted hydroxyalkoxy, optionally substituted amino, azido, optionally substituted aryl, optionally substituted aminoalkyl, optionally substituted aminoalkenyl, optionally substituted aminoalkynyl, or absent (e.g., each R 1 and R 2 is, independently, H, halo, hydroxy, optionally substituted alkyl, or optionally substituted alkoxy, e.g., H, halo, hydroxy, alkyl, or alkoxy).
  • R 2 is hydroxy or optionally substituted alkoxy (e.g., methoxy, ethoxy, or any described herein).
  • the polynucleotide, primary construct, or mmRNA includes n number of linked nucleosides having Formula (IIc-1)-(IIc-4):
  • U is O or C(R U ) nu , wherein nu is an integer from 0 to 2 and each R U is, independently, H, halo, or optionally substituted alkyl (e.g., U is —CH 2 — or —CH—).
  • each of R 1 , R 2 , and R 3 is, independently, H, halo, hydroxy, thiol, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aminoalkoxy, optionally substituted alkoxyalkoxy, optionally substituted hydroxyalkoxy, optionally substituted amino, azido, optionally substituted aryl, optionally substituted aminoalkyl, optionally substituted aminoalkenyl, optionally substituted aminoalkynyl, or absent (e.g., each R 1 and R 2 is, independently, H, halo, hydroxy, optionally substituted alkyl, or optionally substituted alkoxy, e.g., H, halo, hydroxy, alkyl, or alkoxy; and each R 3 is, independently, H or optionally substituted alkyl)).
  • R 2 is optionally substituted alkoxy (e.g., methoxy or ethoxy, or any described herein).
  • R 1 is optionally substituted alkyl
  • R 2 is hydroxy.
  • R 1 is hydroxy
  • R 2 is optionally substituted alkyl.
  • R 3 is optionally substituted alkyl.
  • the polynucleotide, primary construct, or mmRNA includes an acyclic modified ribose.
  • the polynucleotide, primary construct, or mmRNA e.g., the first region, the first flanking region, or the second flanking region
  • the polynucleotide, primary construct, or mmRNA includes n number of linked nucleosides having Formula (IId)-(IIf):
  • the polynucleotide, primary construct, or mmRNA includes an acyclic modified hexitol.
  • the polynucleotide, primary construct, or mmRNA e.g., the first region, the first flanking region, or the second flanking region
  • the polynucleotide, primary construct, or mmRNA includes a sugar moiety having a contracted or an expanded ribose ring.
  • the polynucleotide, primary construct, or mmRNA e.g., the first region, the first flanking region, or the second flanking region
  • each of R 1′ , R 1′′ , R 2′ , and R 2′′ is, independently, H, halo, hydroxy, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aminoalkoxy, optionally substituted alkoxyalkoxy, or absent; and wherein the combination of R 2′ and R 3 or the combination of R 2′′ and R 3 can be taken together to form optionally substituted alkylene or optionally substituted heteroalkylene.
  • the polynucleotide, primary construct, or mmRNA includes a locked modified ribose.
  • the polynucleotide, primary construct, or mmRNA e.g., the first region, the first flanking region, or the second flanking region
  • the polynucleotide, primary construct, or mmRNA includes n number of linked nucleosides having Formula (IIn):
  • R 3′ is O, S, or —NR N1 —, wherein R N1 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted aryl and R 3′′ is optionally substituted alkylene (e.g., —CH 2 —, —CH 2 CH 2 —, or —CH 2 CH 2 CH 2 —) or optionally substituted heteroalkylene (e.g., —CH 2 NH—, —CH 2 CH 2 NH—, —CH 2 OCH 2 —, or —CH 2 CH 2 OCH 2 —)(e.g., R 3′ is O and R 3′′ is optionally substituted alkylene (e.g., —CH 2 —, —CH 2 CH 2 —, or —CH 2 CH 2 CH 2 —)).
  • the polynucleotide, primary construct, or mmRNA includes n number of linked nucleosides having Formula (IIn-1)-(II-n2):
  • R 3′ is O, S, or —NR N1 —, wherein R N1 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted aryl and R 3′′ is optionally substituted alkylene (e.g., —CH 2 —, —CH 2 CH 2 —, or —CH 2 CH 2 CH 2 —) or optionally substituted heteroalkylene (e.g., —CH 2 NH—, —CH 2 CH 2 NH—, —CH 2 OCH 2 —, or —CH 2 CH 2 OCH 2 —) (e.g., R 3′ is O and R 3′′ is optionally substituted alkylene (e.g., —CH 2 —, —CH 2 CH 2 —, or —CH 2 CH 2 CH 2 —)).
  • the polynucleotide, primary construct, or mmRNA includes a locked modified ribose that forms a tetracyclic heterocyclyl.
  • the polynucleotide, primary construct, or mmRNA e.g., the first region, the first flanking region, or the second flanking region
  • R 12a , R 12c , T 1′ , T 1′′ , T 2′ , T 2′′ , V 1 , and V 3 are as described herein.
  • any of the formulas for the polynucleotides, primary constructs, or mmRNA can include one or more nucleobases described herein (e.g., Formulas (b1)-(b43)).
  • the present invention provides methods of preparing a polynucleotide, primary construct, or mmRNA, wherein the polynucleotide comprises n number of nucleosides having Formula (Ia), as defined herein:
  • the present invention provides methods of amplifying a polynucleotide, primary construct, or mmRNA comprising at least one nucleotide (e.g., mmRNA molecule), the method comprising: reacting a compound of Formula (IIIa), as defined herein, with a primer, a cDNA template, and an RNA polymerase.
  • a nucleotide e.g., mmRNA molecule
  • the present invention provides methods of preparing a polynucleotide, primary construct, or mmRNA comprising at least one nucleotide (e.g., mmRNA molecule), wherein the polynucleotide comprises n number of nucleosides having Formula (Ia), as defined herein:
  • the present invention provides methods of amplifying a polynucleotide, primary construct, or mmRNA comprising at least one nucleotide (e.g., mmRNA molecule), the method comprising:
  • the present invention provides methods of preparing a modified mRNA comprising at least one nucleotide (e.g., mmRNA molecule), wherein the polynucleotide comprises n number of nucleosides having Formula (Ia-2), as defined herein:
  • the present invention provides methods of amplifying a modified mRNA comprising at least one nucleotide (e.g., mmRNA molecule), the method comprising:
  • reaction may be repeated from 1 to about 7,000 times.
  • B may be a nucleobase of Formula (b1)-(b43).
  • polynucleotides, primary constructs, and mmRNA can optionally include 5′ and/or 3′ flanking regions, which are described herein.
  • RNA Modified RNA (mmRNA) Molecules
  • the present invention also includes building blocks, e.g., modified ribonucleosides, modified ribonucleotides, of modified RNA (mmRNA) molecules.
  • building blocks e.g., modified ribonucleosides, modified ribonucleotides, of modified RNA (mmRNA) molecules.
  • these building blocks can be useful for preparing the polynucleotides, primary constructs, or mmRNA of the invention.
  • the building block molecule has Formula (IIIa) or (IIIa-1):
  • the building block molecule which may be incorporated into a polynucleotide, primary construct, or mmRNA, has Formula (IVa)-(IVb):
  • Formula (IVa) or (IVb) is combined with a modified uracil (e.g., any one of formulas (b1)-(b9), (b21)-(b23), and (b28)-(b31), such as formula (b1), (b8), (b28), (b29), or (b30)).
  • a modified uracil e.g., any one of formulas (b1)-(b9), (b21)-(b23), and (b28)-(b31), such as formula (b1), (b8), (b28), (b29), or (b30)
  • Formula (IVa) or (IVb) is combined with a modified cytosine (e.g., any one of formulas (b10)-(b14), (b24), (b25), and (b32)-(b36), such as formula (b10) or (b32)).
  • a modified cytosine e.g., any one of formulas (b10)-(b14), (b24), (b25), and (b32)-(b36), such as formula (b10) or (b32)
  • Formula (IVa) or (IVb) is combined with a modified guanine (e.g., any one of formulas (b15)-(b17) and (b37)-(b40)).
  • Formula (IVa) or (IVb) is combined with a modified adenine (e.g., any one of formulas (b18)-(b20) and (b41)-(b43)).
  • the building block molecule which may be incorporated into a polynucleotide, primary construct, or mmRNA, has Formula (IVc)-(IVk):
  • one of Formulas (IVc)-(IVk) is combined with a modified uracil (e.g., any one of formulas (b1)-(b9), (b21)-(b23), and (b28)-(b31), such as formula (b1), (b8), (b28), (b29), or (b30)).
  • a modified uracil e.g., any one of formulas (b1)-(b9), (b21)-(b23), and (b28)-(b31), such as formula (b1), (b8), (b28), (b29), or (b30)
  • one of Formulas (IVc)-(IVk) is combined with a modified cytosine (e.g., any one of formulas (b10)-(b14), (b24), (b25), and (b32)-(b36), such as formula (b10) or (b32)).
  • one of Formulas (IVc)-(IVk) is combined with a modified guanine (e.g., any one of formulas (b15)-(b17) and (b37)-(b40)).
  • one of Formulas (IVc)-(IVk) is combined with a modified adenine (e.g., any one of formulas (b18)-(b20) and (b41)-(b43)).
  • the building block molecule which may be incorporated into a polynucleotide, primary construct, or mmRNA, has Formula (Va) or (Vb):
  • B is as described herein (e.g., any one of (b1)-(b43)).
  • the building block molecule which may be incorporated into a polynucleotide, primary construct, or mmRNA, has Formula (IXa)-(IXd):
  • one of Formulas (IXa)-(IXd) is combined with a modified uracil (e.g., any one of formulas (b1)-(b9), (b21)-(b23), and (b28)-(b31), such as formula (b1), (b8), (b28), (b29), or (b30)).
  • a modified uracil e.g., any one of formulas (b1)-(b9), (b21)-(b23), and (b28)-(b31), such as formula (b1), (b8), (b28), (b29), or (b30)
  • one of Formulas (IXa)-(IXd) is combined with a modified cytosine (e.g., any one of formulas (b10)-(b14), (b24), (b25), and (b32)-(b36), such as formula (b10) or (b32)).
  • one of Formulas (IXa)-(IXd) is combined with a modified guanine (e.g., any one of formulas (b15)-(b17) and (b37)-(b40)).
  • one of Formulas (IXa)-(IXd) is combined with a modified adenine (e.g., any one of formulas (b18)-(b20) and (b41)-(b43)).
  • the building block molecule which may be incorporated into a polynucleotide, primary construct, or mmRNA, has Formula (IXe)-(IXg):
  • one of Formulas (IXe)-(IXg) is combined with a modified uracil (e.g., any one of formulas (b1)-(b9), (b21)-(b23), and (b28)-(b31), such as formula (b1), (b8), (b28), (b29), or (b30)).
  • a modified uracil e.g., any one of formulas (b1)-(b9), (b21)-(b23), and (b28)-(b31), such as formula (b1), (b8), (b28), (b29), or (b30)
  • one of Formulas (IXe)-(IXg) is combined with a modified cytosine (e.g., any one of formulas (b10)-(b14), (b24), (b25), and (b32)-(b36), such as formula (b10) or (b32)).
  • one of Formulas (IXe)-(IXg) is combined with a modified guanine (e.g., any one of formulas (b15)-(b17) and (b37)-(b40)).
  • one of Formulas (IXe)-(IXg) is combined with a modified adenine (e.g., any one of formulas (b18)-(b20) and (b41)-(b43)).
  • the building block molecule which may be incorporated into a polynucleotide, primary construct, or mmRNA, has Formula (IXh)-(IXk):
  • one of Formulas (IXh)-(IXk) is combined with a modified uracil (e.g., any one of formulas (b1)-(b9), (b21)-(b23), and (b28)-(b31), such as formula (b1), (b8), (b28), (b29), or (b30)).
  • a modified uracil e.g., any one of formulas (b1)-(b9), (b21)-(b23), and (b28)-(b31), such as formula (b1), (b8), (b28), (b29), or (b30)
  • one of Formulas (IXh)-(IXk) is combined with a modified cytosine (e.g., any one of formulas (b10)-(b14), (b24), (b25), and (b32)-(b36), such as formula (b10) or (b32)).
  • one of Formulas (IXh)-(IXk) is combined with a modified guanine (e.g., any one of formulas (b15)-(b17) and (b37)-(b40)).
  • one of Formulas (IXh)-(IXk) is combined with a modified adenine (e.g., any one of formulas (b18)-(b20) and (b41)-(b43)).
  • the building block molecule which may be incorporated into a polynucleotide, primary construct, or mmRNA, has Formula (IXl)-(IXr):
  • each r1 and r2 is, independently, an integer from 0 to 5 (e.g., from 0 to 3, from 1 to 3, or from 1 to 5) and B is as described herein (e.g., any one of (b1)-(b43)).
  • one of Formulas (IXl)-(IXr) is combined with a modified uracil (e.g., any one of formulas (b1)-(b9), (b21)-(b23), and (b28)-(b31), such as formula (b1), (b8), (b28), (b29), or (b30)).
  • one of Formulas (IXl)-(IXr) is combined with a modified cytosine (e.g., any one of formulas (b10)-(b14), (b24), (b25), and (b32)-(b36), such as formula (b10) or (b32)).
  • one of Formulas (IXl)-(IXr) is combined with a modified guanine (e.g., any one of formulas (b15)-(b17) and (b37)-(b40)).
  • one of Formulas (IXl)-(IXr) is combined with a modified adenine (e.g., any one of formulas (b18)-(b20) and (b41)-(b43)).
  • the building block molecule which may be incorporated into a polynucleotide, primary construct, or mmRNA, can be selected from the group consisting of:
  • each r is, independently, an integer from 0 to 5 (e.g., from 0 to 3, from 1 to 3, or from 1 to 5).
  • the building block molecule which may be incorporated into a polynucleotide, primary construct, or mmRNA, can be selected from the group consisting of:
  • each r is, independently, an integer from 0 to 5 (e.g., from 0 to 3, from 1 to 3, or from 1 to 5) and s1 is as described herein.
  • the building block molecule which may be incorporated into a nucleic acid (e.g., RNA, mRNA, polynucleotide, primary construct, or mmRNA), is a modified uridine (e.g., selected from the group consisting of:
  • Y 1 , Y 3 , Y 4 , Y 6 , and r are as described herein (e.g., each r is, independently, an integer from 0 to 5, such as from 0 to 3, from 1 to 3, or from 1 to 5)).
  • the building block molecule which may be incorporated into a polynucleotide, primary construct, or mmRNA, is a modified cytidine (e.g., selected from the group consisting of:
  • the building block molecule which may be incorporated into a polynucleotide, primary construct, or mmRNA, can be:
  • each r is, independently, an integer from 0 to 5 (e.g., from 0 to 3, from 1 to 3, or from 1 to 5).
  • the building block molecule which may be incorporated into a polynucleotide, primary construct, or mmRNA, is a modified adenosine (e.g., selected from the group consisting of:
  • Y 1 , Y 3 , Y 4 , Y 6 , and r are as described herein (e.g., each r is, independently, an integer from 0 to 5, such as from 0 to 3, from 1 to 3, or from 1 to 5)).
  • the building block molecule which may be incorporated into a polynucleotide, primary construct, or mmRNA, is a modified guanosine (e.g., selected from the group consisting of:
  • Y 1 , Y 3 , Y 4 , Y 6 , and r are as described herein (e.g., each r is, independently, an integer from 0 to 5, such as from 0 to 3, from 1 to 3, or from 1 to 5)).
  • the chemical modification can include replacement of C group at C-5 of the ring (e.g., for a pyrimidine nucleoside, such as cytosine or uracil) with N (e.g., replacement of the >CH group at C-5 with >NR N1 group, wherein R N 1 is H or optionally substituted alkyl).
  • the building block molecule which may be incorporated into a polynucleotide, primary construct, or mmRNA, can be:
  • each r is, independently, an integer from 0 to 5 (e.g., from 0 to 3, from 1 to 3, or from 1 to 5).
  • the chemical modification can include replacement of the hydrogen at C-5 of cytosine with halo (e.g., Br, Cl, F, or I) or optionally substituted alkyl (e.g., methyl).
  • halo e.g., Br, Cl, F, or I
  • optionally substituted alkyl e.g., methyl
  • the building block molecule which may be incorporated into a polynucleotide, primary construct, or mmRNA, can be:
  • each r is, independently, an integer from 0 to 5 (e.g., from 0 to 3, from 1 to 3, or from 1 to 5).
  • the chemical modification can include a fused ring that is formed by the NH 2 at the C-4 position and the carbon atom at the C-5 position.
  • the building block molecule which may be incorporated into a polynucleotide, primary construct, or mmRNA, can be:
  • each r is, independently, an integer from 0 to 5 (e.g., from 0 to 3, from 1 to 3, or from 1 to 5).
  • modified nucleosides and nucleotides which may be incorporated into a polynucleotide, primary construct, or mmRNA (e.g., RNA or mRNA, as described herein), can be modified on the sugar of the ribonucleic acid.
  • the 2′ hydroxyl group (OH) can be modified or replaced with a number of different substituents.
  • substitutions at the 2′-position include, but are not limited to, H, halo, optionally substituted C 1-6 alkyl; optionally substituted C 1-6 alkoxy; optionally substituted C 6-10 aryloxy; optionally substituted C 3-8 cycloalkyl; optionally substituted C 3-8 cycloalkoxy; optionally substituted C 6-10 aryloxy; optionally substituted C 6-10 aryl-C 1-6 alkoxy, optionally substituted C 1-12 (heterocyclyl)oxy; a sugar (e.g., ribose, pentose, or any described herein); a polyethyleneglycol (PEG), —O(CH 2 CH 2 O) n CH 2 CH 2 OR, where R is H or optionally substituted alkyl, and n is an integer from 0 to 20 (e.g., from 0 to 4, from 0 to 8, from 0 to 10, from 0 to 16, from 1 to 4, from 1 to 8, from 1 to 10, from 1 to 16, from
  • RNA includes the sugar group ribose, which is a 5-membered ring having an oxygen.
  • modified nucleotides include replacement of the oxygen in ribose (e.g., with S, Se, or alkylene, such as methylene or ethylene); addition of a double bond (e.g., to replace ribose with cyclopentenyl or cyclohexenyl); ring contraction of ribose (e.g., to form a 4-membered ring of cyclobutane or oxetane); ring expansion of ribose (e.g., to form a 6- or 7-membered ring having an additional carbon or heteroatom, such as for anhydrohexitol, altritol, mannitol, cyclohexanyl, cyclohexenyl, and morpholino that also has a phosphoramidate backbone); multicyclic forms (e.
  • the sugar group can also contain one or more carbons that possess the opposite stereochemical configuration than that of the corresponding carbon in ribose.
  • a polynucleotide, primary construct, or mmRNA molecule can include nucleotides containing, e.g., arabinose, as the sugar.
  • nucleoside is defined as a compound containing a sugar molecule (e.g., a pentose or ribose) or a derivative thereof in combination with an organic base (e.g., a purine or pyrimidine) or a derivative thereof (also referred to herein as “nucleobase”).
  • organic base e.g., a purine or pyrimidine
  • nucleotide is defined as a nucleoside including a phosphate group.
  • the modified nucleotides may by synthesized by any useful method, as described herein (e.g., chemically, enzymatically, or recombinantly to include one or more modified or non-natural nucleosides).
  • the modified nucleotide base pairing encompasses not only the standard adenosine-thymine, adenosine-uracil, or guanosine-cytosine base pairs, but also base pairs formed between nucleotides and/or modified nucleotides comprising non-standard or modified bases, wherein the arrangement of hydrogen bond donors and hydrogen bond acceptors permits hydrogen bonding between a non-standard base and a standard base or between two complementary non-standard base structures.
  • non-standard base pairing is the base pairing between the modified nucleotide inosine and adenine, cytosine or uracil.
  • the modified nucleosides and nucleotides can include a modified nucleobase.
  • nucleobases found in RNA include, but are not limited to, adenine, guanine, cytosine, and uracil.
  • nucleobase found in DNA include, but are not limited to, adenine, guanine, cytosine, and thymine.
  • These nucleobases can be modified or wholly replaced to provide polynucleotides, primary constructs, or mmRNA molecules having enhanced properties, e.g., resistance to nucleases through disruption of the binding of a major groove binding partner.
  • Table 8 below identifies the chemical faces of each canonical nucleotide. Circles identify the atoms comprising the respective chemical regions.
  • B is a modified uracil.
  • exemplary modified uracils include those having Formula (b1)-(b5):
  • each of T 1′ , T 1′′ , T 2′ , and T 2′′ is, independently, H, optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted thioalkoxy, or the combination of T 1′ and T 1′′ or the combination of T 2′ and T 2′′ join together (e.g., as in T 2 ) to form 0 (oxo), S (thio), or Se (seleno);
  • each of V 1 and V 2 is, independently, O, S, N(R Vb ) nv , or C(R Vb ) nv , wherein nv is an integer from 0 to 2 and each R Vb is, independently, H, halo, optionally substituted amino acid, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted hydroxyalkyl, optionally substituted hydroxyalkenyl, optionally substituted hydroxyalkynyl, optionally substituted aminoalkyl (e.g., substituted with an N-protecting group, such as any described herein, e.g., trifluoroacetyl), optionally substituted aminoalkenyl, optionally substituted aminoalkynyl, optionally substituted acylaminoalkyl
  • R 10 is H, halo, optionally substituted amino acid, hydroxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aminoalkyl, optionally substituted hydroxyalkyl, optionally substituted hydroxyalkenyl, optionally substituted hydroxyalkynyl, optionally substituted aminoalkenyl, optionally substituted aminoalkynyl, optionally substituted alkoxy, optionally substituted alkoxycarbonylalkyl, optionally substituted alkoxycarbonylalkenyl, optionally substituted alkoxycarbonylalkynyl, optionally substituted alkoxycarbonylalkoxy, optionally substituted carboxyalkoxy, optionally substituted carboxyalkyl, or optionally substituted carbamoylalkyl;
  • R 11 is H or optionally substituted alkyl
  • R 12a is H, optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted hydroxyalkenyl, optionally substituted hydroxyalkynyl, optionally substituted aminoalkyl, optionally substituted aminoalkenyl, or optionally substituted aminoalkynyl, optionally substituted carboxyalkyl (e.g., optionally substituted with hydroxy), optionally substituted carboxyalkoxy, optionally substituted carboxyaminoalkyl, or optionally substituted carbamoylalkyl; and
  • R 12c is H, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted thioalkoxy, optionally substituted amino, optionally substituted hydroxyalkyl, optionally substituted hydroxyalkenyl, optionally substituted hydroxyalkynyl, optionally substituted aminoalkyl, optionally substituted aminoalkenyl, or optionally substituted aminoalkynyl.
  • exemplary modified uracils include those having Formula (b6)-(b9):
  • each of T 1′ , T 1′′ , T 2′ , and T 2′′ is, independently, H, optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted thioalkoxy, or the combination of T 1′ and T 1′′ join together (e.g., as in T 1 ) or the combination of T 2′ and T 2′′ join together (e.g., as in T 2 ) to form 0 (oxo), S (thio), or Se (seleno), or each T 1 and T 2 is, independently, O (oxo), S (thio), or Se (seleno);
  • each of W 1 and W 2 is, independently, N(R Wa ) nw or C(R Wa ) nw , wherein nw is an integer from 0 to 2 and each R Wa is, independently, H, optionally substituted alkyl, or optionally substituted alkoxy;
  • each V 3 is, independently, O, S, N(R Va ) nv , or C(R Va ) nv , wherein nv is an integer from 0 to 2 and each R Va is, independently, H, halo, optionally substituted amino acid, optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted hydroxyalkenyl, optionally substituted hydroxyalkynyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted heterocyclyl, optionally substituted alkheterocyclyl, optionally substituted alkoxy, optionally substituted alkenyloxy, or optionally substituted alkynyloxy, optionally substituted aminoalkyl (e.g., substituted with an N-protecting group, such as any described herein, e.g., trifluoroacetyl, or sulfoalkyl), optionally substituted aminoalkenyl, optionally substituted aminoalkyn
  • R 12a is H, optionally substituted alkyl, optionally substituted hydroxyalkyl, optionally substituted hydroxyalkenyl, optionally substituted hydroxyalkynyl, optionally substituted aminoalkyl, optionally substituted aminoalkenyl, optionally substituted aminoalkynyl, optionally substituted carboxyalkyl (e.g., optionally substituted with hydroxy and/or an O-protecting group), optionally substituted carboxyalkoxy, optionally substituted carboxyaminoalkyl, optionally substituted carbamoylalkyl, or absent;
  • R 12b is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted hydroxyalkyl, optionally substituted hydroxyalkenyl, optionally substituted hydroxyalkynyl, optionally substituted aminoalkyl, optionally substituted aminoalkenyl, optionally substituted aminoalkynyl, optionally substituted alkaryl, optionally substituted heterocyclyl, optionally substituted alkheterocyclyl, optionally substituted amino acid, optionally substituted alkoxycarbonylacyl, optionally substituted alkoxycarbonylalkoxy, optionally substituted alkoxycarbonylalkyl, optionally substituted alkoxycarbonylalkenyl, optionally substituted alkoxycarbonylalkynyl, optionally substituted alkoxycarbonylalkoxy, optionally substituted carboxyalkyl (e.g., optionally substituted with hydroxy and/or an O-protecting group), optionally substitute
  • R 12c is H, halo, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted thioalkoxy, optionally substituted amino, optionally substituted aminoalkyl, optionally substituted aminoalkenyl, or optionally substituted aminoalkynyl.
  • modified uracils include those having Formula (b28)-(b31):
  • each of T 1 and T 2 is, independently, O (oxo), S (thio), or Se (seleno);
  • each R Vb′ and R Vb′′ is, independently, H, halo, optionally substituted amino acid, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted hydroxyalkyl, optionally substituted hydroxyalkenyl, optionally substituted hydroxyalkynyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aminoalkyl (e.g., substituted with an N-protecting group, such as any described herein, e.g., trifluoroacetyl, or sulfoalkyl), optionally substituted aminoalkenyl, optionally substituted aminoalkynyl, optionally substituted acylaminoalkyl (e.g., substituted with an N-protecting group, such as any described herein, e.g., trifluoroacetyl),
  • R 12a is H, optionally substituted alkyl, optionally substituted carboxyaminoalkyl, optionally substituted aminoalkyl (e.g., e.g., substituted with an N-protecting group, such as any described herein, e.g., trifluoroacetyl, or sulfoalkyl), optionally substituted aminoalkenyl, or optionally substituted aminoalkynyl; and
  • R 12b is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted hydroxyalkyl, optionally substituted hydroxyalkenyl, optionally substituted hydroxyalkynyl, optionally substituted aminoalkyl, optionally substituted aminoalkenyl, optionally substituted aminoalkynyl (e.g., e.g., substituted with an N-protecting group, such as any described herein, e.g., trifluoroacetyl, or sulfoalkyl),
  • optionally substituted alkoxycarbonylacyl optionally substituted alkoxycarbonylalkoxy, optionally substituted alkoxycarbonylalkyl, optionally substituted alkoxycarbonylalkenyl, optionally substituted alkoxycarbonylalkynyl, optionally substituted alkoxycarbonylalkoxy, optionally substituted carboxyalkoxy, optionally substituted carboxyalkyl, or optionally substituted carbamoylalkyl.
  • T 1 is O (oxo), and T 2 is S (thio) or Se (seleno). In other embodiments, T 1 is S (thio), and T 2 is 0 (oxo) or Se (seleno).
  • R Vb′ is H, optionally substituted alkyl, or optionally substituted alkoxy.
  • each R 12a and R 12b is, independently, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or optionally substituted hydroxyalkyl.
  • R 12a is H.
  • both R 12a and R 12b are H.
  • each R Vb′ of R 12b is, independently, optionally substituted aminoalkyl (e.g., substituted with an N-protecting group, such as any described herein, e.g., trifluoroacetyl, or sulfoalkyl), optionally substituted aminoalkenyl, optionally substituted aminoalkynyl, or optionally substituted acylaminoalkyl (e.g., substituted with an N-protecting group, such as any described herein, e.g., trifluoroacetyl).
  • an N-protecting group such as any described herein, e.g., trifluoroacetyl
  • the amino and/or alkyl of the optionally substituted aminoalkyl is substituted with one or more of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted sulfoalkyl, optionally substituted carboxy (e.g., substituted with an O-protecting group), optionally substituted hydroxy (e.g., substituted with an O-protecting group), optionally substituted carboxyalkyl (e.g., substituted with an O-protecting group), optionally substituted alkoxycarbonylalkyl (e.g., substituted with an O-protecting group), or N-protecting group.
  • optionally substituted alkyl optionally substituted alkenyl, optionally substituted sulfoalkyl
  • optionally substituted carboxy e.g., substituted with an O-protecting group
  • optionally substituted hydroxy e.g., substituted with an O-protecting group
  • optionally substituted carboxyalkyl e.g.,
  • optionally substituted aminoalkyl is substituted with an optionally substituted sulfoalkyl or optionally substituted alkenyl.
  • R 12a and R Vb′′ are both H.
  • T 1 is O (oxo)
  • T 2 is S (thio) or Se (seleno).
  • R Vb′ is optionally substituted alkoxycarbonylalkyl or optionally substituted carbamoylalkyl.
  • the optional substituent for R 12a , R 12b , R 12c , or R Va is a polyethylene glycol group (e.g., —(CH 2 ) s2 (OCH 2 CH 2 ) s1 (CH 2 ) s3 OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C 1-20 alkyl); or an amino-polyethylene glycol group (e.g., —NR N1 (CH 2 ) s2 (CH 2 CH 2 O) s1 (CH 2 ) s3 NR N1 , wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently
  • B is a modified cytosine.
  • exemplary modified cytosines include compounds of Formula (b10)-(b14):
  • each of T 3′ and T 3′′ is, independently, H, optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted thioalkoxy, or the combination of T 3′ and T 3′′ join together (e.g., as in T 3 ) to form O (oxo), S (thio), or Se (seleno);
  • each V 4 is, independently, O, S, N(R Vc ) nv , or C(R Vc ) nv , wherein nv is an integer from 0 to 2 and each R Vc is, independently, H, halo, optionally substituted amino acid, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted heterocyclyl, optionally substituted alkheterocyclyl, or optionally substituted alkynyloxy (e.g., optionally substituted with any substituent described herein, such as those selected from (1)-(21) for alkyl), wherein the combination of R 13b and R Vc can be taken together to form optionally substituted heterocyclyl;
  • each V 5 is, independently, N(R Vd ) nv , or C(R Vd ) nv , wherein nv is an integer from 0 to 2 and each R Vd is, independently, H, halo, optionally substituted amino acid, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted heterocyclyl, optionally substituted alkheterocyclyl, or optionally substituted alkynyloxy (e.g., optionally substituted with any substituent described herein, such as those selected from (1)-(21) for alkyl) (e.g., V 5 is —CH or N);
  • each of R 13a and R 13b is, independently, H, optionally substituted acyl, optionally substituted acyloxyalkyl, optionally substituted alkyl, or optionally substituted alkoxy, wherein the combination of R 13b and R 14 can be taken together to form optionally substituted heterocyclyl;
  • each R 14 is, independently, H, halo, hydroxy, thiol, optionally substituted acyl, optionally substituted amino acid, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted hydroxyalkyl (e.g., substituted with an O-protecting group), optionally substituted hydroxyalkenyl, optionally substituted hydroxyalkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aminoalkoxy, optionally substituted alkoxyalkoxy, optionally substituted acyloxyalkyl, optionally substituted amino (e.g., —NHR, wherein R is H, alkyl, aryl, or phosphoryl), azido, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted alkheterocyclyl, optionally
  • each of R 15 and R 16 is, independently, H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl.
  • modified cytosines include those having Formula (b32)-(b35):
  • each of T 1 and T 3 is, independently, O (oxo), S (thio), or Se (seleno);
  • each of R 13a and R 13b is, independently, H, optionally substituted acyl, optionally substituted acyloxyalkyl, optionally substituted alkyl, or optionally substituted alkoxy, wherein the combination of R 13b and R 14 can be taken together to form optionally substituted heterocyclyl;
  • each R 14 is, independently, H, halo, hydroxy, thiol, optionally substituted acyl, optionally substituted amino acid, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted hydroxyalkyl (e.g., substituted with an O-protecting group), optionally substituted hydroxyalkenyl, optionally substituted hydroxyalkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aminoalkoxy, optionally substituted alkoxyalkoxy, optionally substituted acyloxyalkyl, optionally substituted amino (e.g., —NHR, wherein R is H, alkyl, aryl, or phosphoryl), azido, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted alkheterocyclyl, optionally
  • each of R 15 and R 16 is, independently, H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl (e.g., R 15 is H, and R 16 is H or optionally substituted alkyl).
  • R 15 is H, and R 16 is H or optionally substituted alkyl.
  • R 14 is H, acyl, or hydroxyalkyl.
  • R 14 is halo.
  • both R 14 and R 15 are H.
  • both R 15 and R 16 are H.
  • each of R 14 and R 15 and R 16 is H.
  • each of R 13a and R 13b is independently, H or optionally substituted alkyl.
  • modified cytosines include compounds of Formula (b36):
  • each R 13b is, independently, H, optionally substituted acyl, optionally substituted acyloxyalkyl, optionally substituted alkyl, or optionally substituted alkoxy, wherein the combination of R 13b and R 14b can be taken together to form optionally substituted heterocyclyl;
  • each R 14a and R 14b is, independently, H, halo, hydroxy, thiol, optionally substituted acyl, optionally substituted amino acid, optionally substituted alkyl, optionally substituted haloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted hydroxyalkyl (e.g., substituted with an O-protecting group), optionally substituted hydroxyalkenyl, optionally substituted alkoxy, optionally substituted alkenyloxy, optionally substituted alkynyloxy, optionally substituted aminoalkoxy, optionally substituted alkoxyalkoxy, optionally substituted acyloxyalkyl, optionally substituted amino (e.g., —NHR, wherein R is H, alkyl, aryl, phosphoryl, optionally substituted aminoalkyl, or optionally substituted carboxyaminoalkyl), azido, optionally substituted aryl, optionally substituted heterocyclyl,
  • each of R 15 is, independently, H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl.
  • R 14b is an optionally substituted amino acid (e.g., optionally substituted lysine). In some embodiments, R 14a is H.
  • B is a modified guanine.
  • exemplary modified guanines include compounds of Formula (b15)-(b17):
  • each of T 4′ , T 4′′ , T 5′ , T 5′′ , T 6′ , and T 6′′ is independently, H, optionally substituted alkyl, or optionally substituted alkoxy, and wherein the combination of T 4′ and T 4′′ (e.g., as in T 4 ) or the combination of T 5′ and T 5′′ (e.g., as in T 5 ) or the combination of T 6′ and T 6′′ (e.g., as in T 6 ) join together form O (oxo), S (thio), or Se (seleno);
  • each of V 5 and V 6 is, independently, O, S, N(R Vd ) nv , or C(R Vd ) nv , wherein nv is an integer from 0 to 2 and each R Vd is, independently, H, halo, thiol, optionally substituted amino acid, cyano, amidine, optionally substituted aminoalkyl, optionally substituted aminoalkenyl, optionally substituted aminoalkynyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted alkenyloxy, or optionally substituted alkynyloxy (e.g., optionally substituted with any substituent described herein, such as those selected from (1)-(21) for alkyl), optionally substituted thioalkoxy, or optionally substituted amino; and
  • each of R 17 , R 18 , R 19a , R 19b , R 21 , R 22 , R 23 , and R 24 is, independently, H, halo, thiol, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted thioalkoxy, optionally substituted amino, or optionally substituted amino acid.
  • Exemplary modified guanosines include compounds of Formula (b37)-(b40):
  • each of T 4′ is, independently, H, optionally substituted alkyl, or optionally substituted alkoxy, and each T 4 is, independently, O (oxo), S (thio), or Se (seleno);
  • each of R 18 , R 19a , R 19b , and R 21 is, independently, H, halo, thiol, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted thioalkoxy, optionally substituted amino, or optionally substituted amino acid.
  • R 18 is H or optionally substituted alkyl.
  • T 4 is oxo.
  • each of R 19a and R 19b is, independently, H or optionally substituted alkyl.
  • B is a modified adenine.
  • exemplary modified adenines include compounds of Formula (b18)-(b20):
  • each R 25 is, independently, H, halo, thiol, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted thioalkoxy, or optionally substituted amino;
  • each of R 26a and R 26b is, independently, H, optionally substituted acyl, optionally substituted amino acid, optionally substituted carbamoylalkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted hydroxyalkyl, optionally substituted hydroxyalkenyl, optionally substituted hydroxyalkynyl, optionally substituted alkoxy, or polyethylene glycol group (e.g., —(CH 2 ) s2 (OCH 2 CH 2 ) s1 (CH 2 ) s3 OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C 1-20 alkyl); or an amino-polyethylene glycol
  • each R 27 is, independently, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted thioalkoxy or optionally substituted amino;
  • each R 28 is, independently, H, optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl;
  • each R 29 is, independently, H, optionally substituted acyl, optionally substituted amino acid, optionally substituted carbamoylalkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted hydroxyalkyl, optionally substituted hydroxyalkenyl, optionally substituted alkoxy, or optionally substituted amino.
  • Exemplary modified adenines include compounds of Formula (b41)-(b43):
  • each R 25 is, independently, H, halo, thiol, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted thioalkoxy, or optionally substituted amino;
  • each of R 26a and R 26b is, independently, H, optionally substituted acyl, optionally substituted amino acid, optionally substituted carbamoylalkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted hydroxyalkyl, optionally substituted hydroxyalkenyl, optionally substituted hydroxyalkynyl, optionally substituted alkoxy, or polyethylene glycol group (e.g., —(CH 2 ) s2 (OCH 2 CH 2 ) s1 (CH 2 ) s3 OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C 1-20 alkyl); or an amino-polyethylene glycol
  • each R 27 is, independently, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted thioalkoxy, or optionally substituted amino.
  • R 26a is H, and R 26b is optionally substituted alkyl. In some embodiments, each of R 26a and R 26b is, independently, optionally substituted alkyl. In particular embodiments, R 27 is optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted thioalkoxy. In other embodiments, R 25 is optionally substituted alkyl, optionally substituted alkoxy, or optionally substituted thioalkoxy.
  • the optional substituent for R 26a , R 26b , or R 29 is a polyethylene glycol group (e.g., —(CH 2 ) s2 (OCH 2 CH 2 ) s1 (CH 2 ) s3 OR′, wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from 0 to 10 (e.g., from 0 to 4, from 0 to 6, from 1 to 4, from 1 to 6, or from 1 to 10), and R′ is H or C 1-20 alkyl); or an amino-polyethylene glycol group (e.g., —NR N1 (CH 2 ) s2 (CH 2 CH 2 O) s1 (CH 2 ) s3 NR N1 , wherein s1 is an integer from 1 to 10 (e.g., from 1 to 6 or from 1 to 4), each of s2 and s3, independently, is an integer from
  • B may have Formula (b21):
  • X 12 is, independently, O, S, optionally substituted alkylene (e.g., methylene), or optionally substituted heteroalkylene
  • xa is an integer from 0 to 3
  • R 12a and T 2 are as described herein.
  • B may have Formula (b22):
  • R 10′ is, independently, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted aminoalkyl, optionally substituted aminoalkenyl, optionally substituted aminoalkynyl, optionally substituted alkoxy, optionally substituted alkoxycarbonylalkyl, optionally substituted alkoxycarbonylalkenyl, optionally substituted alkoxycarbonylalkynyl, optionally substituted alkoxycarbonylalkoxy, optionally substituted carboxyalkoxy, optionally substituted carboxyalkyl, or optionally substituted carbamoylalkyl, and R 11 , R 12a , T 1 , and T 2 are as described herein.
  • B may have Formula (b23):
  • R 10 is optionally substituted heterocyclyl (e.g., optionally substituted furyl, optionally substitued thienyl, or optionally substitued pyrrolyl), optionally substituted aryl (e.g., optionally substituted phenyl or optionally substituted naphthyl), or any substituent described herein (e.g., for R 10 ); and wherein R 11 (e.g., H or any substituent described herein), R 12a (e.g., H or any substituent described herein), T 1 (e.g., oxo or any substituent described herein), and T 2 (e.g., oxo or any substituent described herein) are as described herein.
  • B may have Formula (b24):
  • R 14′ is, independently, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heterocyclyl, optionally substituted alkaryl, optionally substituted alkheterocyclyl, optionally substituted aminoalkyl, optionally substituted aminoalkenyl, optionally substituted aminoalkynyl, optionally substituted alkoxy, optionally substituted alkoxycarbonylalkenyl, optionally substituted alkoxycarbonylalkynyl, optionally substituted alkoxycarbonylalkyl, optionally substituted alkoxycarbonylalkoxy, optionally substituted carboxyalkoxy, optionally substituted carboxyalkyl, or optionally substituted carbamoylalkyl, and R 13a , R 13b , R 15 , and T 3 are as described herein.
  • B may have Formula (b25):
  • R 14′ is optionally substituted heterocyclyl (e.g., optionally substituted furyl, optionally substitued thienyl, or optionally substitued pyrrolyl), optionally substituted aryl (e.g., optionally substituted phenyl or optionally substituted naphthyl), or any substituent described herein (e.g., for R 14 or R 14′ ); and wherein R 13a (e.g., H or any substituent described herein), R 13b (e.g., H or any substituent described herein), R 15 (e.g., H or any substituent described herein), and T 3 (e.g., oxo or any substituent described herein) are as described herein.
  • R 13a e.g., H or any substituent described herein
  • R 13b e.g., H or any substituent described herein
  • R 15 e.g., H or any substituent described herein
  • T 3 e.g., ox
  • B is a nucleobase selected from the group consisting of cytosine, guanine, adenine, and uracil. In some embodiments, B may be:
  • the modified nucleobase is a modified uracil.
  • exemplary nucleobases and nucleosides having a modified uracil include pseudouridine ( ⁇ ), pyridin-4-one ribonucleoside, 5-aza-uridine, 6-aza-uridine, 2-thio-5-aza-uridine, 2-thio-uridine (s 2 U), 4-thio-uridine (s 4 U), 4-thio-pseudouridine, 2-thio-pseudouridine, 5-hydroxy-uridine (ho 5 U), 5-aminoallyl-uridine, 5-halo-uridine (e.g., 5-iodo-uridine or 5-bromo-uridine), 3-methyl-uridine (m 3 U), 5-methoxy-uridine (mo 5 U), uridine 5-oxyacetic acid (cmo 5 U), uridine 5-oxyacetic acid methyl ester (mcmo 5 U), 5-carboxymethyl-uridine (cm 5 U), 1-car
  • the modified nucleobase is a modified cytosine.
  • exemplary nucleobases and nucleosides having a modified cytosine include 5-aza-cytidine, 6-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine (m 3 C), N4-acetyl-cytidine (ac 4 C), 5-formyl-cytidine (f 5 C), N4-methyl-cytidine (m 4 C), 5-methyl-cytidine (m 5 C), 5-halo-cytidine (e.g., 5-iodo-cytidine), 5-hydroxymethyl-cytidine (hm 5 C), 1-methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine, 2-thio-cytidine (s 2 C), 2-thio-5-methyl-cytidine, 4-thio-pseudoisocy
  • the modified nucleobase is a modified adenine.
  • exemplary nucleobases and nucleosides having a modified adenine include 2-amino-purine, 2,6-diaminopurine, 2-amino-6-halo-purine (e.g., 2-amino-6-chloro-purine), 6-halo-purine (e.g., 6-chloro-purine), 2-amino-6-methyl-purine, 8-azido-adenosine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza-2-amino-purine, 7-deaza-8-aza-2-amino-purine, 7-deaza-2,6-diaminopurine, 7-deaza-8-aza-2,6-diaminopurine, 1-methyl-adenosine (m 1 A), 2-methyl-adenine (m 2 A), N6-methyl-adenosine (m 1
  • the modified nucleobase is a modified guanine.
  • exemplary nucleobases and nucleosides having a modified guanine include inosine (I), 1-methyl-inosine (m 1 I), wyosine (imG), methylwyosine (mimG), 4-demethyl-wyosine (imG-14), isowyosine (imG2), wybutosine (yW), peroxywybutosine (o 2 yW), hydroxywybutosine (OHyW), undermodified hydroxywybutosine (OHyW*), 7-deaza-guanosine, queuosine (Q), epoxyqueuosine (oQ), galactosyl-queuosine (galQ), mannosyl-queuosine (manQ), 7-cyano-7-deaza-guanosine (preQ 0 ), 7-aminomethyl-7-deaza-guanosine (
  • the nucleobase of the nucleotide can be independently selected from a purine, a pyrimidine, a purine or pyrimidine analog.
  • the nucleobase can each be independently selected from adenine, cytosine, guanine, uracil, or hypoxanthine.
  • the nucleobase can also include, for example, naturally-occurring and synthetic derivatives of a base, including pyrazolo[3,4-d]pyrimidines, 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo (e.g., 8-bromo), 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and
  • each letter refers to the representative base and/or derivatives thereof, e.g., A includes adenine or adenine analogs, e.g., 7-deaza adenine).
  • the modified nucleotides which may be incorporated into a polynucleotide, primary construct, or mmRNA molecule, can be modified on the internucleoside linkage (e.g., phosphate backbone).
  • internucleoside linkage e.g., phosphate backbone
  • the phrases “phosphate” and “phosphodiester” are used interchangeably.
  • Backbone phosphate groups can be modified by replacing one or more of the oxygen atoms with a different substituent.
  • the modified nucleosides and nucleotides can include the wholesale replacement of an unmodified phosphate moiety with another internucleoside linkage as described herein.
  • modified phosphate groups include, but are not limited to, phosphorothioate, phosphoroselenates, boranophosphates, boranophosphate esters, hydrogen phosphonates, phosphoramidates, phosphorodiamidates, alkyl or aryl phosphonates, and phosphotriesters.
  • Phosphorodithioates have both non-linking oxygens replaced by sulfur.
  • the phosphate linker can also be modified by the replacement of a linking oxygen with nitrogen (bridged phosphoramidates), sulfur (bridged phosphorothioates), and carbon (bridged methylene-phosphonates).
  • the ⁇ -thio substituted phosphate moiety is provided to confer stability to RNA and DNA polymers through the unnatural phosphorothioate backbone linkages.
  • Phosphorothioate DNA and RNA have increased nuclease resistance and subsequently a longer half-life in a cellular environment.
  • Phosphorothioate linked polynucleotides, primary constructs, or mmRNA molecules are expected to also reduce the innate immune response through weaker binding/activation of cellular innate immune molecules.
  • a modified nucleoside includes an alpha-thio-nucleoside (e.g., 5′-O-(1-thiophosphate)-adenosine, 5′-O-(1-thiophosphate)-cytidine ( ⁇ -thio-cytidine), 5′-O-(1-thiophosphate)-guanosine, 5′-O-(1-thiophosphate)-uridine, or 5′-O-(1-thiophosphate)-pseudouridine).
  • alpha-thio-nucleoside e.g., 5′-O-(1-thiophosphate)-adenosine, 5′-O-(1-thiophosphate)-cytidine ( ⁇ -thio-cytidine), 5′-O-(1-thiophosphate)-guanosine, 5′-O-(1-thiophosphate)-uridine, or 5′-O-(1-thiophosphate)-p
  • internucleoside linkages that may be employed according to the present invention, including internucleoside linkages which do not contain a phosphorous atom, are described herein below.
  • the polynucleotides, primary constructs, and mmRNA of the invention can include a combination of modifications to the sugar, the nucleobase, and/or the internucleoside linkage. These combinations can include any one or more modifications described herein.
  • any of the nucleotides described herein in Formulas (Ia), (Ia-1)-(Ia-3), (Ib)-(If), (IIa)-(IIp), (IIb-1), (IIb-2), (IIc-1)-(IIc-2), (IIn-1), (IIn-2), (IVa)-(IVl), and (IXa)-(IXr) can be combined with any of the nucleobases described herein (e.g., in Formulas (b1)-(b43) or any other described herein).
  • polypeptides, primary constructs, and mmRNA molecules for use in accordance with the invention may be prepared according to any useful technique, as described herein.
  • the modified nucleosides and nucleotides used in the synthesis of polynucleotides, primary constructs, and mmRNA molecules disclosed herein can be prepared from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (e.g., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are provided, a skilled artisan would be able to optimize and develop additional process conditions. Optimum reaction conditions may vary with the particular reactants or solvent used, but such conditions can be determined by one skilled in the art by routine optimization procedures.
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C) infrared spectroscopy, spectrophotometry (e.g., UV-visible), or mass spectrometry, or by chromatography such as high performance liquid chromatography (HPLC) or thin layer chromatography.
  • HPLC high performance liquid chromatography
  • Preparation of polypeptides, primary constructs, and mmRNA molecules of the present invention can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups can be readily determined by one skilled in the art.
  • the chemistry of protecting groups can be found, for example, in Greene, et al., Protective Groups in Organic Synthesis, 2d. Ed., Wiley & Sons, 1991, which is incorporated herein by reference in its entirety.
  • Suitable solvents can be substantially nonreactive with the starting materials (reactants), the intermediates, or products at the temperatures at which the reactions are carried out, i.e., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected.
  • An example method includes fractional recrystallization using a “chiral resolving acid” which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods are, for example, optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
  • an optically active resolving agent e.g., dinitrobenzoylphenylglycine
  • Suitable elution solvent composition can be determined by one skilled in the art.
  • Modified nucleosides and nucleotides can be prepared according to the synthetic methods described in Ogata et al., J. Org. Chem. 74:2585-2588 (2009); Purmal et al., Nucl. Acids Res. 22(1): 72-78, (1994); Fukuhara et al., Biochemistry, 1(4): 563-568 (1962); and Xu et al., Tetrahedron, 48(9): 1729-1740 (1992), each of which are incorporated by reference in their entirety.
  • polypeptides, primary constructs, and mmRNA of the invention may or may not be uniformly modified along the entire length of the molecule.
  • nucleotide e.g., purine or pyrimidine, or any one or more or all of A, G, U, C
  • a polynucleotide of the invention or in a given predetermined sequence region thereof (e.g. one or more of the sequence regions represented in FIG. 1 ).
  • nucleotides X in a polynucleotide of the invention are modified, wherein X may any one of nucleotides A, G, U, C, or any one of the combinations A+G, A+U, A+C, G+U, G+C, U+C, A+G+U, A+G+C, G+U+C or A+G+C.
  • nucleotide modifications may exist at various positions in the polynucleotide, primary construct, or mmRNA.
  • nucleotide analogs or other modification(s) may be located at any position(s) of a polynucleotide, primary construct, or mmRNA such that the function of the polynucleotide, primary construct, or mmRNA is not substantially decreased.
  • a modification may also be a 5′ or 3′ terminal modification.
  • the polynucleotide, primary construct, or mmRNA may contain from about 1% to about 100% modified nucleotides (either in relation to overall nucleotide content, or in relation to one or more types of nucleotide, i.e.
  • any one or more of A, G, U or C) or any intervening percentage e.g., from 1% to 20%, from 1% to 25%, from 1% to 50%, from 1% to 60%, from 1% to 70%, from 1% to 80%, from 1% to 90%, from 1% to 95%, from 10% to 20%, from 10% to 25%, from 10% to 50%, from 10% to 60%, from 10% to 70%, from 10% to 80%, from 10% to 90%, from 10% to 95%, from 10% to 100%, from 20% to 25%, from 20% to 50%, from 20% to 60%, from 20% to 70%, from 20% to 80%, from 20% to 90%, from 20% to 95%, from 20% to 100%, from 50% to 60%, from 50% to 70%, from 50% to 80%, from 50% to 90%, from 50% to 95%, from 50% to 100%, from 70% to 80%, from 70% to 90%, from 70% to 95%, from 70% to 100%, from 80% to 90%, from 80% to 95%, from 90% to 100%, and from 95% to 100%).
  • any intervening percentage e.g.,
  • the polynucleotide, primary construct, or mmRNA includes a modified pyrimidine (e.g., a modified uracil/uridine/U or modified cytosine/cytidine/C).
  • the uracil or uridine (generally: U) in the polynucleotide, primary construct, or mmRNA molecule may be replaced with from about 1% to about 100% of a modified uracil or modified uridine (e.g., from 1% to 20%, from 1% to 25%, from 1% to 50%, from 1% to 60%, from 1% to 70%, from 1% to 80%, from 1% to 90%, from 1% to 95%, from 10% to 20%, from 10% to 25%, from 10% to 50%, from 10% to 60%, from 10% to 70%, from 10% to 80%, from 10% to 90%, from 10% to 95%, from 10% to 100%, from 20% to 25%, from 20% to 50%, from 20% to 60%, from 20% to 70%, from 20% to 80%, from 20% to 80%, from 20% to
  • the modified uracil or uridine can be replaced by a compound having a single unique structure or by a plurality of compounds having different structures (e.g., 2, 3, 4 or more unique structures, as described herein).
  • the cytosine or cytidine (generally: C) in the polynucleotide, primary construct, or mmRNA molecule may be replaced with from about 1% to about 100% of a modified cytosine or modified cytidine (e.g., from 1% to 20%, from 1% to 25%, from 1% to 50%, from 1% to 60%, from 1% to 70%, from 1% to 80%, from 1% to 90%, from 1% to 95%, from 10% to 20%, from 10% to 25%, from 10% to 50%, from 10% to 60%, from 10% to 70%, from 10% to 80%, from 10% to 90%, from 10% to 95%, from 10% to 100%, from 20% to 25%, from 20% to 50%, from 20% to 60%, from 20% to 70%, from 20% to 80%, from 20% to 90%, from from 10%
  • the present disclosure provides methods of synthesizing a polynucleotide, primary construct, or mmRNA (e.g., the first region, first flanking region, or second flanking region) including n number of linked nucleosides having Formula (Ia-1):
  • Y 9 is H, hydroxy, phosphoryl, pyrophosphate, sulfate, amino, thiol, optionally substituted amino acid, or a peptide (e.g., including from 2 to 12 amino acids); and each P 1 , P 2 , and P 3 is, independently, a suitable protecting group; and
  • steps a) and b) are repeated from 1 to about 10,000 times.
  • the methods further comprise a nucleotide (e.g., mmRNA molecule) selected from the group consisting of A, C, G and U adenosine, cytosine, guanosine, and uracil.
  • the nucleobase may be a pyrimidine or derivative thereof.
  • the polynucleotide, primary construct, or mmRNA is translatable.
  • polynucleotides, primary constructs, and mmRNA are optional, and are beneficial in some embodiments.
  • a 5′ untranslated region (UTR) and/or a 3′UTR are provided, wherein either or both may independently contain one or more different nucleotide modifications.
  • nucleotide modifications may also be present in the translatable region.
  • polynucleotides, primary constructs, and mmRNA containing a Kozak sequence are also be present in the translatable region.
  • Scheme 1 provides a general method for phosphorylation of nucleosides, including modified nucleosides.
  • Scheme 2 provides the use of multiple protecting and deprotecting steps to promote phosphorylation at the 5′ position of the sugar, rather than the 2′ and 3′ hydroxyl groups.
  • Modified nucleotides can be synthesized in any useful manner.
  • Schemes 3, 4, and 7 provide exemplary methods for synthesizing modified nucleotides having a modified purine nucleobase; and
  • Schemes 5 and 6 provide exemplary methods for synthesizing modified nucleotides having a modified pseudouridine or pseudoisocytidine, respectively.
  • Schemes 8 and 9 provide exemplary syntheses of modified nucleotides.
  • Scheme 10 provides a non-limiting biocatalytic method for producing nucleotides.
  • Scheme 11 provides an exemplary synthesis of a modified uracil, where the N1 position is modified with R 12b , as provided elsewhere, and the 5′-position of ribose is phosphorylated.
  • T 1 , T 2 , R 12a , R 12b , and r are as provided herein.
  • This synthesis, as well as optimized versions thereof, can be used to modify other pyrimidine nucleobases and purine nucleobases (see e.g., Formulas (b1)-(b43)) and/or to install one or more phosphate groups (e.g., at the 5′ position of the sugar).
  • This alkylating reaction can also be used to include one or more optionally substituted alkyl group at any reactive group (e.g., amino group) in any nucleobase described herein (e.g., the amino groups in the Watson-Crick base-pairing face for cytosine, uracil, adenine, and guanine)
  • any reactive group e.g., amino group
  • nucleobase described herein e.g., the amino groups in the Watson-Crick base-pairing face for cytosine, uracil, adenine, and guanine
  • modified nucleotides and modified nucleotide combinations are provided below in Table 9. These combinations of modified nucleotides can be used to form the polypeptides, primary constructs, or mmRNA of the invention. Unless otherwise noted, the modified nucleotides may be completely substituted for the natural nucleotides of the modified nucleic acids or mmRNA of the invention. As a non-limiting example, the natural nucleotide uridine may be substituted with a modified nucleoside described herein.
  • the natural nucleotide uridine may be partially substituted (e.g., about 0.1%, 1%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 99.9%) with at least one of the modified nucleoside disclosed herein.
  • modified nucleotide combinations are provided below in Table 10. These combinations of modified nucleotides can be used to form the polypeptides, primary constructs, or mmRNA of the invention.
  • At least 25% of the cytosines are replaced by a compound of Formula (b10)-(b14) (e.g., at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%).
  • a compound of Formula (b10)-(b14) e.g., at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%).
  • At least 25% of the uracils are replaced by a compound of Formula (b1)-(b9) (e.g., at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%).
  • a compound of Formula (b1)-(b9) e.g., at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%).
  • At least 25% of the cytosines are replaced by a compound of Formula (b10)-(b14), and at least 25% of the uracils are replaced by a compound of Formula (b1)-(b9) (e.g., at least about 30%, at least about 35%, at least about 40%, at least about 45%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, at least about 70%, at least about 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, or about 100%).
  • the present invention provides polynucleotides, primary constructs and mmRNA compositions and complexes in combination with one or more pharmaceutically acceptable excipients.
  • Pharmaceutical compositions may optionally comprise one or more additional active substances, e.g. therapeutically and/or prophylactically active substances.
  • additional active substances e.g. therapeutically and/or prophylactically active substances.
  • General considerations in the formulation and/or manufacture of pharmaceutical agents may be found, for example, in Remington: The Science and Practice of Pharmacy 21 st ed., Lippincott Williams & Wilkins, 2005 (incorporated herein by reference).
  • compositions are administered to humans, human patients or subjects.
  • active ingredient generally refers to polynucleotides, primary constructs and mmRNA to be delivered as described herein.
  • compositions are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to any other animal, e.g., to non-human animals, e.g. non-human mammals. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with merely ordinary, if any, experimentation.
  • Subjects to which administration of the pharmaceutical compositions is contemplated include, but are not limited to, humans and/or other primates; mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, dogs, mice, and/or rats; and/or birds, including commercially relevant birds such as poultry, chickens, ducks, geese, and/or turkeys.
  • Formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with an excipient and/or one or more other accessory ingredients, and then, if necessary and/or desirable, dividing, shaping and/or packaging the product into a desired single- or multi-dose unit.
  • a pharmaceutical composition in accordance with the invention may be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a “unit dose” is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.
  • Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition in accordance with the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 100%, e.g., between 0.5 and 50%, between 1-30%, between 5-80%, at least 80% (w/w) active ingredient.
  • the polynucleotide, primary construct, and mmRNA of the invention can be formulated using one or more excipients to: (1) increase stability; (2) increase cell transfection; (3) permit the sustained or delayed release (e.g., from a depot formulation of the polynucleotide, primary construct, or mmRNA); (4) alter the biodistribution (e.g., target the polynucleotide, primary construct, or mmRNA to specific tissues or cell types); (5) increase the translation of encoded protein in vivo; and/or (6) alter the release profile of encoded protein in vivo.
  • excipients to: (1) increase stability; (2) increase cell transfection; (3) permit the sustained or delayed release (e.g., from a depot formulation of the polynucleotide, primary construct, or mmRNA); (4) alter the biodistribution (e.g., target the polynucleotide, primary construct, or mmRNA to specific tissues or cell types); (5) increase the translation of encoded protein in
  • excipients of the present invention can include, without limitation, lipidoids, liposomes, lipid nanoparticles, polymers, lipoplexes, core-shell nanoparticles, peptides, proteins, cells transfected with polynucleotide, primary construct, or mmRNA (e.g., for transplantation into a subject), hyaluronidase, nanoparticle mimics and combinations thereof.
  • the formulations of the invention can include one or more excipients, each in an amount that together increases the stability of the polynucleotide, primary construct, or mmRNA, increases cell transfection by the polynucleotide, primary construct, or mmRNA, increases the expression of polynucleotide, primary construct, or mmRNA encoded protein, and/or alters the release profile of polynucleotide, primary construct, or mmRNA encoded proteins.
  • the primary construct and mmRNA of the present invention may be formulated using self-assembled nucleic acid nanoparticles.
  • Formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology. In general, such preparatory methods include the step of associating the active ingredient with an excipient and/or one or more other accessory ingredients.
  • a pharmaceutical composition in accordance with the present disclosure may be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses.
  • a “unit dose” refers to a discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient.
  • the amount of the active ingredient may generally be equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage including, but not limited to, one-half or one-third of such a dosage.
  • Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition in accordance with the present disclosure may vary, depending upon the identity, size, and/or condition of the subject being treated and further depending upon the route by which the composition is to be administered.
  • the composition may comprise between 0.1% and 99% (w/w) of the active ingredient.
  • the formulations described herein may contain at least one mmRNA.
  • the formulations may contain 1, 2, 3, 4 or 5 mmRNA.
  • the formulation may contain modified mRNA encoding proteins selected from categories such as, but not limited to, human proteins, veterinary proteins, bacterial proteins, biological proteins, antibodies, immunogenic proteins, therapeutic peptides and proteins, secreted proteins, plasma membrane proteins, cytoplasmic and cytoskeletal proteins, intrancellular membrane bound proteins, nuclear proteins, proteins associated with human disease and/or proteins associated with non-human diseases.
  • the formulation contains at least three modified mRNA encoding proteins.
  • the formulation contains at least five modified mRNA encoding proteins.
  • compositions may additionally comprise a pharmaceutically acceptable excipient, which, as used herein, includes, but is not limited to, any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, and the like, as suited to the particular dosage form desired.
  • a pharmaceutically acceptable excipient includes, but is not limited to, any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, and the like, as suited to the particular dosage form desired.
  • excipients for formulating pharmaceutical compositions and techniques for preparing the composition are known in the art (see Remington: The Science and Practice of Pharmacy, 21 st Edition, A. R. Gennaro, Lippincott, Williams & Wilkins, Baltimore, Md
  • any conventional excipient medium may be contemplated within the scope of the present disclosure, except insofar as any conventional excipient medium may be incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other component(s) of the pharmaceutical composition.
  • the particle size of the lipid nanoparticle may be increased and/or decreased.
  • the change in particle size may be able to help counter biological reaction such as, but not limited to, inflammation or may increase the biological effect of the modified mRNA delivered to mammals.
  • compositions include, but are not limited to, inert diluents, surface active agents and/or emulsifiers, preservatives, buffering agents, lubricating agents, and/or oils. Such excipients may optionally be included in the pharmaceutical formulations of the invention.
  • lipidoids The synthesis of lipidoids has been extensively described and formulations containing these compounds are particularly suited for delivery of polynucleotides, primary constructs or mmRNA (see Mahon et al., Bioconjug Chem. 2010 21:1448-1454; Schroeder et al., J Intern Med. 2010 267:9-21; Akinc et al., Nat. Biotechnol. 2008 26:561-569; Love et al., Proc Natl Acad Sci USA. 2010 107:1864-1869; Siegwart et al., Proc Natl Acad Sci USA. 2011 108:12996-3001; all of which are incorporated herein in their entireties).
  • the present disclosure describes their formulation and use in delivering single stranded polynucleotides, primary constructs, or mmRNA.
  • Complexes, micelles, liposomes or particles can be prepared containing these lipidoids and therefore, can result in an effective delivery of the polynucleotide, primary construct, or mmRNA, as judged by the production of an encoded protein, following the injection of a lipidoid formulation via localized and/or systemic routes of administration.
  • Lipidoid complexes of polynucleotides, primary constructs, or mmRNA can be administered by various means including, but not limited to, intravenous, intramuscular, or subcutaneous routes.
  • nucleic acids may be affected by many parameters, including, but not limited to, the formulation composition, nature of particle PEGylation, degree of loading, oligonucleotide to lipid ratio, and biophysical parameters such as, but not limited to, particle size (Akinc et al., Mol Ther. 2009 17:872-879; herein incorporated by reference in its entirety).
  • particle size Akinc et al., Mol Ther. 2009 17:872-879; herein incorporated by reference in its entirety.
  • small changes in the anchor chain length of poly(ethylene glycol) (PEG) lipids may result in significant effects on in vivo efficacy.
  • Formulations with the different lipidoids including, but not limited to penta[3-(1-laurylaminopropionyl)]-triethylenetetramine hydrochloride (TETA-5LAP; aka 98N12-5, see Murugaiah et al., Analytical Biochemistry, 401:61 (2010); herein incorporated by reference in its entirety), C12-200 (including derivatives and variants), and MD1, can be tested for in vivo activity.
  • TETA-5LAP penta[3-(1-laurylaminopropionyl)]-triethylenetetramine hydrochloride
  • C12-200 including derivatives and variants
  • MD1 can be tested for in vivo activity.
  • the lipidoid referred to herein as “C12-200” is disclosed by Love et al., Proc Natl Acad Sci USA. 2010 107:1864-1869 (see FIG. 2 ) and Liu and Huang, Molecular Therapy. 2010 669-670 (see FIG. 2 ); both of which are herein incorporated by reference in their entirety.
  • the lipidoid formulations can include particles comprising either 3 or 4 or more components in addition to polynucleotide, primary construct, or mmRNA.
  • formulations with certain lipidoids include, but are not limited to, 98N12-5 and may contain 42% lipidoid, 48% cholesterol and 10% PEG (C14 alkyl chain length).
  • formulations with certain lipidoids include, but are not limited to, C12-200 and may contain 50% lipidoid, 10% disteroylphosphatidyl choline, 38.5% cholesterol, and 1.5% PEG-DMG.
  • a polynucleotide, primary construct, or mmRNA formulated with a lipidoid for systemic intravenous administration can target the liver.
  • lipidoid may have a molar ratio of 50/10/38.5/1.5 of C12-200/disteroylphosphatidyl choline/cholesterol/PEG-DMG, with a weight ratio of 7 to 1 total lipid to polynucleotide, primary construct, or mmRNA, and a mean particle size of 80 nm may be effective to deliver polynucleotide, primary construct, or mmRNA to hepatocytes (see, Love et al., Proc Natl Acad Sci USA.
  • an MD1 lipidoid-containing formulation may be used to effectively deliver polynucleotide, primary construct, or mmRNA to hepatocytes in vivo.
  • the characteristics of optimized lipidoid formulations for intramuscular or subcutaneous routes may vary significantly depending on the target cell type and the ability of formulations to diffuse through the extracellular matrix into the blood stream. While a particle size of less than 150 nm may be desired for effective hepatocyte delivery due to the size of the endothelial fenestrae (see, Akinc et al., Mol Ther.
  • lipidoid-formulated polynucleotide, primary construct, or mmRNA to deliver the formulation to other cells types including, but not limited to, endothelial cells, myeloid cells, and muscle cells may not be similarly size-limited.
  • Use of lipidoid formulations to deliver siRNA in vivo to other non-hepatocyte cells such as myeloid cells and endothelium has been reported (see Akinc et al., Nat Biotechnol. 2008 26:561-569; Leuschner et al., Nat Biotechnol. 2011 29:1005-1010; Cho et al. Adv. Funct. Mater.
  • lipidoid formulations may have a similar component molar ratio. Different ratios of lipidoids and other components including, but not limited to, disteroylphosphatidyl choline, cholesterol and PEG-DMG, may be used to optimize the formulation of the polynucleotide, primary construct, or mmRNA for delivery to different cell types including, but not limited to, hepatocytes, myeloid cells, muscle cells, etc.
  • the component molar ratio may include, but is not limited to, 50% C12-200, 10% disteroylphosphatidyl choline, 38.5% cholesterol, and %1.5 PEG-DMG (see Leuschner et al., Nat Biotechnol 2011 29:1005-1010; herein incorporated by reference in its entirety).
  • the use of lipidoid formulations for the localized delivery of nucleic acids to cells (such as, but not limited to, adipose cells and muscle cells) via either subcutaneous or intramuscular delivery may not require all of the formulation components desired for systemic delivery, and as such may comprise only the lipidoid and the polynucleotide, primary construct, or mmRNA.
  • Combinations of different lipidoids may be used to improve the efficacy of polynucleotide, primary construct, or mmRNA directed protein production as the lipidoids may be able to increase cell transfection by the polynucleotide, primary construct, or mmRNA; and/or increase the translation of encoded protein (see Whitehead et al., Mol. Ther. 2011, 19:1688-1694, herein incorporated by reference in its entirety).
  • the polynucleotide, primary construct, and mmRNA of the invention can be formulated using one or more liposomes, lipoplexes, or lipid nanoparticles.
  • pharmaceutical compositions of polynucleotide, primary construct, or mmRNA include liposomes. Liposomes are artificially-prepared vesicles which may primarily be composed of a lipid bilayer and may be used as a delivery vehicle for the administration of nutrients and pharmaceutical formulations.
  • Liposomes can be of different sizes such as, but not limited to, a multilamellar vesicle (MLV) which may be hundreds of nanometers in diameter and may contain a series of concentric bilayers separated by narrow aqueous compartments, a small unicellular vesicle (SUV) which may be smaller than 50 nm in diameter, and a large unilamellar vesicle (LUV) which may be between 50 and 500 nm in diameter.
  • MLV multilamellar vesicle
  • SUV small unicellular vesicle
  • LUV large unilamellar vesicle
  • Liposome design may include, but is not limited to, opsonins or ligands in order to improve the attachment of liposomes to unhealthy tissue or to activate events such as, but not limited to, endocytosis.
  • Liposomes may contain a low or a high pH in order to improve the delivery of the pharmaceutical formulations.
  • liposomes may depend on the physicochemical characteristics such as, but not limited to, the pharmaceutical formulation entrapped and the liposomal ingredients, the nature of the medium in which the lipid vesicles are dispersed, the effective concentration of the entrapped substance and its potential toxicity, any additional processes involved during the application and/or delivery of the vesicles, the optimization size, polydispersity and the shelf-life of the vesicles for the intended application, and the batch-to-batch reproducibility and possibility of large-scale production of safe and efficient liposomal products.
  • compositions described herein may include, without limitation, liposomes such as those formed from 1,2-dioleyloxy-N,N-dimethylaminopropane (DODMA) liposomes, DiLa2 liposomes from Marina Biotech (Bothell, Wash.), 1,2-dilinoleyloxy-3-dimethylaminopropane (DLin-DMA), 2,2-dilinoleyl-4-(2-dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA), and MC3 (US20100324120; herein incorporated by reference in its entirety) and liposomes which may deliver small molecule drugs such as, but not limited to, DOXIL® from Janssen Biotech, Inc. (Horsham, Pa.).
  • DOXIL® 1,2-dioleyloxy-N,N-dimethylaminopropane
  • compositions described herein may include, without limitation, liposomes such as those formed from the synthesis of stabilized plasmid-lipid particles (SPLP) or stabilized nucleic acid lipid particle (SNALP) that have been previously described and shown to be suitable for oligonucleotide delivery in vitro and in vivo (see Wheeler et al. Gene Therapy. 1999 6:271-281; Zhang et al. Gene Therapy. 1999 6:1438-1447; Jeffs et al. Pharm Res. 2005 22:362-372; Morrissey et al., Nat Biotechnol. 2005 2:1002-1007; Zimmermann et al., Nature. 2006 441:111-114; Heyes et al.
  • SPLP stabilized plasmid-lipid particles
  • SNALP stabilized nucleic acid lipid particle
  • the original manufacture method by Wheeler et al. was a detergent dialysis method, which was later improved by Jeffs et al. and is referred to as the spontaneous vesicle formation method.
  • the liposome formulations are composed of 3 to 4 lipid components in addition to the polynucleotide, primary construct, or mmRNA.
  • a liposome can contain, but is not limited to, 55% cholesterol, 20% disteroylphosphatidyl choline (DSPC), 10% PEG-S-DSG, and 15% 1,2-dioleyloxy-N,N-dimethylaminopropane (DODMA), as described by Jeffs et al.
  • DSPC disteroylphosphatidyl choline
  • PEG-S-DSG 10% PEG-S-DSG
  • DODMA 1,2-dioleyloxy-N,N-dimethylaminopropane
  • certain liposome formulations may contain, but are not limited to, 48% cholesterol, 20% DSPC, 2% PEG-c-DMA, and 30% cationic lipid, where the cationic lipid can be 1,2-distearloxy-N,N-dimethylaminopropane (DSDMA), DODMA, DLin-DMA, or 1,2-dilinolenyloxy-3-dimethylaminopropane (DLenDMA), as described by Heyes et al.
  • DSDMA 1,2-distearloxy-N,N-dimethylaminopropane
  • DODMA 1,2-dilinolenyloxy-3-dimethylaminopropane
  • compositions may include liposomes which may be formed to deliver mmRNA which may encode at least one immunogen.
  • the mmRNA may be encapsulated by the liposome and/or it may be contained in an aqueous core which may then be encapsulated by the liposome (see International Pub. Nos. WO2012031046, WO2012031043, WO2012030901 and WO2012006378; each of which is herein incorporated by reference in their entirety).
  • the mmRNA which may encode an immunogen may be formulated in a cationic oil-in-water emulsion where the emulsion particle comprises an oil core and a cationic lipid which can interact with the mmRNA anchoring the molecule to the emulsion particle (see International Pub. No. WO2012006380; herein incorporated by reference in its entirety).
  • the lipid formulation may include at least cationic lipid, a lipid which may enhance transfection and a least one lipid which contains a hydrophilic head group linked to a lipid moiety (International Pub. No. WO2011076807 and U.S. Pub. No. 20110200582; each of which is herein incorporated by reference in their entirety).
  • the polynucleotides, primary constructs and/or mmRNA encoding an immunogen may be formulated in a lipid vesicle which may have crosslinks between functionalized lipid bilayers (see U.S. Pub. No. 20120177724, herein incorporated by reference in its entirety).
  • the polynucleotides, primary constructs and/or mmRNA may be formulated in a lipid vesicle which may have crosslinks between functionalized lipid bilayers.
  • the polynucleotides, primary constructs and/or mmRNA may be formulated in a liposome comprising a cationic lipid.
  • the liposome may have a molar ratio of nitrogen atoms in the cationic lipid to the phophates in the RNA (N:P ratio) of between 1:1 and 20:1 as described in International Publication No. WO2013006825, herein incorporated by reference in its entirety.
  • the liposome may have a N:P ratio of greater than 20:1 or less than 1:1.
  • the polynucleotides, primary constructs and/or mmRNA may be formulated in a lipid-polycation complex.
  • the formation of the lipid-polycation complex may be accomplished by methods known in the art and/or as described in U.S. Pub. No. 20120178702, herein incorporated by reference in its entirety.
  • the polycation may include a cationic peptide or a polypeptide such as, but not limited to, polylysine, polyornithine and/or polyarginine and the cationic peptides described in International Pub. No. WO2012013326; herein incorporated by reference in its entirety.
  • the polynucleotides, primary constructs and/or mmRNA may be formulated in a lipid-polycation complex which may further include a neutral lipid such as, but not limited to, cholesterol or dioleoyl phosphatidylethanolamine (DOPE).
  • a neutral lipid such as, but not limited to, cholesterol or dioleoyl phosphatidylethanolamine (DOPE).
  • DOPE dioleoyl phosphatidylethanolamine
  • the liposome formulation may be influenced by, but not limited to, the selection of the cationic lipid component, the degree of cationic lipid saturation, the nature of the PEGylation, ratio of all components and biophysical parameters such as size.
  • the liposome formulation was composed of 57.1% cationic lipid, 7.1% dipalmitoylphosphatidylcholine, 34.3% cholesterol, and 1.4% PEG-c-DMA.
  • changing the composition of the cationic lipid could more effectively deliver siRNA to various antigen presenting cells (Basha et al. Mol Ther. 2011 19:2186-2200; herein incorporated by reference in its entirety).
  • the ratio of PEG in the lipid nanoparticle (LNP) formulations may be increased or decreased and/or the carbon chain length of the PEG lipid may be modified from C14 to C18 to alter the pharmacokinetics and/or biodistribution of the LNP formulations.
  • LNP formulations may contain 1-5% of the lipid molar ratio of PEG-c-DOMG as compared to the cationic lipid, DSPC and cholesterol.
  • the PEG-c-DOMG may be replaced with a PEG lipid such as, but not limited to, PEG-DSG (1,2-Distearoyl-sn-glycerol, methoxypolyethylene glycol) or PEG-DPG (1,2-Dipalmitoyl-sn-glycerol, methoxypolyethylene glycol).
  • PEG-DSG 1,2-Distearoyl-sn-glycerol, methoxypolyethylene glycol
  • PEG-DPG 1,2-Dipalmitoyl-sn-glycerol, methoxypolyethylene glycol
  • the cationic lipid may be selected from any lipid known in the art such as, but not limited to, DLin-MC3-DMA, DLin-DMA, C12-200 and DLin-KC2-DMA.
  • the polynucleotides, primary constructs or mmRNA may be formulated in a lipid nanoparticle such as those described in International Publication No. WO2012170930, herein incorporated by reference in its entirety.
  • the cationic lipid may be selected from, but not limited to, a cationic lipid described in International Publication Nos. WO2012040184, WO2011153120, WO2011149733, WO2011090965, WO2011043913, WO2011022460, WO2012061259, WO2012054365, WO2012044638, WO2010080724, WO201021865 and WO2008103276, U.S. Pat. Nos. 7,893,302, 7,404,969 and 8,283,333 and US Patent Publication No. US20100036115 and US20120202871; each of which is herein incorporated by reference in their entirety.
  • the cationic lipid may be selected from, but not limited to, formula A described in International Publication Nos. WO2012040184, WO2011153120, WO2011149733, WO2011090965, WO2011043913, WO2011022460, WO2012061259, WO2012054365 and WO2012044638; each of which is herein incorporated by reference in their entirety.
  • the cationic lipid may be selected from, but not limited to, formula CLI-CLXXIX of International Publication No. WO2008103276, formula CLI-CLXXIX of U.S. Pat. No. 7,893,302, formula CLI-CLXXXXII of U.S. Pat. No.
  • the cationic lipid may be selected from (20Z,23Z)-N,N-dimethylnonacosa-20,23-dien-10-amine, (17Z,20Z)-N,N-dimemylhexacosa-17,20-dien-9-amine, (1Z,19Z)-N5N-dimethylpentacosa-16,19-dien-8-amine, (13Z,16Z)-N,N-dimethyldocosa-13,16-dien-5-amine, (12Z,15Z)-N,N-dimethylhenicosa-12,15-dien-4-amine, (14Z,17Z)-N,N-dimethyltricosa-14,17-dien-6-amine, (15Z,18Z)-N,N-dimethyltetracosa-15,
  • the lipid may be a cleavable lipid such as those described in International Publication No. WO2012170889, herein incorporated by reference in its entirety.
  • the cationic lipid may be synthesized by methods known in the art and/or as described in International Publication Nos. WO2012040184, WO2011153120, WO2011149733, WO2011090965, WO2011043913, WO2011022460, WO2012061259, WO2012054365, WO2012044638, WO2010080724 and WO201021865; each of which is herein incorporated by reference in their entirety.
  • the LNP formulations of the polynucleotides, primary constructs and/or mmRNA may contain PEG-c-DOMG at 3% lipid molar ratio. In another embodiment, the LNP formulations polynucleotides, primary constructs and/or mmRNA may contain PEG-c-DOMG at 1.5% lipid molar ratio.
  • the pharmaceutical compositions of the polynucleotides, primary constructs and/or mmRNA may include at least one of the PEGylated lipids described in International Publication No. 2012099755, herein incorporated by reference.
  • the LNP formulation may contain PEG-DMG 2000 (1,2-dimyristoyl-sn-glycero-3-phophoethanolamine-N-[methoxy(polyethylene glycol)-2000).
  • the LNP formulation may contain PEG-DMG 2000, a cationic lipid known in the art and at least one other component.
  • the LNP formulation may contain PEG-DMG 2000, a cationic lipid known in the art, DSPC and cholesterol.
  • the LNP formulation may contain PEG-DMG 2000, DLin-DMA, DSPC and cholesterol.
  • the LNP formulation may contain PEG-DMG 2000, DLin-DMA, DSPC and cholesterol in a molar ratio of 2:40:10:48 (see e.g., Geall et al., Nonviral delivery of self-amplifying RNA vaccines, PNAS 2012; PMID: 22908294; herein incorporated by reference in its entirety).
  • modified RNA described herein may be formulated in a nanoparticle to be delivered by a parenteral route as described in U.S. Pub. No. 20120207845; herein incorporated by reference in its entirety.
  • the LNP formulation may be formulated by the methods described in International Publication Nos. WO2011127255 or WO2008103276, each of which is herein incorporated by reference in their entirety.
  • modified RNA described herein may be encapsulated in LNP formulations as described in WO2011127255 and/or WO2008103276; each of which is herein incorporated by reference in their entirety.
  • LNP formulations described herein may comprise a polycationic composition.
  • the polycationic composition may be selected from formula 1-60 of US Patent Publication No. US20050222064; herein incorporated by reference in its entirety.
  • the LNP formulations comprising a polycationic composition may be used for the delivery of the modified RNA described herein in vivo and/or in vitro.
  • the LNP formulations described herein may additionally comprise a permeability enhancer molecule.
  • a permeability enhancer molecule are described in US Patent Publication No. US20050222064; herein incorporated by reference in its entirety.
  • the pharmaceutical compositions may be formulated in liposomes such as, but not limited to, DiLa2 liposomes (Marina Biotech, Bothell, Wash.), SMARTICLES® (Marina Biotech, Bothell, Wash.), neutral DOPC (1,2-dioleoyl-sn-glycero-3-phosphocholine) based liposomes (e.g., siRNA delivery for ovarian cancer (Landen et al. Cancer Biology & Therapy 2006 5(12)1708-1713); herein incorporated by reference in its entirety) and hyaluronan-coated liposomes (Quiet Therapeutics, Israel).
  • DiLa2 liposomes Marina Biotech, Bothell, Wash.
  • SMARTICLES® Marina Biotech, Bothell, Wash.
  • neutral DOPC 1,2-dioleoyl-sn-glycero-3-phosphocholine
  • hyaluronan-coated liposomes Quiet Therapeutics, Israel
  • the nanoparticle formulations may be a carbohydrate nanoparticle comprising a carbohydrate carrier and a modified nucleic acid molecule (e.g., mmRNA).
  • the carbohydrate carrier may include, but is not limited to, an anhydride-modified phytoglycogen or glycogen-type material, phtoglycogen octenyl succinate, phytoglycogen beta-dextrin, anhydride-modified phytoglycogen beta-dextrin. (See e.g., International Publication No. WO2012109121; herein incorporated by reference in its entirety).
  • Lipid nanoparticle formulations may be improved by replacing the cationic lipid with a biodegradable cationic lipid which is known as a rapidly eliminated lipid nanoparticle (reLNP).
  • Ionizable cationic lipids such as, but not limited to, DLinDMA, DLin-KC2-DMA, and DLin-MC3-DMA, have been shown to accumulate in plasma and tissues over time and may be a potential source of toxicity.
  • the rapid metabolism of the rapidly eliminated lipids can improve the tolerability and therapeutic index of the lipid nanoparticles by an order of magnitude from a 1 mg/kg dose to a 10 mg/kg dose in rat.
  • ester linkage can improve the degradation and metabolism profile of the cationic component, while still maintaining the activity of the reLNP formulation.
  • the ester linkage can be internally located within the lipid chain or it may be terminally located at the terminal end of the lipid chain.
  • the internal ester linkage may replace any carbon in the lipid chain.
  • the internal ester linkage may be located on either side of the saturated carbon.
  • reLNPs include,
  • an immune response may be elicited by delivering a lipid nanoparticle which may include a nanospecies, a polymer and an immunogen.
  • a lipid nanoparticle which may include a nanospecies, a polymer and an immunogen.
  • the polymer may encapsulate the nanospecies or partially encapsulate the nanospecies.
  • the immunogen may be a recombinant protein, a modified RNA and/or a primary construct described herein.
  • the lipid nanoparticle may be formulated for use in a vaccine such as, but not limited to, against a pathogen.
  • Lipid nanoparticles may be engineered to alter the surface properties of particles so the lipid nanoparticles may penetrate the mucosal barrier.
  • Mucus is located on mucosal tissue such as, but not limted to, oral (e.g., the buccal and esophageal membranes and tonsil tissue), ophthalmic, gastrointestinal (e.g., stomach, small intestine, large intestine, colon, rectum), nasal, respiratory (e.g., nasal, pharyngeal, tracheal and bronchial membranes), genital (e.g., vaginal, cervical and urethral membranes).
  • oral e.g., the buccal and esophageal membranes and tonsil tissue
  • ophthalmic e.g., gastrointestinal (e.g., stomach, small intestine, large intestine, colon, rectum)
  • nasal, respiratory e.g., nasal, pharyngeal, tracheal and bron
  • Nanoparticles larger than 10-200 nm which are preferred for higher drug encapsulation efficiency and the ability to provide the sustained delivery of a wide array of drugs have been thought to be too large to rapidly diffuse through mucosal barriers. Mucus is continuously secreted, shed, discarded or digested and recycled so most of the trapped particles may be removed from the mucosla tissue within seconds or within a few hours. Large polymeric nanoparticles (200 nm-500 nm in diameter) which have been coated densely with a low molecular weight polyethylene glycol (PEG) diffused through mucus only 4 to 6-fold lower than the same particles diffusing in water (Lai et al. PNAS 2007 104(5):1482-487; Lai et al.
  • PEG polyethylene glycol
  • the transport of nanoparticles may be determined using rates of permeation and/or fluorescent microscopy techniques including, but not limited to, fluorescence recovery after photobleaching (FRAP) and high resolution multiple particle tracking (MPT).
  • FRAP fluorescence recovery after photobleaching
  • MPT high resolution multiple particle tracking
  • compositions which can penetrate a mucosal barrier may be made as described in U.S. Pat. No. 8,241,670, herein incorporated by reference in its entirety.
  • the lipid nanoparticle engineered to penetrate mucus may comprise a polymeric material (i.e. a polymeric core) and/or a polymer-vitamin conjugate and/or a tri-block co-polymer.
  • the polymeric material may include, but is not limited to, polyamines, polyethers, polyamides, polyesters, polycarbamates, polyureas, polycarbonates, poly(styrenes), polyimides, polysulfones, polyurethanes, polyacetylenes, polyethylenes, polyethyeneimines, polyisocyanates, polyacrylates, polymethacrylates, polyacrylonitriles, and polyarylates.
  • the polymeric material may be biodegradable and/or biocompatible.
  • the polymeric material may additionally be irradiated.
  • the polymeric material may be gamma irradiated (See e.g., International App. No. WO201282165, herein incorporated by reference in its entirety).
  • Non-limiting examples of specific polymers include poly(caprolactone) (PCL), ethylene vinyl acetate polymer (EVA), poly(lactic acid) (PLA), poly(L-lactic acid) (PLLA), poly(glycolic acid) (PGA), poly(lactic acid-co-glycolic acid) (PLGA), poly(L-lactic acid-co-glycolic acid) (PLLGA), poly(D,L-lactide) (PDLA), poly(L-lactide) (PLLA), poly(D,L-lactide-co-caprolactone), poly(D,L-lactide-co-caprolactone-co-glycolide), poly(D,L-lactide-co-PEO-co-D,L-lactide), poly(D,L-lactide-co-PPO-co-D,L-lactide), polyalkyl cyanoacralate, polyurethane, poly-L-lysine (PLL), hydroxypropyl methacrylate (
  • the lipid nanoparticle may be coated or associated with a co-polymer such as, but not limited to, a block co-polymer (such as a branched polyether-polyamide block copolymer described in International Publication No. WO2013012476, herein incorporated by reference in its entirety), and (poly(ethylene glycol))-(poly(propylene oxide))-(poly(ethylene glycol)) triblock copolymer (see e.g., US Publication 20120121718 and US Publication 20100003337 and U.S. Pat. No. 8,263,665; each of which is herein incorporated by reference in their entirety).
  • a block co-polymer such as a branched polyether-polyamide block copolymer described in International Publication No. WO2013012476, herein incorporated by reference in its entirety
  • the co-polymer may be a polymer that is generally regarded as safe (GRAS) and the formation of the lipid nanoparticle may be in such a way that no new chemical entities are created.
  • the lipid nanoparticle may comprise poloxamers coating PLGA nanoparticles without forming new chemical entities which are still able to rapidly penetrate human mucus (Yang et al. Angew. Chem. Int. Ed. 2011 50:2597-2600; herein incorporated by reference in its entirety).
  • the vitamin of the polymer-vitamin conjugate may be vitamin E.
  • the vitamin portion of the conjugate may be substituted with other suitable components such as, but not limited to, vitamin A, vitamin E, other vitamins, cholesterol, a hydrophobic moiety, or a hydrophobic component of other surfactants (e.g., sterol chains, fatty acids, hydrocarbon chains and alkylene oxide chains).
  • the lipid nanoparticle engineered to penetrate mucus may include surface altering agents such as, but not limited to, mmRNA, anionic proteins (e.g., bovine serum albumin), surfactants (e.g., cationic surfactants such as for example dimethyldioctadecyl-ammonium bromide), sugars or sugar derivatives (e.g., cyclodextrin), nucleic acids, polymers (e.g., heparin, polyethylene glycol and poloxamer), mucolytic agents (e.g., N-acetylcysteine, mugwort, bromelain, papain, clerodendrum, acetylcysteine, bromhexine, carbocisteine, eprazinone, mesna, ambroxol, sobrerol, domiodol, letosteine, stepronin, tiopronin, gelsolin, thymosin ⁇ 4 dor
  • the surface altering agent may be embedded or enmeshed in the particle's surface or disposed (e.g., by coating, adsorption, covalent linkage, or other process) on the surface of the lipid nanoparticle.
  • the mucus penetrating lipid nanoparticles may comprise at least one mmRNA described herein.
  • the mmRNA may be encapsulated in the lipid nanoparticle and/or disposed on the surface of the paricle.
  • the mmRNA may be covalently coupled to the lipid nanoparticle.
  • Formulations of mucus penetrating lipid nanoparticles may comprise a plurality of nanoparticles. Further, the formulations may contain particles which may interact with the mucus and alter the structural and/or adhesive properties of the surrounding mucus to decrease mucoadhesion which may increase the delivery of the mucus penetrating lipid nanoparticles to the mucosal tissue.
  • the polynucleotide, primary construct, or mmRNA is formulated as a lipoplex, such as, without limitation, the ATUPLEXTM system, the DACC system, the DBTC system and other siRNA-lipoplex technology from Silence Therapeutics (London, United Kingdom), STEMFECTTM from STEMGENT® (Cambridge, Mass.), and polyethylenimine (PEI) or protamine-based targeted and non-targeted delivery of nucleic acids acids acids (Aleku et al. Cancer Res. 2008 68:9788-9798; Strumberg et al.
  • a lipoplex such as, without limitation, the ATUPLEXTM system, the DACC system, the DBTC system and other siRNA-lipoplex technology from Silence Therapeutics (London, United Kingdom), STEMFECTTM from STEMGENT® (Cambridge, Mass.), and polyethylenimine (PEI) or protamine-based targeted and non-targeted delivery of nucleic acids acids acids (Aleku
  • such formulations may also be constructed or compositions altered such that they passively or actively are directed to different cell types in vivo, including but not limited to hepatocytes, immune cells, tumor cells, endothelial cells, antigen presenting cells, and leukocytes (Akinc et al. Mol. Ther. 2010 18:1357-1364; Song et al., Nat Biotechnol. 2005 23:709-717; Judge et al., J Clin Invest.
  • DLin-DMA DLin-KC2-DMA
  • DLin-MC3-DMA-based lipid nanoparticle formulations which have been shown to bind to apolipoprotein E and promote binding and uptake of these formulations into hepatocytes in vivo (Akinc et al. Mol. Ther. 2010 18:1357-1364; herein incorporated by reference in its entirety).
  • Formulations can also be selectively targeted through expression of different ligands on their surface as exemplified by, but not limited by, folate, transferrin, N-acetylgalactosamine (GalNAc), and antibody targeted approaches (Kolhatkar et al., Curr Drug Discov Technol. 2011 8:197-206; Musacchio and Torchilin, Front Biosci. 2011 16:1388-1412; Yu et al., Mol Membr Biol. 2010 27:286-298; Patil et al., Crit Rev Ther Drug Carrier Syst. 2008 25:1-61; Benoit et al., Biomacromolecules.
  • the polynucleotide, primary construct, or mmRNA is formulated as a solid lipid nanoparticle.
  • a solid lipid nanoparticle may be spherical with an average diameter between 10 to 1000 nm. SLN possess a solid lipid core matrix that can solubilize lipophilic molecules and may be stabilized with surfactants and/or emulsifiers.
  • the lipid nanoparticle may be a self-assembly lipid-polymer nanoparticle (see Zhang et al., ACS Nano, 2008, 2 (8), pp 1696-1702; herein incorporated by reference in its entirety).
  • Liposomes, lipoplexes, or lipid nanoparticles may be used to improve the efficacy of polynucleotide, primary construct, or mmRNA directed protein production as these formulations may be able to increase cell transfection by the polynucleotide, primary construct, or mmRNA; and/or increase the translation of encoded protein.
  • One such example involves the use of lipid encapsulation to enable the effective systemic delivery of polyplex plasmid DNA (Heyes et al., Mol Ther. 2007 15:713-720; herein incorporated by reference in its entirety).
  • the liposomes, lipoplexes, or lipid nanoparticles may also be used to increase the stability of the polynucleotide, primary construct, or mmRNA.
  • the polynucleotides, primary constructs, and/or the mmRNA of the present invention can be formulated for controlled release and/or targeted delivery.
  • controlled release refers to a pharmaceutical composition or compound release profile that conforms to a particular pattern of release to effect a therapeutic outcome.
  • the polynucleotides, primary constructs or the mmRNA may be encapsulated into a delivery agent described herein and/or known in the art for controlled release and/or targeted delivery.
  • the term “encapsulate” means to enclose, surround or encase. As it relates to the formulation of the compounds of the invention, encapsulation may be substantial, complete or partial.
  • substantially encapsulated means that at least greater than 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, 99.9 or greater than 99.999% of the pharmaceutical composition or compound of the invention may be enclosed, surrounded or encased within the delivery agent.
  • Partially encapsulation means that less than 10, 10, 20, 30, 40 50 or less of the pharmaceutical composition or compound of the invention may be enclosed, surrounded or encased within the delivery agent.
  • encapsulation may be determined by measuring the escape or the activity of the pharmaceutical composition or compound of the invention using fluorescence and/or electron micrograph.
  • At least 1, 5, 10, 20, 30, 40, 50, 60, 70, 80, 85, 90, 95, 96, 97, 98, 99, 99.9, 99.99 or greater than 99.99% of the pharmaceutical composition or compound of the invention are encapsulated in the delivery agent.
  • the controlled release formulation may include, but is not limited to, tri-block co-polymers.
  • the formulation may include two different types of tri-block co-polymers (International Pub. No. WO2012131104 and WO2012131106; each of which is herein incorporated by reference in its entirety).
  • the polynucleotides, primary constructs, or the mmRNA may be encapsulated into a lipid nanoparticle or a rapidly eliminated lipid nanoparticle and the lipid nanoparticles or a rapidly eliminated lipid nanoparticle may then be encapsulated into a polymer, hydrogel and/or surgical sealant described herein and/or known in the art.
  • the polymer, hydrogel or surgical sealant may be PLGA, ethylene vinyl acetate (EVAc), poloxamer, GELSITE® (Nanotherapeutics, Inc.
  • HYLENEX® Hazyme Therapeutics, San Diego Calif.
  • surgical sealants such as fibrinogen polymers (Ethicon Inc. Cornelia, Ga.), TISSELL® (Baxter International, Inc Deerfield, Ill.), PEG-based sealants, and COSEAL® (Baxter International, Inc Deerfield, Ill.).
  • the lipid nanoparticle may be encapsulated into any polymer known in the art which may form a gel when injected into a subject.
  • the lipid nanoparticle may be encapsulated into a polymer matrix which may be biodegradable.
  • the polynucleotide, primary construct, or mmRNA formulation for controlled release and/or targeted delivery may also include at least one controlled release coating.
  • Controlled release coatings include, but are not limited to, OPADRY®, polyvinylpyrrolidone/vinyl acetate copolymer, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, EUDRAGIT RL®, EUDRAGIT RS® and cellulose derivatives such as ethylcellulose aqueous dispersions (AQUACOAT® and SURELEASE®).
  • the controlled release and/or targeted delivery formulation may comprise at least one degradable polyester which may contain polycationic side chains.
  • Degradable polyesters include, but are not limited to, poly(serine ester), poly(L-lactide-co-L-lysine), poly(4-hydroxy-L-proline ester), and combinations thereof.
  • the degradable polyesters may include a PEG conjugation to form a PEGylated polymer.
  • the polynucleotides, primary constructs, and/or the mmRNA of the present invention may be encapsulated in a therapeutic nanoparticle.
  • Therapeutic nanoparticles may be formulated by methods described herein and known in the art such as, but not limited to, International Pub Nos. WO2010005740, WO2010030763, WO2010005721, WO2010005723, WO2012054923, US Pub. Nos. US20110262491, US20100104645, US20100087337, US20100068285, US20110274759, US20100068286 and US20120288541 and U.S. Pat. Nos.
  • therapeutic polymer nanoparticles may be identified by the methods described in US Pub No. US20120140790, herein incorporated by reference in its entirety.
  • the therapeutic nanoparticle may be formulated for sustained release.
  • sustained release refers to a pharmaceutical composition or compound that conforms to a release rate over a specific period of time. The period of time may include, but is not limited to, hours, days, weeks, months and years.
  • the sustained release nanoparticle may comprise a polymer and a therapeutic agent such as, but not limited to, the polynucleotides, primary constructs, and mmRNA of the present invention (see International Pub No. 2010075072 and US Pub No. US20100216804, US20110217377 and US20120201859, each of which is herein incorporated by reference in their entirety).
  • the therapeutic nanoparticles may be formulated to be target specific.
  • the thereapeutic nanoparticles may include a corticosteroid (see International Pub. No. WO2011084518; herein incorporated by reference in its entirety).
  • the therapeutic nanoparticles may be formulated to be cancer specific.
  • the therapeutic nanoparticles may be formulated in nanoparticles described in International Pub No. WO2008121949, WO2010005726, WO2010005725, WO2011084521 and US Pub No. US20100069426, US20120004293 and US20100104655, each of which is herein incorporated by reference in their entirety.
  • the nanoparticles of the present invention may comprise a polymeric matrix.
  • the nanoparticle may comprise two or more polymers such as, but not limited to, polyethylenes, polycarbonates, polyanhydrides, polyhydroxyacids, polypropylfumerates, polycaprolactones, polyamides, polyacetals, polyethers, polyesters, poly(orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polystyrenes, polyamines, polylysine, poly(ethylene imine), poly(serine ester), poly(L-lactide-co-L-lysine), poly(4-hydroxy-L-proline ester) or combinations thereof.
  • the therapeutic nanoparticle comprises a diblock copolymer.
  • the diblock copolymer may include PEG in combination with a polymer such as, but not limited to, polyethylenes, polycarbonates, polyanhydrides, polyhydroxyacids, polypropylfumerates, polycaprolactones, polyamides, polyacetals, polyethers, polyesters, poly(orthoesters), polycyanoacrylates, polyvinyl alcohols, polyurethanes, polyphosphazenes, polyacrylates, polymethacrylates, polycyanoacrylates, polyureas, polystyrenes, polyamines, polylysine, poly(ethylene imine), poly(serine ester), poly(L-lactide-co-L-lysine), poly(4-hydroxy-L-proline ester) or combinations thereof
  • a polymer such as, but not limited to, polyethylenes, polycarbonates, polyanhydrides, polyhydroxyacids, polypropylfumerates,
  • the therapeutic nanoparticle comprises a PLGA-PEG block copolymer (see US Pub. No. US20120004293 and U.S. Pat. No. 8,236,330, each of which is herein incorporated by reference in their entirety).
  • the therapeutic nanoparticle is a stealth nanoparticle comprising a diblock copolymer of PEG and PLA or PEG and PLGA (see U.S. Pat. No. 8,246,968 and International Publication No. WO2012166923, each of which is herein incorporated by reference in its entirety).
  • the therapeutic nanoparticle may comprise a multiblock copolymer (See e.g., U.S. Pat. Nos. 8,263,665 and 8,287,910; each of which is herein incorporated by reference in its entirety).
  • the block copolymers described herein may be included in a polyion complex comprising a non-polymeric micelle and the block copolymer.
  • a polyion complex comprising a non-polymeric micelle and the block copolymer.
  • the therapeutic nanoparticle may comprise at least one acrylic polymer.
  • Acrylic polymers include but are not limited to, acrylic acid, methacrylic acid, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, amino alkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), polycyanoacrylates and combinations thereof
  • the therapeutic nanoparticles may comprise at least one cationic polymer described herein and/or known in the art.
  • the therapeutic nanoparticles may comprise at least one amine-containing polymer such as, but not limited to polylysine, polyethylene imine, poly(amidoamine) dendrimers, poly(beta-amino esters) (See e.g., U.S. Pat. No. 8,287,849; herein incorporated by reference in its entirety) and combinations thereof.
  • amine-containing polymer such as, but not limited to polylysine, polyethylene imine, poly(amidoamine) dendrimers, poly(beta-amino esters) (See e.g., U.S. Pat. No. 8,287,849; herein incorporated by reference in its entirety) and combinations thereof.
  • the therapeutic nanoparticles may comprise at least one degradable polyester which may contain polycationic side chains.
  • Degradable polyesters include, but are not limited to, poly(serine ester), poly(L-lactide-co-L-lysine), poly(4-hydroxy-L-proline ester), and combinations thereof.
  • the degradable polyesters may include a PEG conjugation to form a PEGylated polymer.
  • the therapeutic nanoparticle may include a conjugation of at least one targeting ligand.
  • the targeting ligand may be any ligand known in the art such as, but not limited to, a monoclonal antibody. (Kirpotin et al, Cancer Res. 2006 66:6732-6740; herein incorporated by reference in its entirety).
  • the therapeutic nanoparticle may be formulated in an aqueous solution which may be used to target cancer (see International Pub No. WO2011084513 and US Pub No. US20110294717, each of which is herein incorporated by reference in their entirety).
  • the polynucleotides, primary constructs, or mmRNA may be encapsulated in, linked to and/or associated with synthetic nanocarriers.
  • Synthetic nanocarriers include, but are not limited to, those described in International Pub. Nos. WO2010005740, WO2010030763, WO201213501, WO2012149252, WO2012149255, WO2012149259, WO2012149265, WO2012149268, WO2012149282, WO2012149301, WO2012149393, WO2012149405, WO2012149411, WO2012149454 and WO2013019669, and US Pub. Nos.
  • the synthetic nanocarriers may be formulated using methods known in the art and/or described herein. As a non-limiting example, the synthetic nanocarriers may be formulated by the methods described in International Pub Nos. WO2010005740, WO2010030763 and WO201213501 and US Pub. Nos. US20110262491, US20100104645, US20100087337 and US2012024422, each of which is herein incorporated by reference in their entirety. In another embodiment, the synthetic nanocarrier formulations may be lyophilized by methods described in International Pub. No. WO2011072218 and U.S. Pat. No. 8,211,473; each of which is herein incorporated by reference in their entirety.
  • the synthetic nanocarriers may contain reactive groups to release the polynucleotides, primary constructs and/or mmRNA described herein (see International Pub. No. WO20120952552 and US Pub No. US20120171229, each of which is herein incorporated by reference in their entirety).
  • the synthetic nanocarriers may contain an immunostimulatory agent to enhance the immune response from delivery of the synthetic nanocarrier.
  • the synthetic nanocarrier may comprise a Th1 immunostimulatory agent which may enhance a Th1-based response of the immune system (see International Pub No. WO2010123569 and US Pub. No. US20110223201, each of which is herein incorporated by reference in its entirety).
  • the synthetic nanocarriers may be formulated for targeted release.
  • the synthetic nanocarrier is formulated to release the polynucleotides, primary constructs and/or mmRNA at a specified pH and/or after a desired time interval.
  • the synthetic nanoparticle may be formulated to release the polynucleotides, primary constructs and/or mmRNA after 24 hours and/or at a pH of 4.5 (see International Pub. Nos. WO2010138193 and WO2010138194 and US Pub Nos. US20110020388 and US20110027217, each of which is herein incorporated by reference in their entireties).
  • the synthetic nanocarriers may be formulated for controlled and/or sustained release of the polynucleotides, primary constructs and/or mmRNA described herein.
  • the synthetic nanocarriers for sustained release may be formulated by methods known in the art, described herein and/or as described in International Pub No. WO2010138192 and US Pub No. 20100303850, each of which is herein incorporated by reference in their entirety.
  • the synthetic nanocarrier may be formulated for use as a vaccine.
  • the synthetic nanocarrier may encapsulate at least one polynucleotide, primary construct and/or mmRNA which encode at least one antigen.
  • the synthetic nanocarrier may include at least one antigen and an excipient for a vaccine dosage form (see International Pub No. WO2011150264 and US Pub No. US20110293723, each of which is herein incorporated by reference in their entirety).
  • a vaccine dosage form may include at least two synthetic nanocarriers with the same or different antigens and an excipient (see International Pub No. WO2011150249 and US Pub No.
  • the vaccine dosage form may be selected by methods described herein, known in the art and/or described in International Pub No. WO2011150258 and US Pub No. US20120027806, each of which is herein incorporated by reference in their entirety).
  • the synthetic nanocarrier may comprise at least one polynucleotide, primary construct and/or mmRNA which encodes at least one adjuvant.
  • the adjuvant may comprise dimethyldioctadecylammonium-bromide, dimethyldioctadecylammonium-chloride, dimethyldioctadecylammonium-phosphate or dimethyldioctadecylammonium-acetate (DDA) and an apolar fraction or part of said apolar fraction of a total lipid extract of a mycobacterium (See e.g, U.S. Pat. No. 8,241,610; herein incorporated by reference in its entirety).
  • the synthetic nanocarrier may comprise at least one polynucleotide, primary construct and/or mmRNA and an adjuvant.
  • the synthetic nanocarrier comprising and adjuvant may be formulated by the methods described in International Pub No. WO2011150240 and US Pub No. US20110293700, each of which is herein incorporated by reference in its entirety.
  • the synthetic nanocarrier may encapsulate at least one polynucleotide, primary construct and/or mmRNA which encodes a peptide, fragment or region from a virus.
  • the synthetic nanocarrier may include, but is not limited to, the nanocarriers described in International Pub No. WO2012024621, WO201202629, WO2012024632 and US Pub No. US20120064110, US20120058153 and US20120058154, each of which is herein incorporated by reference in their entirety.
  • the synthetic nanocarrier may be coupled to a polynucleotide, primary construct or mmRNA which may be able to trigger a humoral and/or cytotoxic T lymphocyte (CTL) response (See e.g., International Publication No. WO2013019669, herein incorporated by reference in its entirety).
  • CTL cytotoxic T lymphocyte
  • the nanoparticle may be optimized for oral administration.
  • the nanoparticle may comprise at least one cationic biopolymer such as, but not limited to, chitosan or a derivative thereof.
  • the nanoparticle may be formulated by the methods described in U.S. Pub. No. 20120282343; herein incorporated by reference in its entirety.
  • the polynucleotide, primary construct, and mmRNA of the invention can be formulated using natural and/or synthetic polymers.
  • Non-limiting examples of polymers which may be used for delivery include, but are not limited to, DYNAMIC POLYCONJUGATE® (Arrowhead Reasearch Corp., Pasadena, Calif.) formulations from MIRUS® Bio (Madison, Wis.) and Roche Madison (Madison, Wis.), PHASERXTM polymer formulations such as, without limitation, SMARTT POLYMER TECHNOLOGYTM (PHASERX®, Seattle, Wash.), DMRI/DOPE, poloxamer, VAXFECTIN® adjuvant from Vical (San Diego, Calif.), chitosan, cyclodextrin from Calando Pharmaceuticals (Pasadena, Calif.), dendrimers and poly(lactic-co-glycolic acid) (PLGA) polymers.
  • DYNAMIC POLYCONJUGATE®
  • RONDELTM RNAi/Oligonucleotide Nanoparticle Delivery
  • PHASERX® pH responsive co-block polymers
  • chitosan formulation includes a core of positively charged chitosan and an outer portion of negatively charged substrate (U.S. Pub. No. 20120258176; herein incorporated by reference in its entirety).
  • Chitosan includes, but is not limited to N-trimethyl chitosan, mono-N-carboxymethyl chitosan (MCC), N-palmitoyl chitosan (NPCS), EDTA-chitosan, low molecular weight chitosan, chitosan derivatives, or combinations thereof
  • the polymers used in the present invention have undergone processing to reduce and/or inhibit the attachement of unwanted substances such as, but not limited to, bacteria, to the surface of the polymer.
  • the polymer may be processed by methods known and/or described in the art and/or described in International Pub. No. WO2012150467, herein incorporated by reference in its entirety.
  • PLGA formulations include, but are not limited to, PLGA injectable depots (e.g., ELIGARD® which is formed by dissolving PLGA in 66% N-methyl-2-pyrrolidone (NMP) and the remainder being aqueous solvent and leuprolide. Once injected, the PLGA and leuprolide peptide precipitates into the subcutaneous space).
  • PLGA injectable depots e.g., ELIGARD® which is formed by dissolving PLGA in 66% N-methyl-2-pyrrolidone (NMP) and the remainder being aqueous solvent and leuprolide. Once injected, the PLGA and leuprolide peptide precipitates into the subcutaneous space).
  • NMP N-methyl-2-pyrrolidone
  • the polymer complex On binding to the hepatocyte and entry into the endosome, the polymer complex disassembles in the low-pH environment, with the polymer exposing its positive charge, leading to endosomal escape and cytoplasmic release of the siRNA from the polymer.
  • the polymer Through replacement of the N-acetylgalactosamine group with a mannose group, it was shown one could alter targeting from asialoglycoprotein receptor-expressing hepatocytes to sinusoidal endothelium and Kupffer cells.
  • Another polymer approach involves using transferrin-targeted cyclodextrin-containing polycation nanoparticles.
  • the polymer formulation can permit the sustained or delayed release of polynucleotide, primary construct, or mmRNA (e.g., following intramuscular or subcutaneous injection).
  • the altered release profile for the polynucleotide, primary construct, or mmRNA can result in, for example, translation of an encoded protein over an extended period of time.
  • the polymer formulation may also be used to increase the stability of the polynucleotide, primary construct, or mmRNA.
  • Biodegradable polymers have been previously used to protect nucleic acids other than mmRNA from degradation and been shown to result in sustained release of payloads in vivo (Rozema et al., Proc Natl Acad Sci USA.
  • the pharmaceutical compositions may be sustained release formulations.
  • the sustained release formulations may be for subcutaneous delivery.
  • Sustained release formulations may include, but are not limited to, PLGA microspheres, ethylene vinyl acetate (EVAc), poloxamer, GELSITE® (Nanotherapeutics, Inc. Alachua, Fla.), HYLENEX® (Halozyme Therapeutics, San Diego Calif.), surgical sealants such as fibrinogen polymers (Ethicon Inc. Cornelia, Ga.), TISSELL® (Baxter International, Inc Deerfield, Ill.), PEG-based sealants, and COSEAL® (Baxter International, Inc Deerfield, Ill.).
  • modified mRNA may be formulated in PLGA microspheres by preparing the PLGA microspheres with tunable release rates (e.g., days and weeks) and encapsulating the modified mRNA in the PLGA microspheres while maintaining the integrity of the modified mRNA during the encapsulation process.
  • EVAc are non-biodegradeable, biocompatible polymers which are used extensively in pre-clinical sustained release implant applications (e.g., extended release products Ocusert a pilocarpine ophthalmic insert for glaucoma or progestasert a sustained release progesterone intrauterine deivce; transdermal delivery systems Testoderm, Duragesic and Selegiline; catheters).
  • Poloxamer F-407 NF is a hydrophilic, non-ionic surfactant triblock copolymer of polyoxyethylene-polyoxypropylene-polyoxyethylene having a low viscosity at temperatures less than 5° C. and forms a solid gel at temperatures greater than 15° C.
  • PEG-based surgical sealants comprise two synthetic PEG components mixed in a delivery device which can be prepared in one minute, seals in 3 minutes and is reabsorbed within 30 days.
  • GELSITE® and natural polymers are capable of in-situ gelation at the site of administration. They have been shown to interact with protein and peptide therapeutic candidates through ionic ineraction to provide a stabilizing effect.
  • Polymer formulations can also be selectively targeted through expression of different ligands as exemplified by, but not limited by, folate, transferrin, and N-acetylgalactosamine (GalNAc) (Benoit et al., Biomacromolecules. 2011 12:2708-2714; Rozema et al., Proc Natl Acad Sci USA. 2007 104:12982-12887; Davis, Mol. Pharm. 2009 6:659-668; Davis, Nature 2010 464:1067-1070; each of which is herein incorporated by reference in its entirety).
  • GalNAc N-acetylgalactosamine
  • the modified nucleic acid, and mmRNA of the invention may be formulated with or in a polymeric compound.
  • the polymer may include at least one polymer such as, but not limited to, polyethenes, polyethylene glycol (PEG), poly(1-lysine)(PLL), PEG grafted to PLL, cationic lipopolymer, biodegradable cationic lipopolymer, polyethyleneimine (PEI), cross-linked branched poly(alkylene imines), a polyamine derivative, a modified poloxamer, a biodegradable polymer, elastic biodegradable polymer, biodegradable block copolymer, biodegradable random copolymer, biodegradable polyester copolymer, biodegradable polyester block copolymer, biodegradable polyester block random copolymer, multiblock copolymers, linear biodegradable copolymer, poly[ ⁇ -(4-aminobutyl)-L-glycolic acid) (PAGA), bio
  • the modified nucleic acid or mmRNA of the invention may be formulated with the polymeric compound of PEG grafted with PLL as described in U.S. Pat. No. 6,177,274; herein incorporated by reference in its entirety.
  • the formulation may be used for transfecting cells in vitro or for in vivo delivery of the modified nucleic acid and mmRNA.
  • the modified nucleic acid and mmRNA may be suspended in a solution or medium with a cationic polymer, in a dry pharmaceutical composition or in a solution that is capable of being dried as described in U.S. Pub. Nos. 20090042829 and 20090042825; each of which are herein incorporated by reference in their entireties.
  • the polynucleotides, primary constructs or mmRNA of the invention may be formulated with a PLGA-PEG block copolymer (see US Pub. No. US20120004293 and U.S. Pat. No. 8,236,330, herein incorporated by reference in their entireties) or PLGA-PEG-PLGA block copolymers (See U.S. Pat. No. 6,004,573, herein incorporated by reference in its entirety).
  • the polynucleotides, primary constructs or mmRNA of the invention may be formulated with a diblock copolymer of PEG and PLA or PEG and PLGA (see U.S. Pat. No. 8,246,968, herein incorporated by reference in its entirety).
  • a polyamine derivative may be used to deliver nucleic acids or to treat and/or prevent a disease or to be included in an implantable or injectable device (U.S. Pub. No. 20100260817 herein incorporated by reference in its entirety).
  • a pharmaceutical composition may include the modified nucleic acids and mmRNA and the polyamine derivative described in U.S. Pub. No. 20100260817 (the contents of which are incorporated herein by reference in its entirety.
  • polynucleotides, primary constructs and mmRNA of the present invention may be delivered using a polyaminde polymer such as, but not limited to, a polymer comprising a 1,3-dipolar addition polymer prepared by combining a carbohydrate diazide monomer with a dilkyne unite comprising oligoamines (U.S. Pat. No. 8,236,280; herein incorporated by reference in its entirety).
  • a polyaminde polymer such as, but not limited to, a polymer comprising a 1,3-dipolar addition polymer prepared by combining a carbohydrate diazide monomer with a dilkyne unite comprising oligoamines (U.S. Pat. No. 8,236,280; herein incorporated by reference in its entirety).
  • the polynucleotides, primary constructs or mmRNA of the present invention may be formulated with at least one polymer and/or derivatives thereof described in International Publication Nos. WO2011115862, WO2012082574 and WO2012068187 and U.S. Pub. No. 20120283427, each of which are herein incorporated by reference in their entireties.
  • the modified nucleic acid or mmRNA of the present invention may be formulated with a polymer of formula Z as described in WO2011115862, herein incorporated by reference in its entirety.
  • the modified nucleic acid or mmRNA may be formulated with a polymer of formula Z, Z′ or Z′′ as described in International Pub. Nos.
  • WO2012082574 or WO2012068187 and U.S. Pub. No. 2012028342 each of which are herein incorporated by reference in their entireties.
  • the polymers formulated with the modified RNA of the present invention may be synthesized by the methods described in International Pub. Nos. WO2012082574 or WO2012068187, each of which are herein incorporated by reference in their entireties.
  • the polynucleotides, primary constructs or mmRNA of the invention may be formulated with at least one acrylic polymer.
  • Acrylic polymers include but are not limited to, acrylic acid, methacrylic acid, acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, amino alkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), polycyanoacrylates and combinations thereof
  • Formulations of polynucleotides, primary constructs or mmRNA of the invention may include at least one amine-containing polymer such as, but not limited to polylysine, polyethylene imine, poly(amidoamine) dendrimers or combinations thereof
  • the modified nucleic acid or mmRNA of the invention may be formulated in a pharmaceutical compound including a poly(alkylene imine), a biodegradable cationic lipopolymer, a biodegradable block copolymer, a biodegradable polymer, or a biodegradable random copolymer, a biodegradable polyester block copolymer, a biodegradable polyester polymer, a biodegradable polyester random copolymer, a linear biodegradable copolymer, PAGA, a biodegradable cross-linked cationic multi-block copolymer or combinations thereof.
  • the biodegradable cationic lipopolymer may be made by methods known in the art and/or described in U.S. Pat.
  • the poly(alkylene imine) may be made using methods known in the art and/or as described in U.S. Pub. No. 20100004315, herein incorporated by reference in its entirety.
  • the biodegradabale polymer, biodegradable block copolymer, the biodegradable random copolymer, biodegradable polyester block copolymer, biodegradable polyester polymer, or biodegradable polyester random copolymer may be made using methods known in the art and/or as described in U.S. Pat. Nos.
  • the linear biodegradable copolymer may be made using methods known in the art and/or as described in U.S. Pat. No. 6,652,886.
  • the PAGA polymer may be made using methods known in the art and/or as described in U.S. Pat. No. 6,217,912 herein incorporated by reference in its entirety.
  • the PAGA polymer may be copolymerized to form a copolymer or block copolymer with polymers such as but not limited to, poly-L-lysine, polyargine, polyornithine, histones, avidin, protamines, polylactides and poly(lactide-co-glycolides).
  • the biodegradable cross-linked cationic multi-block copolymers may be made my methods known in the art and/or as described in U.S. Pat. No. 8,057,821 or U.S. Pub. No. 2012009145 each of which are herein incorporated by reference in their entireties.
  • the multi-block copolymers may be synthesized using linear polyethyleneimine (LPEI) blocks which have distinct patterns as compared to branched polyethyleneimines.
  • LPEI linear polyethyleneimine
  • the composition or pharmaceutical composition may be made by the methods known in the art, described herein, or as described in U.S. Pub. No. 20100004315 or U.S. Pat. Nos. 6,267,987 and 6,217,912 each of which are herein incorporated by reference in their entireties.
  • the polynucleotides, primary constructs, and mmRNA of the invention may be formulated with at least one degradable polyester which may contain polycationic side chains.
  • Degradable polyesters include, but are not limited to, poly(serine ester), poly(L-lactide-co-L-lysine), poly(4-hydroxy-L-proline ester), and combinations thereof.
  • the degradable polyesters may include a PEG conjugation to form a PEGylated polymer.
  • the polynucleotides, primary construct, mmRNA of the invention may be formulated with at least one crosslinkable polyester.
  • Crosslinkable polyesters include those known in the art and described in US Pub. No. 20120269761, herein incorporated by reference in its entirety.
  • the polymers described herein may be conjugated to a lipid-terminating PEG.
  • PLGA may be conjugated to a lipid-terminating PEG forming PLGA-DSPE-PEG.
  • PEG conjugates for use with the present invention are described in International Publication No. WO2008103276, herein incorporated by reference in its entirety.
  • the polymers may be conjugated using a ligand conjugate such as, but not limited to, the conjugates described in U.S. Pat. No. 8,273,363, herein incorporated by reference in its entirety.
  • the modified RNA described herein may be conjugated with another compound.
  • conjugates are described in U.S. Pat. Nos. 7,964,578 and 7,833,992, each of which are herein incorporated by reference in their entireties.
  • modified RNA of the present invention may be conjugated with conjugates of formula I-122 as described in U.S. Pat. Nos. 7,964,578 and 7,833,992, each of which are herein incorporated by reference in their entireties.
  • the polynucleotides, primary constructs and/or mmRNA described herein may be conjugated with a metal such as, but not limited to, gold. (See e.g., Giljohann et al. Journ. Amer. Chem. Soc.
  • polynucleotides, primary constructs and/or mmRNA described herein may be conjugated and/or encapsulated in gold-nanoparticles.
  • a gene delivery composition may include a nucleotide sequence and a poloxamer.
  • the modified nucleic acid and mmRNA of the present inveition may be used in a gene delivery composition with the poloxamer described in U.S. Pub. No. 20100004313.
  • the polymer formulation of the present invention may be stabilized by contacting the polymer formulation, which may include a cationic carrier, with a cationic lipopolymer which may be covalently linked to cholesterol and polyethylene glycol groups.
  • the polymer formulation may be contacted with a cationic lipopolymer using the methods described in U.S. Pub. No. 20090042829 herein incorporated by reference in its entirety.
  • the cationic carrier may include, but is not limited to, polyethylenimine, poly(trimethylenimine), poly(tetramethylenimine), polypropylenimine, aminoglycoside-polyamine, dideoxy-diamino-b-cyclodextrin, spermine, spermidine, poly(2-dimethylamino)ethyl methacrylate, poly(lysine), poly(histidine), poly(arginine), cationized gelatin, dendrimers, chitosan, 1,2-Dioleoyl-3-Trimethylammonium-Propane(DOTAP), N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTMA), 1-[2-(oleoyloxy)ethyl]-2-oleyl-3-(2-hydroxyethyl)imidazolinium chloride (DOTIM), 2,3-dioleyloxy-
  • the polynucleotides, primary constructs and/or mmRNA of the invention may be formulated in a polyplex of one or more polymers (U.S. Pub. No. 20120237565 and 20120270927; each of which is herein incorporated by reference in its entirety).
  • the polyplex comprises two or more cationic polymers.
  • the catioinic polymer may comprise a poly(ethylene imine) (PEI) such as linear PEI.
  • the polynucleotide, primary construct, and mmRNA of the invention can also be formulated as a nanoparticle using a combination of polymers, lipids, and/or other biodegradable agents, such as, but not limited to, calcium phosphate.
  • Components may be combined in a core-shell, hybrid, and/or layer-by-layer architecture, to allow for fine-tuning of the nanoparticle so to delivery of the polynucleotide, primary construct and mmRNA may be enhanced (Wang et al., Nat Mater. 2006 5:791-796; Fuller et al., Biomaterials. 2008 29:1526-1532; DeKoker et al., Adv Drug Deliv Rev.
  • the nanoparticle may comprise a plurality of polymers such as, but not limited to hydrophilic-hydrophobic polymers (e.g., PEG-PLGA), hydrophobic polymers (e.g., PEG) and/or hydrophilic polymers (International Pub. No. WO20120225129; herein incorporated by reference in its entirety).
  • hydrophilic-hydrophobic polymers e.g., PEG-PLGA
  • hydrophobic polymers e.g., PEG
  • hydrophilic polymers International Pub. No. WO20120225129
  • Biodegradable calcium phosphate nanoparticles in combination with lipids and/or polymers have been shown to deliver polynucleotides, primary constructs and mmRNA in vivo.
  • a lipid coated calcium phosphate nanoparticle which may also contain a targeting ligand such as anisamide, may be used to deliver the polynucleotide, primary construct and mmRNA of the present invention.
  • a targeting ligand such as anisamide
  • calcium phosphate with a PEG-polyanion block copolymer may be used to delivery polynucleotides, primary constructs and mmRNA (Kazikawa et al., J Contr Rel. 2004 97:345-356; Kazikawa et al., J Contr Rel. 2006 111:368-370; herein incorporated by reference in its entirety).
  • a PEG-charge-conversional polymer (Pitella et al., Biomaterials. 2011 32:3106-3114) may be used to form a nanoparticle to deliver the polynucleotides, primary constructs and mmRNA of the present invention.
  • the PEG-charge-conversional polymer may improve upon the PEG-polyanion block copolymers by being cleaved into a polycation at acidic pH, thus enhancing endosomal escape.
  • core-shell nanoparticles have additionally focused on a high-throughput approach to synthesize cationic cross-linked nanogel cores and various shells (Siegwart et al., Proc Natl Acad Sci USA. 2011 108:12996-13001).
  • the complexation, delivery, and internalization of the polymeric nanoparticles can be precisely controlled by altering the chemical composition in both the core and shell components of the nanoparticle.
  • the core-shell nanoparticles may efficiently deliver siRNA to mouse hepatocytes after they covalently attach cholesterol to the nanoparticle.
  • a hollow lipid core comprising a middle PLGA layer and an outer neutral lipid layer containg PEG may be used to delivery of the polynucleotide, primary construct and mmRNA of the present invention.
  • a luciferease-expressing tumor it was determined that the lipid-polymer-lipid hybrid nanoparticle significantly suppressed luciferase expression, as compared to a conventional lipoplex (Shi et al, Angew Chem Int Ed. 2011 50:7027-7031; herein incorporated by reference in its entirety).
  • the lipid nanoparticles may comprise a core of the modified nucleic acid molecules disclosed herein and a polymer shell.
  • the polymer shell may be any of the polymers described herein and are known in the art.
  • the polymer shell may be used to protect the modified nucleic acids in the core.
  • Core-shell nanoparticles for use with the modified nucleic acid molecules of the present invention are described and may be formed by the methods described in U.S. Pat. No. 8,313,777 herein incorporated by reference in its entirety.
  • the core-shell nanoparticles may comprise a core of the modified nucleic acid molecules disclosed herein and a polymer shell.
  • the polymer shell may be any of the polymers described herein and are known in the art.
  • the polymer shell may be used to protect the modified nucleic acid molecules in the core.
  • the core-shell nanoparticle may be used to treat an eye disease or disorder (See e.g. US Publication No. 20120321719, herein incorporated by reference in its entirety).
  • the polymer used with the formulations described herein may be a modified polymer (such as, but not limited to, a modified polyacetal) as described in International Publication No. WO2011120053, herein incorporated by reference in its entirety.
  • the polynucleotide, primary construct, and mmRNA of the invention can be formulated with peptides and/or proteins in order to increase transfection of cells by the polynucleotide, primary construct, or mmRNA.
  • peptides such as, but not limited to, cell penetrating peptides and proteins and peptides that enable intracellular delivery may be used to deliver pharmaceutical formulations.
  • a non-limiting example of a cell penetrating peptide which may be used with the pharmaceutical formulations of the present invention includes a cell-penetrating peptide sequence attached to polycations that facilitates delivery to the intracellular space, e.g., HIV-derived TAT peptide, penetratins, transportans, or hCT derived cell-penetrating peptides (see, e.g., Caron et al., Mol. Ther. 3(3):310-8 (2001); Langel, Cell-Penetrating Peptides: Processes and Applications (CRC Press, Boca Raton Fla., 2002); El-Andaloussi et al., Curr. Pharm. Des.
  • compositions can also be formulated to include a cell penetrating agent, e.g., liposomes, which enhance delivery of the compositions to the intracellular space.
  • a cell penetrating agent e.g., liposomes
  • Polynucleotides, primary constructs, and mmRNA of the invention may be complexed to peptides and/or proteins such as, but not limited to, peptides and/or proteins from Aileron Therapeutics (Cambridge, Mass.) and Permeon Biologics (Cambridge, Mass.) in order to enable intracellular delivery (Cronican et al., ACS Chem. Biol. 2010 5:747-752; McNaughton et al., Proc. Natl. Acad. Sci. USA 2009 106:6111-6116; Sawyer, Chem Biol Drug Des. 2009 73:3-6; Verdine and Hilinski, Methods Enzymol. 2012; 503:3-33; all of which are herein incorporated by reference in its entirety).
  • Aileron Therapeutics Cambridge, Mass.
  • Permeon Biologics Cambridge, Mass.
  • the cell-penetrating polypeptide may comprise a first domain and a second domain.
  • the first domain may comprise a supercharged polypeptide.
  • the second domain may comprise a protein-binding partner.
  • protein-binding partner includes, but are not limited to, antibodies and functional fragments thereof, scaffold proteins, or peptides.
  • the cell-penetrating polypeptide may further comprise an intracellular binding partner for the protein-binding partner.
  • the cell-penetrating polypeptide may be capable of being secreted from a cell where the polynucleotide, primary construct, or mmRNA may be introduced.
  • Formulations of the including peptides or proteins may be used to increase cell transfection by the polynucleotide, primary construct, or mmRNA, alter the biodistribution of the polynucleotide, primary construct, or mmRNA (e.g., by targeting specific tissues or cell types), and/or increase the translation of encoded protein.
  • a polynucleotide, primary construct, or mmRNA alter the biodistribution of the polynucleotide, primary construct, or mmRNA (e.g., by targeting specific tissues or cell types), and/or increase the translation of encoded protein.
  • the polynucleotide, primary construct, and mmRNA of the invention can be transfected ex vivo into cells, which are subsequently transplanted into a subject.
  • the pharmaceutical compositions may include red blood cells to deliver modified RNA to liver and myeloid cells, virosomes to deliver modified RNA in virus-like particles (VLPs), and electroporated cells such as, but not limited to, from MAXCYTE® (Gaithersburg, Md.) and from ERYTECH® (Lyon, France) to deliver modified RNA. Examples of use of red blood cells, viral particles and electroporated cells to deliver payloads other than mmRNA have been documented (Godfrin et al., Expert Opin Biol Ther.
  • polynucleotides, primary constructs and mmRNA may be delivered in synthetic VLPs synthesized by the methods described in International Pub No. WO2011085231 and US Pub No. 20110171248, each of which are herein incorporated by reference in their entireties.
  • Cell-based formulations of the polynucleotide, primary construct, and mmRNA of the invention may be used to ensure cell transfection (e.g., in the cellular carrier), alter the biodistribution of the polynucleotide, primary construct, or mmRNA (e.g., by targeting the cell carrier to specific tissues or cell types), and/or increase the translation of encoded protein.
  • nucleic acid into a cell
  • non-viral mediated techniques include, but are not limited to, electroporation, calcium phosphate mediated transfer, nucleofection, sonoporation, heat shock, magnetofection, liposome mediated transfer, microinjection, microprojectile mediated transfer (nanoparticles), cationic polymer mediated transfer (DEAE-dextran, polyethylenimine, polyethylene glycol (PEG) and the like) or cell fusion.
  • Sonoporation or cellular sonication
  • sound e.g., ultrasonic frequencies
  • Sonoporation methods are known to those in the art and are used to deliver nucleic acids in vivo (Yoon and Park, Expert Opin Drug Deliv. 2010 7:321-330; Postema and Gilja, Curr Pharm Biotechnol. 2007 8:355-361; Newman and Bettinger, Gene Ther. 2007 14:465-475; all herein incorporated by reference in their entirety).
  • Electroporation techniques are also well known in the art and are used to deliver nucleic acids in vivo and clinically (Andre et al., Curr Gene Ther. 2010 10:267-280; Chiarella et al., Curr Gene Ther. 2010 10:281-286; Hojman, Curr Gene Ther. 2010 10:128-138; all herein incorporated by reference in their entirety).
  • polynucleotides, primary constructs or mmRNA may be delivered by electroporation as described in Example 8.
  • the intramuscular or subcutaneous localized injection of polynucleotide, primary construct, or mmRNA of the invention can include hyaluronidase, which catalyzes the hydrolysis of hyaluronan.
  • hyaluronidase catalyzes the hydrolysis of hyaluronan.
  • hyaluronidase By catalyzing the hydrolysis of hyaluronan, a constituent of the interstitial barrier, hyaluronidase lowers the viscosity of hyaluronan, thereby increasing tissue permeability (Frost, Expert Opin. Drug Deliv. (2007) 4:427-440; herein incorporated by reference in its entirety). It is useful to speed their dispersion and systemic distribution of encoded proteins produced by transfected cells.
  • the hyaluronidase can be used to increase the number of cells exposed to a polynucleotide, primary construct, or mmRNA of the invention administered intramus
  • the polynucleotide, primary construct or mmRNA of the invention may be encapsulated within and/or absorbed to a nanoparticle mimic.
  • a nanoparticle mimic can mimic the delivery function organisms or particles such as, but not limited to, pathogens, viruses, bacteria, fungus, parasites, prions and cells.
  • the polynucleotide, primary construct or mmRNA of the invention may be encapsulated in a non-viron particle which can mimic the delivery function of a virus (see International Pub. No. WO2012006376 herein incorporated by reference in its entirety).
  • the polynucleotides, primary constructs or mmRNA of the invention can be attached or otherwise bound to at least one nanotube such as, but not limited to, rosette nanotubes, rosette nanotubes having twin bases with a linker, carbon nanotubes and/or single-walled carbon nanotubes,
  • the polynucleotides, primary constructs or mmRNA may be bound to the nanotubes through forces such as, but not limited to, steric, ionic, covalent and/or other forces.
  • the nanotube can release one or more polynucleotides, primary constructs or mmRNA into cells.
  • the size and/or the surface structure of at least one nanotube may be altered so as to govern the interaction of the nanotubes within the body and/or to attach or bind to the polynucleotides, primary constructs or mmRNA disclosed herein.
  • the building block and/or the functional groups attached to the building block of the at least one nanotube may be altered to adjust the dimensions and/or properties of the nanotube.
  • the length of the nanotubes may be altered to hinder the nanotubes from passing through the holes in the walls of normal blood vessels but still small enough to pass through the larger holes in the blood vessels of tumor tissue.
  • At least one nanotube may also be coated with delivery enhancing compounds including polymers, such as, but not limited to, polyethylene glycol.
  • delivery enhancing compounds including polymers, such as, but not limited to, polyethylene glycol.
  • at least one nanotube and/or the polynucleotides, primary constructs or mmRNA may be mixed with pharmaceutically acceptable excipients and/or delivery vehicles.
  • the polynucleotides, primary constructs or mmRNA are attached and/or otherwise bound to at least one rosette nanotube.
  • the rosette nanotubes may be formed by a process known in the art and/or by the process described in International Publication No. WO2012094304, herein incorporated by reference in its entirety.
  • At least one polynucleotide, primary construct and/or mmRNA may be attached and/or otherwise bound to at least one rosette nanotube by a process as described in International Publication No.
  • rosette nanotubes or modules forming rosette nanotubes are mixed in aqueous media with at least one polynucleotide, primary construct and/or mmRNA under conditions which may cause at least one polynucleotide, primary construct or mmRNA to attach or otherwise bind to the rosette nanotubes.
  • the polynucleotides, primary constructs or mmRNA may be attached to and/or otherwise bound to at least one carbon nanotube.
  • the polynucleotides, primary constructs or mmRNA may be bound to a linking agent and the linked agent may be bound to the carbon nanotube (See e.g., U.S. Pat. No. 8,246,995; herein incorporated by reference in its entirety).
  • the carbon nanotube may be a single-walled nanotube (See e.g., U.S. Pat. No. 8,246,995; herein incorporated by reference in its entirety).

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US13/791,910 US20140010861A1 (en) 2012-04-02 2013-03-09 Modified polynucleotides for the production of proteins associated with human disease
US14/105,221 US20140255468A1 (en) 2012-04-02 2013-12-13 Modified polynucleotides encoding programmed cell death 1
US14/105,210 US20150044277A1 (en) 2012-04-02 2013-12-13 Modified polynucleotides encoding caspase 3
US14/105,214 US20140171485A1 (en) 2012-04-02 2013-12-13 Modified polynucleotides encoding cd28 molecule
US14/105,224 US9220755B2 (en) 2012-04-02 2013-12-13 Modified polynucleotides for the production of proteins associated with blood and lymphatic disorders
US14/105,217 US20140255467A1 (en) 2012-04-02 2013-12-13 Modified polynucleotides encoding cytotoxic t-lymphocyte-associated protein 4
US14/171,235 US20140206755A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating arylsulfatase a protein deficiency
US14/171,242 US20140200264A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating carboxypeptidase n, polypeptide 1 protein deficiency
US14/171,249 US9089604B2 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating galactosylceramidase protein deficiency
US14/171,226 US9061059B2 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating protein deficiency
US14/508,631 US20150050354A1 (en) 2012-04-02 2014-10-07 Modified polynucleotides for the treatment of otic diseases and conditions
US15/060,707 US9782462B2 (en) 2012-04-02 2016-03-04 Modified polynucleotides for the production of proteins associated with human disease
US15/440,523 US20180086807A1 (en) 2012-04-02 2017-02-23 Modified polynucleotides for the production of proteins associated with human disease
US16/665,985 US20210115101A1 (en) 2012-04-02 2019-10-28 Modified polynucleotides for the production of proteins associated with human disease
US18/634,220 US20240327476A1 (en) 2012-04-02 2024-04-12 Modified polynucleotides for the production of proteins associated with human disease

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US14/105,224 Continuation US9220755B2 (en) 2012-04-02 2013-12-13 Modified polynucleotides for the production of proteins associated with blood and lymphatic disorders
US14/105,214 Continuation US20140171485A1 (en) 2012-04-02 2013-12-13 Modified polynucleotides encoding cd28 molecule
US14/105,221 Continuation US20140255468A1 (en) 2012-04-02 2013-12-13 Modified polynucleotides encoding programmed cell death 1
US14/105,210 Continuation US20150044277A1 (en) 2012-04-02 2013-12-13 Modified polynucleotides encoding caspase 3
US14/105,217 Continuation US20140255467A1 (en) 2012-04-02 2013-12-13 Modified polynucleotides encoding cytotoxic t-lymphocyte-associated protein 4
US14/171,226 Continuation US9061059B2 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating protein deficiency
US14/171,235 Continuation US20140206755A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating arylsulfatase a protein deficiency
US14/171,242 Continuation US20140200264A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating carboxypeptidase n, polypeptide 1 protein deficiency
US14/171,249 Continuation US9089604B2 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating galactosylceramidase protein deficiency
US14/508,631 Continuation-In-Part US20150050354A1 (en) 2012-04-02 2014-10-07 Modified polynucleotides for the treatment of otic diseases and conditions
US15/060,707 Continuation US9782462B2 (en) 2012-04-02 2016-03-04 Modified polynucleotides for the production of proteins associated with human disease

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US13/791,922 Active 2033-05-02 US8999380B2 (en) 2012-04-02 2013-03-09 Modified polynucleotides for the production of biologics and proteins associated with human disease
US14/103,188 Active US9220792B2 (en) 2012-04-02 2013-12-11 Modified polynucleotides encoding aquaporin-5
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US14/105,217 Abandoned US20140255467A1 (en) 2012-04-02 2013-12-13 Modified polynucleotides encoding cytotoxic t-lymphocyte-associated protein 4
US14/105,208 Active 2034-05-10 US9675668B2 (en) 2012-04-02 2013-12-13 Modified polynucleotides encoding hepatitis A virus cellular receptor 2
US14/105,210 Abandoned US20150044277A1 (en) 2012-04-02 2013-12-13 Modified polynucleotides encoding caspase 3
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US14/105,214 Abandoned US20140171485A1 (en) 2012-04-02 2013-12-13 Modified polynucleotides encoding cd28 molecule
US14/106,988 Active US9301993B2 (en) 2012-04-02 2013-12-16 Modified polynucleotides encoding apoptosis inducing factor 1
US14/107,079 Active US9149506B2 (en) 2012-04-02 2013-12-16 Modified polynucleotides encoding septin-4
US14/107,029 Abandoned US20140113959A1 (en) 2012-04-02 2013-12-16 Modified polynucleotides encoding caspase 6
US14/106,957 Active US9050297B2 (en) 2012-04-02 2013-12-16 Modified polynucleotides encoding aryl hydrocarbon receptor nuclear translocator
US14/171,249 Active US9089604B2 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating galactosylceramidase protein deficiency
US14/171,226 Active US9061059B2 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating protein deficiency
US14/170,910 Abandoned US20140155474A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating cystic fibrosis
US14/170,751 Abandoned US20140200263A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating galactosidase, alpha protein deficiency
US14/170,897 Abandoned US20140155472A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating argininosuccinate synthase 1 protein deficiency
US14/170,747 Abandoned US20140194494A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating protein deficiency
US14/171,119 Abandoned US20140179771A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating dolichyl-phosphate (udp-n-acetylglucosamine) n-acetylglucosaminephosphotransferase 1 (glcnac-1-p transferase) protein deficiency
US14/170,914 Abandoned US20140155475A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating lipase a, lysosomal acid, cholesterol esterase protein deficiency
US14/170,744 Abandoned US20140148502A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating protein deficiency
US14/170,903 Abandoned US20140155473A1 (en) 2012-04-02 2014-02-03 Modified glucosidase, beta, acid polynucleotides for treating protein deficiency
US14/171,242 Abandoned US20140200264A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating carboxypeptidase n, polypeptide 1 protein deficiency
US14/171,235 Abandoned US20140206755A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating arylsulfatase a protein deficiency
US14/878,400 Expired - Fee Related US9814760B2 (en) 2012-04-02 2015-10-08 Modified polynucleotides for the production of biologics and proteins associated with human disease
US15/403,517 Active US10493167B2 (en) 2012-04-02 2017-01-11 In vivo production of proteins
US15/425,645 Active US10463751B2 (en) 2012-04-02 2017-02-06 Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
US15/789,138 Abandoned US20190240351A1 (en) 2012-04-02 2017-10-20 Modified polynucleotides for the production of proteins
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US16/442,168 Active US10583203B2 (en) 2012-04-02 2019-06-14 In vivo production of proteins
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US16/811,648 Abandoned US20210077634A1 (en) 2012-04-02 2020-03-06 In vivo production of proteins
US17/020,522 Abandoned US20210299278A1 (en) 2012-04-02 2020-09-14 Modified polynucleotides for the production of biologics and proteins associated with human disease
US18/161,598 Pending US20240131193A1 (en) 2012-04-02 2023-01-30 Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
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US14/103,188 Active US9220792B2 (en) 2012-04-02 2013-12-11 Modified polynucleotides encoding aquaporin-5
US14/104,591 Active US9233141B2 (en) 2012-04-02 2013-12-12 Modified polynucleotides for the production of proteins associated with blood and lymphatic disorders
US14/104,585 Abandoned US20140193482A1 (en) 2012-04-02 2013-12-12 Modified polynucleotides encoding v-myc avian myelocytomatosis viral oncogene homolog
US14/104,556 Active US9114113B2 (en) 2012-04-02 2013-12-12 Modified polynucleotides encoding citeD4
US14/104,568 Active US9095552B2 (en) 2012-04-02 2013-12-12 Modified polynucleotides encoding copper metabolism (MURR1) domain containing 1
US14/105,217 Abandoned US20140255467A1 (en) 2012-04-02 2013-12-13 Modified polynucleotides encoding cytotoxic t-lymphocyte-associated protein 4
US14/105,208 Active 2034-05-10 US9675668B2 (en) 2012-04-02 2013-12-13 Modified polynucleotides encoding hepatitis A virus cellular receptor 2
US14/105,210 Abandoned US20150044277A1 (en) 2012-04-02 2013-12-13 Modified polynucleotides encoding caspase 3
US14/105,221 Abandoned US20140255468A1 (en) 2012-04-02 2013-12-13 Modified polynucleotides encoding programmed cell death 1
US14/105,214 Abandoned US20140171485A1 (en) 2012-04-02 2013-12-13 Modified polynucleotides encoding cd28 molecule
US14/106,988 Active US9301993B2 (en) 2012-04-02 2013-12-16 Modified polynucleotides encoding apoptosis inducing factor 1
US14/107,079 Active US9149506B2 (en) 2012-04-02 2013-12-16 Modified polynucleotides encoding septin-4
US14/107,029 Abandoned US20140113959A1 (en) 2012-04-02 2013-12-16 Modified polynucleotides encoding caspase 6
US14/106,957 Active US9050297B2 (en) 2012-04-02 2013-12-16 Modified polynucleotides encoding aryl hydrocarbon receptor nuclear translocator
US14/171,249 Active US9089604B2 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating galactosylceramidase protein deficiency
US14/171,226 Active US9061059B2 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating protein deficiency
US14/170,910 Abandoned US20140155474A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating cystic fibrosis
US14/170,751 Abandoned US20140200263A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating galactosidase, alpha protein deficiency
US14/170,897 Abandoned US20140155472A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating argininosuccinate synthase 1 protein deficiency
US14/170,747 Abandoned US20140194494A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating protein deficiency
US14/171,119 Abandoned US20140179771A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating dolichyl-phosphate (udp-n-acetylglucosamine) n-acetylglucosaminephosphotransferase 1 (glcnac-1-p transferase) protein deficiency
US14/170,914 Abandoned US20140155475A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating lipase a, lysosomal acid, cholesterol esterase protein deficiency
US14/170,744 Abandoned US20140148502A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating protein deficiency
US14/170,903 Abandoned US20140155473A1 (en) 2012-04-02 2014-02-03 Modified glucosidase, beta, acid polynucleotides for treating protein deficiency
US14/171,242 Abandoned US20140200264A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating carboxypeptidase n, polypeptide 1 protein deficiency
US14/171,235 Abandoned US20140206755A1 (en) 2012-04-02 2014-02-03 Modified polynucleotides for treating arylsulfatase a protein deficiency
US14/878,400 Expired - Fee Related US9814760B2 (en) 2012-04-02 2015-10-08 Modified polynucleotides for the production of biologics and proteins associated with human disease
US15/403,517 Active US10493167B2 (en) 2012-04-02 2017-01-11 In vivo production of proteins
US15/425,645 Active US10463751B2 (en) 2012-04-02 2017-02-06 Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
US15/789,138 Abandoned US20190240351A1 (en) 2012-04-02 2017-10-20 Modified polynucleotides for the production of proteins
US15/790,246 Active US10772975B2 (en) 2012-04-02 2017-10-23 Modified Polynucleotides for the production of biologics and proteins associated with human disease
US16/442,168 Active US10583203B2 (en) 2012-04-02 2019-06-14 In vivo production of proteins
US16/577,734 Active 2034-06-10 US11564998B2 (en) 2012-04-02 2019-09-20 Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
US16/811,648 Abandoned US20210077634A1 (en) 2012-04-02 2020-03-06 In vivo production of proteins
US17/020,522 Abandoned US20210299278A1 (en) 2012-04-02 2020-09-14 Modified polynucleotides for the production of biologics and proteins associated with human disease
US18/161,598 Pending US20240131193A1 (en) 2012-04-02 2023-01-30 Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
US18/760,652 Pending US20250018062A1 (en) 2012-04-02 2024-07-01 Modified polynucleotides for the production of biologics and proteins associated with human disease

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Cited By (182)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140037560A1 (en) * 2011-02-01 2014-02-06 Isp Investments Inc. Novel peptides involved in the scf c-kit signaling pathway and compositions comprising same
US9061021B2 (en) 2010-11-30 2015-06-23 Shire Human Genetic Therapies, Inc. mRNA for use in treatment of human genetic diseases
US9095552B2 (en) 2012-04-02 2015-08-04 Moderna Therapeutics, Inc. Modified polynucleotides encoding copper metabolism (MURR1) domain containing 1
US9107886B2 (en) 2012-04-02 2015-08-18 Moderna Therapeutics, Inc. Modified polynucleotides encoding basic helix-loop-helix family member E41
WO2015160893A1 (en) * 2014-04-15 2015-10-22 Applied Genetic Technologies Corporation Codon optimized nucleic acid encoding a retinitis pigmentosa gtpase regulator (rpgr)
US9181321B2 (en) 2013-03-14 2015-11-10 Shire Human Genetic Therapies, Inc. CFTR mRNA compositions and related methods and uses
US9181319B2 (en) 2010-08-06 2015-11-10 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
US9186372B2 (en) 2011-12-16 2015-11-17 Moderna Therapeutics, Inc. Split dose administration
WO2016004113A1 (en) * 2014-06-30 2016-01-07 Biogen Ma Inc. Optimized factor ix gene
WO2015196130A3 (en) * 2014-06-19 2016-03-03 Moderna Therapeutics, Inc. Alternative nucleic acid molecules and uses thereof
US9283287B2 (en) 2012-04-02 2016-03-15 Moderna Therapeutics, Inc. Modified polynucleotides for the production of nuclear proteins
WO2016049487A1 (en) * 2014-09-26 2016-03-31 Dow Agrosciences Llc Heterologous expression of glycine n-acyltransferase proteins
WO2016054554A1 (en) * 2014-10-03 2016-04-07 University Of Massachusetts Heterologous targeting peptide grafted aavs
US20160120893A1 (en) * 2013-06-21 2016-05-05 President And Fellows Of Harvard College Methods and compositions relating to modulation of the permeability of the blood brain barrier
WO2015196128A3 (en) * 2014-06-19 2016-05-19 Moderna Therapeutics, Inc. Alternative nucleic acid molecules and uses thereof
US9364414B2 (en) 2011-02-01 2016-06-14 Isp Investments Inc. Method to protect skin from ultraviolet radiation using novel peptides involved in the improvement of microparasol organization in keratinocytes
WO2016086088A3 (en) * 2014-11-25 2016-08-18 Northwestern University Wound healing through sirt1 overexpression
US9512456B2 (en) 2012-08-14 2016-12-06 Modernatx, Inc. Enzymes and polymerases for the synthesis of RNA
US9522176B2 (en) 2013-10-22 2016-12-20 Shire Human Genetic Therapies, Inc. MRNA therapy for phenylketonuria
WO2016205027A1 (en) * 2015-06-15 2016-12-22 Oklahoma Medical Research Foundation Ubiquitin interacting motif peptides as therapeutics
US9533047B2 (en) 2011-03-31 2017-01-03 Modernatx, Inc. Delivery and formulation of engineered nucleic acids
WO2017019756A1 (en) * 2015-07-28 2017-02-02 Lankaneu Institute For Medical Research Methods and compositions for the treatment of immunomodulatory diseases and disorders
US9572897B2 (en) 2012-04-02 2017-02-21 Modernatx, Inc. Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
US9597380B2 (en) 2012-11-26 2017-03-21 Modernatx, Inc. Terminally modified RNA
US9629804B2 (en) 2013-10-22 2017-04-25 Shire Human Genetic Therapies, Inc. Lipid formulations for delivery of messenger RNA
US9668980B2 (en) 2014-07-02 2017-06-06 Rana Therapeutics, Inc. Encapsulation of messenger RNA
US9701965B2 (en) 2010-10-01 2017-07-11 Modernatx, Inc. Engineered nucleic acids and methods of use thereof
US9713641B2 (en) 2015-10-01 2017-07-25 Potenza Therapeutics, Inc. Anti-TIGIT antigen-binding proteins and methods of use thereof
US9738718B2 (en) 2015-01-28 2017-08-22 Glaxosmithkline Intellectual Property Development Limited ICOS binding proteins
WO2017173256A1 (en) * 2016-04-01 2017-10-05 Kite Pharma, Inc. Chimeric antigen and t cell receptors and methods of use
US9850269B2 (en) 2014-04-25 2017-12-26 Translate Bio, Inc. Methods for purification of messenger RNA
WO2018009814A1 (en) * 2016-07-08 2018-01-11 The Trustees Of The University Of Pennsylvania Methods and compositions for treatment of disorders and diseases involving rdh12
US9943595B2 (en) 2014-12-05 2018-04-17 Translate Bio, Inc. Messenger RNA therapy for treatment of articular disease
US9957499B2 (en) 2013-03-14 2018-05-01 Translate Bio, Inc. Methods for purification of messenger RNA
WO2018102317A1 (en) * 2016-11-29 2018-06-07 The Regents Of The University Of California Modulation of p53 for the treatment of cancer
US10023626B2 (en) 2013-09-30 2018-07-17 Modernatx, Inc. Polynucleotides encoding immune modulating polypeptides
US10022455B2 (en) 2014-05-30 2018-07-17 Translate Bio, Inc. Biodegradable lipids for delivery of nucleic acids
WO2018165482A1 (en) * 2017-03-10 2018-09-13 Memorial Sloan Kettering Cancer Center Methods for treatment or prevention of leukemia
US10077439B2 (en) 2013-03-15 2018-09-18 Modernatx, Inc. Removal of DNA fragments in mRNA production process
US10087247B2 (en) 2013-03-14 2018-10-02 Translate Bio, Inc. Methods and compositions for delivering mRNA coded antibodies
WO2018191322A1 (en) * 2017-04-12 2018-10-18 Tempo Bioscience, Inc. Biosensors for cellular osmolarity
US10106800B2 (en) 2005-09-28 2018-10-23 Biontech Ag Modification of RNA, producing an increased transcript stability and translation efficiency
US20180320176A1 (en) * 2015-11-05 2018-11-08 The General Hospital Corporation Intrathecal delivery of nucleic acid sequences encoding abcd1 for treatment of adrenomyeloneuropathy
US10130649B2 (en) 2013-03-15 2018-11-20 Translate Bio, Inc. Synergistic enhancement of the delivery of nucleic acids via blended formulations
US10138507B2 (en) 2013-03-15 2018-11-27 Modernatx, Inc. Manufacturing methods for production of RNA transcripts
US10138213B2 (en) 2014-06-24 2018-11-27 Translate Bio, Inc. Stereochemically enriched compositions for delivery of nucleic acids
WO2018217982A1 (en) * 2017-05-26 2018-11-29 The Wistar Institute Of Anatomy And Biology Dtert vaccines and methods of treatment using the same
US10144942B2 (en) 2015-10-14 2018-12-04 Translate Bio, Inc. Modification of RNA-related enzymes for enhanced production
WO2018226931A1 (en) * 2017-06-07 2018-12-13 David Weiner Mage-a vaccines and methods of treatment using the same
US10155031B2 (en) 2012-11-28 2018-12-18 Biontech Rna Pharmaceuticals Gmbh Individualized vaccines for cancer
WO2018232149A1 (en) * 2017-06-14 2018-12-20 The Trustees Of The University Of Pennsylvania Gene therapy for ocular disorders
US10172924B2 (en) 2015-03-19 2019-01-08 Translate Bio, Inc. MRNA therapy for pompe disease
WO2019009979A1 (en) * 2017-07-06 2019-01-10 The Medical College Of Wisconsin, Inc. NEW IN VITRO AND IN VIVO ENRICHMENT STRATEGY TARGETING CSH-DERIVED LYMPHOCYTES TRANSDUCED BY A VECTOR FOR DISEASE THERAPY
CN109385487A (zh) * 2018-09-11 2019-02-26 浙江省食品药品检验研究院 贵细中草药西洋参的重组酶介导扩增恒温检测方法及试剂盒
WO2019051047A1 (en) * 2017-09-07 2019-03-14 University Of Florida Research Foundation, Inc. CHIMERIC ANTIGEN RECEPTOR T-LYMPHOCYTES EXPRESSING THE INTERLEUKIN-8 RECEPTOR
US10238754B2 (en) 2011-06-08 2019-03-26 Translate Bio, Inc. Lipid nanoparticle compositions and methods for MRNA delivery
US10245229B2 (en) 2012-06-08 2019-04-02 Translate Bio, Inc. Pulmonary delivery of mRNA to non-lung target cells
WO2019028281A3 (en) * 2017-08-02 2019-04-11 The Regents Of The University Of California OPTIMIZED PEPTIDES FOR TARGETING HUMAN NERFS AND THEIR USE IN GUIDED SURGERY THROUGH THE IMAGING, DIAGNOSTICS AND ADMINISTRATION OF THERAPEUTIC AGENTS
US10258698B2 (en) 2013-03-14 2019-04-16 Modernatx, Inc. Formulation and delivery of modified nucleoside, nucleotide, and nucleic acid compositions
US10266843B2 (en) 2016-04-08 2019-04-23 Translate Bio, Inc. Multimeric coding nucleic acid and uses thereof
US20190117796A1 (en) * 2016-05-27 2019-04-25 Transcriptx, Inc. Treatment of primary ciliary dyskinesia with synthetic messenger rna
WO2019079338A1 (en) * 2017-10-16 2019-04-25 Centro de Investigaciones Energeticas, Medioambientales Y Tecnologicas, O.A., M.P. LENTIVIRAL VECTORS FOR PKLR ADMINISTRATION TO TREAT PYRUVATE KINASE DEFICIENCY
WO2019113123A1 (en) * 2017-12-04 2019-06-13 Precithera, Inc. TGF-ß RECEPTOR FUSION PROTEINS AND OTHER TGF-ß ANTAGONISTS FOR REDUCING TGF-ß SIGNALING
WO2019118760A1 (en) * 2017-12-13 2019-06-20 Inovio Pharmaceuticals, Inc. Cancer vaccines targeting mesothelin and uses thereof
US10329349B2 (en) 2017-07-27 2019-06-25 Iteos Therapeutics Sa Anti-TIGIT antibodies
US10370431B2 (en) 2013-02-15 2019-08-06 Bioverativ Therapeutics Inc. Optimized factor VIII gene
US10385088B2 (en) 2013-10-02 2019-08-20 Modernatx, Inc. Polynucleotide molecules and uses thereof
US10385380B2 (en) 2014-10-02 2019-08-20 The Regents Of The University Of California Personalized protease assay to measure protease activity in neoplasms
US10407683B2 (en) 2014-07-16 2019-09-10 Modernatx, Inc. Circular polynucleotides
US10428156B2 (en) 2014-09-05 2019-10-01 Abbvie Stemcentrx Llc Anti-MFI2 antibodies and methods of use
WO2019210325A1 (en) * 2018-04-27 2019-10-31 Rocket Pharmaceuticals, Ltd. Gene therapy for cns degeneration
WO2019213434A1 (en) * 2018-05-02 2019-11-07 The Trustees Of The University Of Pennsylvania Compositions and methods of phospholipase a2 receptor chimeric autoantibody receptor t cells
US10485884B2 (en) 2012-03-26 2019-11-26 Biontech Rna Pharmaceuticals Gmbh RNA formulation for immunotherapy
US10494636B2 (en) 2016-05-18 2019-12-03 Modernatx, Inc. Polynucleotides encoding α-galactosidase A for the treatment of Fabry disease
US10558661B2 (en) 2016-11-29 2020-02-11 Sap Se Query plan generation based on table adapter
US20200061211A1 (en) * 2018-08-22 2020-02-27 Blueallele, Llc Methods for delivering gene editing reagents to cells within organs
US10576168B2 (en) * 2015-12-16 2020-03-03 Ucl Business Ltd Treatment of lysosomal storage diseases
US10576166B2 (en) 2009-12-01 2020-03-03 Translate Bio, Inc. Liver specific delivery of messenger RNA
US10584321B2 (en) 2015-02-13 2020-03-10 University Of Massachusetts Compositions and methods for transient delivery of nucleases
US10590161B2 (en) 2013-03-15 2020-03-17 Modernatx, Inc. Ion exchange purification of mRNA
US10597456B2 (en) 2016-04-01 2020-03-24 Amgen Inc. Chimeric receptors and methods of use thereof
US10640766B2 (en) 2017-04-12 2020-05-05 Tempo Bioscience, Inc. Biosensors for chloride ions
US10689450B2 (en) 2016-04-01 2020-06-23 Kite Pharma, Inc BCMA binding molecules and methods of use thereof
US10711270B2 (en) 2014-10-03 2020-07-14 University Of Massachusetts High efficiency library-identified AAV vectors
US10738355B2 (en) 2011-05-24 2020-08-11 Tron-Translationale Onkologie An Der Universitätsmedizin Der Johannes Gutenberg-Universität Mainz Ggmbh Individualized vaccines for cancer
US20200255859A1 (en) * 2017-07-31 2020-08-13 Reflection Biotechnologies Limited Cellular models of and therapies for ocular diseases
US10780052B2 (en) 2013-10-22 2020-09-22 Translate Bio, Inc. CNS delivery of MRNA and uses thereof
WO2020198685A1 (en) * 2019-03-27 2020-10-01 Sigilon Therapeutics, Inc. Compositions, devices and methods for treating fabry disease
WO2020219766A1 (en) * 2019-04-24 2020-10-29 The Trustees Of The University Of Pennsylvania Compositions useful in treatment of rett syndrome
US10835583B2 (en) 2016-06-13 2020-11-17 Translate Bio, Inc. Messenger RNA therapy for the treatment of ornithine transcarbamylase deficiency
US10849920B2 (en) 2015-10-05 2020-12-01 Modernatx, Inc. Methods for therapeutic administration of messenger ribonucleic acid drugs
WO2020257731A1 (en) * 2019-06-20 2020-12-24 The Trustees Of The University Of Pennsylvania Compositions and methods for treatment of maple syrup urine disease
US10927383B2 (en) * 2016-06-30 2021-02-23 Ethris Gmbh Cas9 mRNAs
WO2021067687A1 (en) * 2019-10-03 2021-04-08 Board Of Regents, The University Of Texas System Vcx/y peptides and use thereof
US20210123077A1 (en) * 2019-04-27 2021-04-29 Ocugen, Inc. Adeno-associated virus vector mediated gene therapy for ophthalmic diseases
WO2021087282A1 (en) * 2019-10-30 2021-05-06 Amicus Therapeutics, Inc. Recombinant cdkl5 proteins, gene therapy and production methods
WO2021097088A1 (en) * 2019-11-12 2021-05-20 University Of Virginia Patent Foundation Optidicer construct for age-related macular degeneration
US11027025B2 (en) 2013-07-11 2021-06-08 Modernatx, Inc. Compositions comprising synthetic polynucleotides encoding CRISPR related proteins and synthetic sgRNAs and methods of use
US11065316B2 (en) 2015-08-28 2021-07-20 Immatics Biotechnologies Gmbh Peptides and T cells for use in immunother[[r]]apeutic treatment of various cancers
US11078247B2 (en) 2016-05-04 2021-08-03 Curevac Ag RNA encoding a therapeutic protein
US11090392B2 (en) 2015-12-14 2021-08-17 The Trustees Of The University Of Pennsylvania Gene therapy for ocular disorders
US11103596B2 (en) 2015-05-11 2021-08-31 Ucl Business Plc Fabry disease gene therapy
WO2021163695A3 (en) * 2020-02-14 2021-09-23 H. Lee Moffitt Cancer Center And Research Institute, Inc. Novel t cell receptors (tcrs) that react to neoantigens
US11142570B2 (en) 2017-02-17 2021-10-12 Bristol-Myers Squibb Company Antibodies to alpha-synuclein and uses thereof
WO2021211614A1 (en) * 2020-04-14 2021-10-21 University Of Florida Research Foundation, Incorporated Aav-based gene therapies for treatment of autoimmune diseases
US11156617B2 (en) 2015-02-12 2021-10-26 BioNTech RNA Pharmaceuticals GbmH Predicting T cell epitopes useful for vaccination
WO2021222118A1 (en) * 2020-04-27 2021-11-04 The Trustees Of The University Of Pennsylvania Compositions useful in treatment of cdkl5 deficiency disorder (cdd)
US11167043B2 (en) 2017-12-20 2021-11-09 Translate Bio, Inc. Composition and methods for treatment of ornithine transcarbamylase deficiency
US11173190B2 (en) 2017-05-16 2021-11-16 Translate Bio, Inc. Treatment of cystic fibrosis by delivery of codon-optimized mRNA encoding CFTR
US11174500B2 (en) 2018-08-24 2021-11-16 Translate Bio, Inc. Methods for purification of messenger RNA
US11173120B2 (en) 2014-09-25 2021-11-16 Biontech Rna Pharmaceuticals Gmbh Stable formulations of lipids and liposomes
US11191849B2 (en) 2016-06-30 2021-12-07 Arbutus Biopharma Corporation Compositions and methods for delivering messenger RNA
US20210395751A1 (en) * 2018-10-31 2021-12-23 The University Of Sydney Compositions and methods for treating viral infections
US11222711B2 (en) 2013-05-10 2022-01-11 BioNTech SE Predicting immunogenicity of T cell epitopes
US20220010281A1 (en) * 2018-10-29 2022-01-13 Ottawa Hospital Research Institute Genetically-engineered mesenchymal stem cells overexpressing aoah and uses thereof
US11224642B2 (en) 2013-10-22 2022-01-18 Translate Bio, Inc. MRNA therapy for argininosuccinate synthetase deficiency
WO2022026516A1 (en) * 2020-07-29 2022-02-03 The Board Of Regents Of The University Of Texas System Transgene cassettes, aav vectors, and aav viral vectors for expression of human codon-optimized cstb
WO2022031708A1 (en) * 2020-08-03 2022-02-10 Prevail Therapeutics, Inc. Aav vectors encoding parkin and uses thereof
US11254936B2 (en) 2012-06-08 2022-02-22 Translate Bio, Inc. Nuclease resistant polynucleotides and uses thereof
US11253605B2 (en) 2017-02-27 2022-02-22 Translate Bio, Inc. Codon-optimized CFTR MRNA
US20220071915A1 (en) * 2016-05-18 2022-03-10 Modernatx, Inc. Polynucleotides encoding citrin for the treatment of citrullinemia type 2
US11286501B2 (en) 2016-04-20 2022-03-29 Centro De Investigaciones Energeticas, Medioambientales Y Tecnologicas O.A, M.P. Methods of treating or preventing pyruvate kinase deficiency
WO2022072325A1 (en) * 2020-09-29 2022-04-07 NeuExcell Therapeutics Inc. Neurod1 combination vector
US11298426B2 (en) 2003-10-14 2022-04-12 BioNTech SE Recombinant vaccines and use thereof
US20220127318A1 (en) * 2019-01-15 2022-04-28 Cornell University Recombinant lubricins, and compositions and methods for using the same
US11358993B2 (en) 2016-04-15 2022-06-14 Research Institute At Nationwide Children's Hospital Adeno-associated virus vector delivery of B-sarcoglycan and microrna-29 and the treatment of muscular dystrophy
US11377470B2 (en) 2013-03-15 2022-07-05 Modernatx, Inc. Ribonucleic acid purification
WO2022147249A1 (en) * 2020-12-30 2022-07-07 Mayo Foundation For Medical Education And Research Suppression-replacement gene therapy
US11401339B2 (en) 2018-08-23 2022-08-02 Seagen Inc. Anti-TIGIT antibodies
US11434486B2 (en) 2015-09-17 2022-09-06 Modernatx, Inc. Polynucleotides containing a morpholino linker
US11453720B2 (en) 2017-03-30 2022-09-27 Potenza Therapeutics, Inc. Anti-TIGIT antigen-binding proteins and methods of use thereof
WO2022217037A1 (en) * 2021-04-09 2022-10-13 Board Of Regents, The University Of Texas System Compositions and methods for treatment of chronic lung diseases
US20220325255A1 (en) * 2021-03-31 2022-10-13 The Board Of Regents Of The University Of Texas System Compositions and methods for treating viral infections targeting trim7
US11473083B2 (en) 2015-12-21 2022-10-18 Novartis Ag Compositions and methods for decreasing tau expression
WO2022221320A1 (en) * 2021-04-12 2022-10-20 The Regents Of The University Of California Gene therapy for arrhythmogenic right ventricular cardiomyopathy
US11492628B2 (en) 2015-10-07 2022-11-08 BioNTech SE 3′-UTR sequences for stabilization of RNA
US11541107B2 (en) 2015-08-28 2023-01-03 Immatics Biotechnologies Gmbh Peptides and T cells for use in immunotherapeutic treatment of various cancers
US11547765B2 (en) 2016-06-21 2023-01-10 The University Of North Carolina At Chapel Hill Optimized mini-dystrophin genes and expression cassettes and their use
US11555073B2 (en) 2018-12-20 2023-01-17 23Andme, Inc. Anti-CD96 antibodies and methods of use thereof
WO2023019193A1 (en) * 2021-08-11 2023-02-16 The Trustees Of Indiana University Epigenetic modulators for tissue reprogramming
US11603399B2 (en) 2013-03-13 2023-03-14 Modernatx, Inc. Long-lived polynucleotide molecules
TWI796299B (zh) * 2016-08-26 2023-03-21 德商英麥提克生物技術股份有限公司 用於頭頸鱗狀細胞癌和其他癌症免疫治療的新型肽和支架
WO2023049846A1 (en) * 2021-09-24 2023-03-30 The Trustees Of The University Of Pennsylvania Compositions useful for treatment of charcot-marie-tooth disease
US20230112986A1 (en) * 2016-05-18 2023-04-13 Modernatx, Inc. Polynucleotides encoding porphobilinogen deaminase for the treatment of acute intermittent porphyria
US20230175037A1 (en) * 2020-09-11 2023-06-08 Glympse Bio, Inc. Ex vivo protease activity detection for disease detection/diagnostic, staging, monitoring and treatment
US11702483B2 (en) * 2014-04-07 2023-07-18 Minerva Biotechnologies Corporation Method of treating an NME7 expressing cancer with a peptide
US20230265386A1 (en) * 2020-02-21 2023-08-24 Sky Perfect International Limited Methods and compositions for modulating arginine levels in immune cells
US11753461B2 (en) 2016-02-01 2023-09-12 Bioverativ Therapeutics Inc. Optimized factor VIII genes
US20230341397A1 (en) * 2020-09-11 2023-10-26 Montana Molecular Llc Protease biosensors and methods of virus detection
WO2023196539A3 (en) * 2022-04-07 2023-11-23 Aleta Biotherapeutics Inc. Compositions and methods for treatment of cancer
WO2023230003A1 (en) * 2022-05-23 2023-11-30 Yale University Compositions and methods for treating liver disease
US20230405109A1 (en) * 2020-11-11 2023-12-21 City Of Hope Nucleic acids, proteins, and vaccines of sars-cov-2
EP4327829A1 (en) 2022-08-26 2024-02-28 Ethris GmbH Stabilization of lipid or lipidoid nanoparticle suspensions
WO2024042236A1 (en) 2022-08-26 2024-02-29 Ethris Gmbh Stable lipid or lipidoid nanoparticle suspensions
CN117756911A (zh) * 2023-12-26 2024-03-26 无锡佰翱得生物科学股份有限公司 一种溶质载体蛋白urat1及其制备方法和应用
WO2024026336A3 (en) * 2022-07-26 2024-04-11 The Board Of Trustees Of The Leland Stanford Junior University Methods and reagents for detection, quantitation, and genotyping of epstein-barr virus
WO2024097737A1 (en) * 2022-11-01 2024-05-10 Ohio State Innovation Foundation Gene therapy for bves-related disorders
WO2024097772A1 (en) * 2022-11-01 2024-05-10 Lacerta Therapeutics, Inc. Compositions and methods for treatment of friedreich's ataxia
US12037413B2 (en) 2019-02-04 2024-07-16 Minerva Biotechnologies Corporation Anti-NME antibody and method of treating cancer or cancer metastasis
US12049514B2 (en) 2020-06-08 2024-07-30 Minerva Biotechnologies Corporation Anti-NME antibody and method of treating cancer or cancer metastasis
US12109274B2 (en) 2015-09-17 2024-10-08 Modernatx, Inc. Polynucleotides containing a stabilizing tail region
RU2830879C2 (ru) * 2017-12-13 2024-11-26 Иновио Фармасьютикалз, Инк. Мезотелин-нацеленные вакцины от рака и их применение
US12162994B2 (en) 2018-03-02 2024-12-10 Sigilon Therapeutics, Inc. Biocompatible hydrogel capsules and process for preparing same
US12161760B2 (en) 2018-04-04 2024-12-10 Sigilon Therapeutics, Inc. Implantable particles and related methods
US12161729B2 (en) 2021-01-14 2024-12-10 Alume Biosciences, Inc. Methods and compositions for visualizing a ureter in a surgical procedure
US12173307B2 (en) 2020-06-24 2024-12-24 Bioverativ Therapeutics Inc. Methods for the purification of viral vectors
US12195505B2 (en) 2018-11-21 2025-01-14 Translate Bio, Inc. Treatment of cystic fibrosis by delivery of nebulized mRNA encoding CFTR
US12239693B2 (en) 2018-04-27 2025-03-04 The Medical College Of Wisconsin, Inc. Use of lentivector-transduced T-Rapa cells for amelioration of lysosomal storage disorders
WO2025045767A1 (en) 2023-08-25 2025-03-06 Ethris Gmbh Stabilized lipid and lipidoid nanoparticle formulations with specific surfactant properties for enhanced pharmaceutical applications
WO2024226729A3 (en) * 2023-04-26 2025-03-20 Astellas Gene Therapies, Inc. Compositions and methods for opa1 gene therapy
US12258573B2 (en) 2019-08-21 2025-03-25 Research Institute At Nationwide Children's Hospital Adeno-associated virus vector delivery of alpha-sarcoglycan and the treatment of muscular dystrophy
US12263230B2 (en) 2018-01-31 2025-04-01 Research Institute At Nationwide Children's Hospital Gene therapy for limb-girdle muscular dystrophy type 2C
US12270813B2 (en) 2017-06-09 2025-04-08 BioNTech SE Methods for predicting the usefulness of disease specific amino acid modifications for immunotherapy
US12285497B2 (en) 2021-10-15 2025-04-29 Research Institute At Nationwide Children's Hospital Self-complementary adeno-associated virus vector and its use in treatment of muscular dystrophy
WO2025122940A1 (en) * 2023-12-06 2025-06-12 Oyster Point Pharma, Inc. Aav vector encoding diamine oxidase and uses thereof
US12377170B2 (en) 2019-02-26 2025-08-05 Research Institute At Nationwide Children's Hospital Adeno-associated virus vector delivery of β-sarcoglycan and the treatment of muscular dystrophy
US12385034B2 (en) 2016-06-24 2025-08-12 Modernatx, Inc. Methods and apparatus for filtration
US12391928B2 (en) 2018-06-29 2025-08-19 Research Institute At Nationwide Children's Hospital Recombinant adeno-associated virus products and methods for treating limb girdle muscular dystrophy 2A
US12403164B2 (en) 2019-09-30 2025-09-02 Bioverativ Therapeutics Inc. Lentiviral vector formulations
US12415868B1 (en) 2020-06-26 2025-09-16 Minerva Biotechnologies Corporation Anti-NME antibody and method of treating cancer or cancer metastasis
US12453740B2 (en) 2018-09-25 2025-10-28 Emory University Nucleic acids for cell recognition and integration
US12472239B2 (en) 2015-11-16 2025-11-18 Research Institute At Nationwide Children's Hospital Guide RNA for repairing a mutant human titin gene using CRISPR technology

Families Citing this family (650)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9879266B2 (en) 2002-11-14 2018-01-30 Thermo Fisher Scientific Inc. Methods and compositions for selecting siRNA of improved functionality
US9228186B2 (en) 2002-11-14 2016-01-05 Thermo Fisher Scientific Inc. Methods and compositions for selecting siRNA of improved functionality
DE10254601A1 (de) 2002-11-22 2004-06-03 Ganymed Pharmaceuticals Ag Differentiell in Tumoren exprimierte Genprodukte und deren Verwendung
DE102004024617A1 (de) 2004-05-18 2005-12-29 Ganymed Pharmaceuticals Ag Differentiell in Tumoren exprimierte Genprodukte und deren Verwendung
EP1790664A1 (en) 2005-11-24 2007-05-30 Ganymed Pharmaceuticals AG Monoclonal antibodies against claudin-18 for treatment of cancer
US9642912B2 (en) 2006-03-06 2017-05-09 Crescita Therapeutics Inc. Topical formulations for treating skin conditions
US9308181B2 (en) 2006-03-06 2016-04-12 Nuvo Research Inc. Topical formulations, systems and methods
EP3415161A1 (en) 2008-06-26 2018-12-19 Acceleron Pharma Inc. The use of an actriib antagonist for the treatment of anemia
US10236078B2 (en) 2008-11-17 2019-03-19 Veracyte, Inc. Methods for processing or analyzing a sample of thyroid tissue
US8669057B2 (en) 2009-05-07 2014-03-11 Veracyte, Inc. Methods and compositions for diagnosis of thyroid conditions
SI3243526T1 (sl) 2010-07-06 2020-02-28 Glaxosmithkline Biologicals S.A. Dostava RNA za sprožitev večih imunskih poti
HUE026646T2 (en) 2010-07-06 2016-07-28 Glaxosmithkline Biologicals Sa Preferred liposomes containing lipids of PKA value for delivery of RNA
PL2591114T3 (pl) 2010-07-06 2017-08-31 Glaxosmithkline Biologicals Sa Immunizacja dużych ssaków małymi dawkami rna
RS63329B1 (sr) 2010-08-31 2022-07-29 Glaxosmithkline Biologicals Sa Pegilovani lipozomi za isporuku rnk koja kodira imunogen
CN103501803B (zh) 2010-09-22 2015-12-02 科罗拉多大学董事会 Smad7的治疗应用
CN103269713B (zh) 2010-10-11 2016-01-20 诺华有限公司 抗原递送平台
CN103748078B (zh) 2011-06-08 2016-11-09 夏尔人类遗传性治疗公司 可裂解脂质
HUE043894T2 (hu) 2011-06-10 2019-09-30 Bioverativ Therapeutics Inc Koagulációt elõsegítõ vegyületek és alkalmazásuk módszerei
WO2012177647A2 (en) 2011-06-20 2012-12-27 Kerry Lane Mycotoxin diagnostics and methods thereof
CN103649127B (zh) 2011-07-01 2021-03-19 恩格姆生物制药公司 用于代谢病症和疾病治疗的组合物、应用和方法
EP3332802A1 (en) 2011-07-06 2018-06-13 GlaxoSmithKline Biologicals SA Immunogenic combination compositions and uses thereof
US9464124B2 (en) 2011-09-12 2016-10-11 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
DK3682905T3 (da) 2011-10-03 2022-02-28 Modernatx Inc Modificerede nukleosider, nukleotider og nukleinsyrer og anvendelser deraf
WO2013053076A1 (en) 2011-10-10 2013-04-18 Zensun （Shanghai）Science & Technology Limited Compositions and methods for treating heart failure
WO2013075008A1 (en) 2011-11-16 2013-05-23 University Of Florida Research Foundation Inc. Aav dual vector systems for gene therapy
MX382822B (es) 2011-12-05 2025-03-13 Factor Bioscience Inc Metodos y productos para transfeccion de celulas.
US8497124B2 (en) 2011-12-05 2013-07-30 Factor Bioscience Inc. Methods and products for reprogramming cells to a less differentiated state
KR20140126357A (ko) 2012-02-01 2014-10-30 컴퓨젠 엘티디. C1orf32 항체 및 이의 암 치료를 위한 용도
US10322949B2 (en) 2012-03-15 2019-06-18 Flodesign Sonics, Inc. Transducer and reflector configurations for an acoustophoretic device
US10967298B2 (en) 2012-03-15 2021-04-06 Flodesign Sonics, Inc. Driver and control for variable impedence load
US10704021B2 (en) 2012-03-15 2020-07-07 Flodesign Sonics, Inc. Acoustic perfusion devices
US9458450B2 (en) 2012-03-15 2016-10-04 Flodesign Sonics, Inc. Acoustophoretic separation technology using multi-dimensional standing waves
US9745548B2 (en) 2012-03-15 2017-08-29 Flodesign Sonics, Inc. Acoustic perfusion devices
US9752113B2 (en) 2012-03-15 2017-09-05 Flodesign Sonics, Inc. Acoustic perfusion devices
US9950282B2 (en) 2012-03-15 2018-04-24 Flodesign Sonics, Inc. Electronic configuration and control for acoustic standing wave generation
US10689609B2 (en) 2012-03-15 2020-06-23 Flodesign Sonics, Inc. Acoustic bioreactor processes
CA2868030C (en) 2012-03-29 2021-05-25 Shire Human Genetic Therapies, Inc. Lipid-derived neutral nanoparticles
HK1206645A1 (en) 2012-03-29 2016-01-15 Shire Human Genetic Therapies, Inc. Ionizable cationic lipids
US10501513B2 (en) 2012-04-02 2019-12-10 Modernatx, Inc. Modified polynucleotides for the production of oncology-related proteins and peptides
US10737953B2 (en) 2012-04-20 2020-08-11 Flodesign Sonics, Inc. Acoustophoretic method for use in bioreactors
WO2013167153A1 (en) 2012-05-09 2013-11-14 Ganymed Pharmaceuticals Ag Antibodies useful in cancer diagnosis
US9534218B2 (en) * 2012-06-18 2017-01-03 Dow Agrosciences Llc Expression of maize codon optimized proteins in pseudomonas fluorescens
UA116217C2 (uk) 2012-10-09 2018-02-26 Санофі Пептидна сполука як подвійний агоніст рецепторів glp1-1 та глюкагону
EP2913396B1 (en) * 2012-10-29 2018-08-29 Saitama Medical University Method of manufacturing differentiated pluripotent stem cell
BR122019025678B1 (pt) 2012-11-01 2023-04-18 Factor Bioscience Inc Composições que compreendem ácido nucleico que codifica uma proteína de edição gênica
HK1214832A1 (zh) 2012-11-28 2016-08-05 恩格姆生物制药公司 用於代謝病症和疾病治療的組合物和方法
US9290557B2 (en) 2012-11-28 2016-03-22 Ngm Biopharmaceuticals, Inc. Compositions comprising variants and fusions of FGF19 polypeptides
RU2721275C2 (ru) 2012-12-12 2020-05-18 Те Брод Инститьют, Инк. Доставка, конструирование и оптимизация систем, способов и композиций для манипуляции с последовательностями и применения в терапии
WO2014093701A1 (en) 2012-12-12 2014-06-19 The Broad Institute, Inc. Functional genomics using crispr-cas systems, compositions, methods, knock out libraries and applications thereof
EP2931319B1 (en) * 2012-12-13 2019-08-21 ModernaTX, Inc. Modified nucleic acid molecules and uses thereof
WO2014096149A1 (en) 2012-12-21 2014-06-26 Sanofi Exendin-4 Derivatives
US9273107B2 (en) 2012-12-27 2016-03-01 Ngm Biopharmaceuticals, Inc. Uses and methods for modulating bile acid homeostasis and treatment of bile acid disorders and diseases
RU2675514C2 (ru) 2012-12-27 2018-12-19 ЭнДжиЭм БАЙОФАРМАСЬЮТИКАЛЗ, ИНК. Способы модуляции гомеостаза желчных кислот и лечение расстройств и заболеваний, ассоциированных с желчными кислотами
EP2749569A1 (en) 2012-12-28 2014-07-02 Annibale Alessandro Puca Variant of BPIFB4 protein
JP2016504050A (ja) * 2013-01-17 2016-02-12 モデルナ セラピューティクス インコーポレイテッドＭｏｄｅｒｎａ Ｔｈｅｒａｐｅｕｔｉｃｓ，Ｉｎｃ． 細胞表現型の改変のためのシグナルセンサーポリヌクレオチド
US10456448B2 (en) 2013-03-08 2019-10-29 The Regents Of The University Of Colorado, A Body Corporate PTD-SMAD7 therapeutics
US10526655B2 (en) 2013-03-14 2020-01-07 Veracyte, Inc. Methods for evaluating COPD status
US8980864B2 (en) 2013-03-15 2015-03-17 Moderna Therapeutics, Inc. Compositions and methods of altering cholesterol levels
US11976329B2 (en) 2013-03-15 2024-05-07 Veracyte, Inc. Methods and systems for detecting usual interstitial pneumonia
US9944918B2 (en) 2013-03-15 2018-04-17 The United States Of America, As Represented By The Secretary, Dept. Of Health & Human Services Synthetic methylmalonyl-CoA mutase transgene for the treatment of MUT class methylmalonic acidemia (MMA)
EP2968602B1 (en) * 2013-03-15 2017-08-30 The United States of America, as represented by the Secretary, Department of Health and Human Services Synthetic methylmalonyl-coa mutase transgene for the treatment of mut class methylmalonic acidemia (mma)
BR112015021866A2 (pt) 2013-03-15 2017-08-29 Bayer Healthcare Llc Domínios de gla como agentes direcionadores
KR102357275B1 (ko) 2013-05-22 2022-02-03 젠순 (상하이) 사이언스 앤드 테크놀로지 캄파니 리미티드 심부전을 치료하기 위한 뉴레귤린의 연장 방출
EP3725885A1 (en) 2013-06-17 2020-10-21 The Broad Institute, Inc. Functional genomics using crispr-cas systems, compositions methods, screens and applications thereof
US9925144B2 (en) * 2013-07-18 2018-03-27 Mannkind Corporation Heat-stable dry powder pharmaceutical compositions and methods
AU2014296278C1 (en) 2013-07-30 2023-02-02 Genevant Sciences Gmbh Block copolymers and their conjugates or complexes with oligonucleotides
KR102354389B1 (ko) * 2013-08-21 2022-01-20 큐어백 아게 Rna―암호화된 단백질의 발현을 증가시키는 방법
EP3041938A1 (en) 2013-09-03 2016-07-13 Moderna Therapeutics, Inc. Circular polynucleotides
JP2016530294A (ja) 2013-09-03 2016-09-29 モデルナ セラピューティクス インコーポレイテッドＭｏｄｅｒｎａ Ｔｈｅｒａｐｅｕｔｉｃｓ，Ｉｎｃ． キメラポリヌクレオチド
US9745569B2 (en) 2013-09-13 2017-08-29 Flodesign Sonics, Inc. System for generating high concentration factors for low cell density suspensions
EP3052479A4 (en) * 2013-10-02 2017-10-25 Moderna Therapeutics, Inc. Polynucleotide molecules and uses thereof
KR20160067219A (ko) * 2013-10-03 2016-06-13 모더나 세라퓨틱스, 인코포레이티드 저밀도 지단백질 수용체를 암호화하는 폴리뉴클레오타이드
CN113769114A (zh) 2013-10-28 2021-12-10 恩格姆生物制药公司 癌症模型及相关方法
US20160279251A1 (en) * 2013-11-12 2016-09-29 University Of Washington Through Its Center For Commercialization Random copolymer therapeutic agent carriers and assemblies thereof
WO2015074010A2 (en) 2013-11-18 2015-05-21 Beth Israel Deaconess Medical Center, Inc. Compositions and methods for cardiac regeneration
EP3080257A1 (en) 2013-12-12 2016-10-19 The Broad Institute Inc. Compositions and methods of use of crispr-cas systems in nucleotide repeat disorders
CN106536729A (zh) * 2013-12-12 2017-03-22 布罗德研究所有限公司 使用粒子递送组分靶向障碍和疾病的crispr‑cas系统和组合物的递送、用途和治疗应用
US9480731B2 (en) * 2013-12-12 2016-11-01 Medy-Tox, Inc. Long lasting effect of new botulinum toxin formulations
EP3080261B1 (en) 2013-12-12 2019-05-22 The Broad Institute, Inc. Delivery, use and therapeutic applications of the crispr-cas systems and compositions for hbv and viral diseases and disorders
EP4219699A1 (en) 2013-12-12 2023-08-02 The Broad Institute, Inc. Engineering of systems, methods and optimized guide compositions with new architectures for sequence manipulation
US20150167017A1 (en) * 2013-12-13 2015-06-18 Moderna Therapeutics, Inc. Alternative nucleic acid molecules and uses thereof
TW201609795A (zh) 2013-12-13 2016-03-16 賽諾菲公司 作為雙重ｇｌｐ－１／ｇｉｐ受體促效劑的艾塞那肽－４（ｅｘｅｎｄｉｎ－４）胜肽類似物
WO2015086730A1 (en) 2013-12-13 2015-06-18 Sanofi Non-acylated exendin-4 peptide analogues
WO2015086733A1 (en) 2013-12-13 2015-06-18 Sanofi Dual glp-1/glucagon receptor agonists
WO2015086729A1 (en) 2013-12-13 2015-06-18 Sanofi Dual glp-1/gip receptor agonists
GB201322574D0 (en) * 2013-12-19 2014-02-05 Equigerminal Sa Retroviral peptides
CN104758922A (zh) 2014-01-03 2015-07-08 上海泽生科技开发有限公司 纽兰格林制剂的配方
WO2015105955A1 (en) 2014-01-08 2015-07-16 Flodesign Sonics, Inc. Acoustophoresis device with dual acoustophoretic chamber
RU2682335C2 (ru) * 2014-01-17 2019-03-19 Сидарс-Синай Медикал Сентр Рецептор-направленные конструкции и их применение
LT3097122T (lt) 2014-01-24 2020-07-27 Ngm Biopharmaceuticals, Inc. Antikūnai, surišantys beta kloto domeną 2, ir jų panaudojimo būdai
ES2787198T3 (es) * 2014-01-31 2020-10-15 Factor Bioscience Inc ARN sintético para su uso en el tratamiento de la epidermólisis ampollosa distrófica
WO2015130832A1 (en) * 2014-02-25 2015-09-03 The Regents Of The University Of California Agents for enhancement of production of biofuel precursors in microalgae
PT3116900T (pt) * 2014-03-09 2020-10-08 Univ Pennsylvania Composições úteis no tratamento da deficiência de ornitina transcarbamilase (otc)
CN115252823A (zh) * 2014-03-21 2022-11-01 建新公司 用于色素性视网膜炎的基因疗法
DK3122878T3 (en) * 2014-03-24 2019-02-04 Translate Bio Inc MRNA THERAPY FOR TREATMENT OF EYE DISEASES
TW201625669A (zh) 2014-04-07 2016-07-16 賽諾菲公司 衍生自艾塞那肽－４（Ｅｘｅｎｄｉｎ－４）之肽類雙重ＧＬＰ－１／升糖素受體促效劑
TW201625668A (zh) 2014-04-07 2016-07-16 賽諾菲公司 作為胜肽性雙重ｇｌｐ－１／昇糖素受體激動劑之艾塞那肽－４衍生物
TW201625670A (zh) 2014-04-07 2016-07-16 賽諾菲公司 衍生自ｅｘｅｎｄｉｎ－４之雙重ｇｌｐ－１／升糖素受體促效劑
KR101791296B1 (ko) * 2014-04-17 2017-10-27 제주대학교 산학협력단 알츠하이머병 관련 돌연변이 유전자를 포함하는 발현 카세트, 벡터, 및 이를 이용하여 형질전환된 세포주
HUE069802T2 (hu) 2014-04-23 2025-04-28 Modernatx Inc Nukleinsav vakcinák
KR102092225B1 (ko) 2014-04-30 2020-03-23 주식회사 엘지화학 고효율 분비능을 가지는 단백질 분비 인자 및 이를 포함하는 발현 벡터
RU2718248C2 (ru) * 2014-05-14 2020-03-31 Эстев Фармасьютикалс, С.А. Аденоассоциированные вирусные векторы для лечения лизосомных болезней накопления
US10323067B2 (en) * 2014-05-14 2019-06-18 Evorx Technologies, Inc. Methods and compositions for controlling gene expression and treating cancer
WO2015183890A2 (en) 2014-05-28 2015-12-03 Ngm Biopharmaceuticals, Inc. Methods and compositions for the treatment of metabolic disorders and diseases
JP6313478B2 (ja) * 2014-05-30 2018-04-18 アカデミア シニカＡｃａｄｅｍｉａ Ｓｉｎｉｃａ Ｍａｇｅ−ａ３ペプチド標的アプタマー及びその使用
AU2015269333B2 (en) 2014-06-04 2020-05-07 Acceleron Pharma, Inc. Methods and compositions for treatment of disorders with follistatin polypeptides
US10010498B2 (en) 2014-06-04 2018-07-03 Acceleron Pharma Inc. Methods for treatment of amyotrophic lateral sclerosis with follistatin fusion proteins
WO2015191693A2 (en) * 2014-06-10 2015-12-17 Massachusetts Institute Of Technology Method for gene editing
EP3521456B1 (en) * 2014-06-10 2023-01-04 CureVac Manufacturing GmbH Methods and means for enhancing rna production
CA2951153A1 (en) 2014-06-16 2015-12-23 Ngm Biopharmaceuticals, Inc. Methods and uses for modulating bile acid homeostasis and treatment of bile acid disorders and diseases
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
US9744483B2 (en) 2014-07-02 2017-08-29 Flodesign Sonics, Inc. Large scale acoustic separation device
WO2016007909A2 (en) 2014-07-11 2016-01-14 Biostrategies LC Materials and methods for treating disorders associated with sulfatase enzymes
US12297505B2 (en) 2014-07-14 2025-05-13 Veracyte, Inc. Algorithms for disease diagnostics
CA2955250A1 (en) 2014-07-16 2016-01-21 Moderna Therapeutics, Inc. Chimeric polynucleotides
US9957494B2 (en) * 2014-07-25 2018-05-01 Shire Human Genetic Therapies, Inc. Crystal structure of human four-phosphate adaptor protein 2 glycolipid transfer protein like domain
WO2016027842A1 (ja) * 2014-08-20 2016-02-25 和光純薬工業株式会社 幹細胞の分化状態の判定方法及びこれに用いられる新規な分化マーカー
ES2688035T3 (es) 2014-08-29 2018-10-30 Gemoab Monoclonals Gmbh Receptor de antígeno universal que expresa células inmunes para direccionamiento de antígenos múltiples diversos, procedimiento para fabricación del mismo y utilización del mismo para tratamiento de cáncer, infecciones y enfermedades autoinmunes
KR20170093780A (ko) 2014-09-02 2017-08-16 아메리칸 실버, 엘엘씨 보툴리눔 톡신 및 콜로이드 은 입자
KR102586707B1 (ko) 2014-10-01 2023-10-11 더 트러스티스 오브 더 유니버시티 오브 펜실바니아 항원 및 어쥬번트로서 인터류킨-21을 갖는 백신
JOP20200115A1 (ar) * 2014-10-10 2017-06-16 Alnylam Pharmaceuticals Inc تركيبات وطرق لتثبيط التعبير الجيني عن hao1 (حمض أوكسيداز هيدروكسيلي 1 (أوكسيداز جليكولات))
CN105561298A (zh) 2014-10-17 2016-05-11 上海泽生科技开发有限公司 神经调节蛋白用于预防、治疗或延迟射血分数保留的心力衰竭的方法和组合物
JP6949711B2 (ja) 2014-10-23 2021-10-20 エヌジーエム バイオファーマシューティカルス，インコーポレーテッド ペプチドバリアントを含む医薬組成物及びその使用方法
JP6384863B2 (ja) * 2014-10-24 2018-09-05 国立大学法人北海道大学 脂質膜構造体
US20160130567A1 (en) 2014-11-02 2016-05-12 Arcturus Therapeutics, Inc. Messenger una molecules and uses thereof
WO2016073768A1 (en) 2014-11-05 2016-05-12 Veracyte, Inc. Systems and methods of diagnosing idiopathic pulmonary fibrosis on transbronchial biopsies using machine learning and high dimensional transcriptional data
WO2016073900A1 (en) * 2014-11-06 2016-05-12 Case Western Reserve University Compositions and methods of treating usher syndrome iii
US10434144B2 (en) 2014-11-07 2019-10-08 Ngm Biopharmaceuticals, Inc. Methods for treatment of bile acid-related disorders and prediction of clinical sensitivity to treatment of bile acid-related disorders
RU2597789C2 (ru) * 2014-11-10 2016-09-20 Илья Владимирович Духовлинов Анальгетическое средство на основе плазмидной днк, кодирующей hnp-1, либо hnp-2, либо hnp-3 (варианты)
WO2016077123A1 (en) 2014-11-10 2016-05-19 Moderna Therapeutics, Inc. Multiparametric nucleic acid optimization
EP3542825A1 (en) 2014-11-10 2019-09-25 Ethris GmbH Induction of osteogenesis by delivering bmp encoding rna
EP3461904A1 (en) 2014-11-10 2019-04-03 ModernaTX, Inc. Alternative nucleic acid molecules containing reduced uracil content and uses thereof
WO2016077625A1 (en) 2014-11-12 2016-05-19 Stayton Patrick S Stabilized polymeric carriers for therapeutic agent delivery
US10954282B2 (en) * 2014-12-09 2021-03-23 Wentao Zhang NBP158 and uses thereof
DK4023755T5 (da) 2014-12-12 2024-07-29 CureVac SE Kunstige nukleinsyremolekyler til forbedret proteinudtrykkelse
WO2016100977A1 (en) 2014-12-19 2016-06-23 The Broad Institute Inc. Methods for profiling the t-cel- receptor repertoire
MX389490B (es) 2014-12-23 2025-03-20 Avon Prod Inc Peptidos y su uso en el tratamiento de la piel.
EP3236995A4 (en) 2014-12-23 2018-07-18 University of Maryland, Baltimore Muc1 decoy peptides for treatment and prevention of bacterial infections
EP3702456A1 (en) 2014-12-24 2020-09-02 The Broad Institute, Inc. Crispr having or associated with destabilization domains
US10335498B2 (en) * 2014-12-29 2019-07-02 University Of Iowa Research Foundation RNA based biomaterial for tissue engineering applications
US11452759B2 (en) * 2015-01-19 2022-09-27 Technion Research & Development Foundation Limited Ubiquitin ligase KPC1 promotes processing of P105 NF-κB1 to p50, eliciting strong tumor suppression
AU2016209295B2 (en) 2015-01-21 2021-08-12 Genevant Sciences Gmbh Methods, compositions, and systems for delivering therapeutic and diagnostic agents into cells
CA2976376A1 (en) * 2015-02-13 2016-08-18 Factor Bioscience Inc. Nucleic acid products and methods of administration thereof
EP3262065B1 (en) * 2015-02-27 2024-04-03 The Charlotte-Mecklenburg Hospital Authority D/B/A Carolinas Healthcare System Methods and compositions for treating dystroglycanopathy disorders
WO2016141347A2 (en) * 2015-03-04 2016-09-09 Wayne State University Systems and methods to diagnose sarcoidosis and identify markers of the condition
JP2018510156A (ja) * 2015-03-20 2018-04-12 ザ トラスティーズ オブ ザ ユニバーシティ オブ ペンシルバニア アジュバントとしてｃｄ４０リガンドを有するワクチン
EP3274457A4 (en) 2015-03-26 2018-08-08 Acceleron Pharma Inc. Follistatin-related fusion proteins and uses thereof
CN109265517B (zh) 2015-03-27 2024-05-10 伊玛提克斯生物技术有限公司 用于各种肿瘤免疫治疗的肽和肽组合物
GB201505305D0 (en) 2015-03-27 2015-05-13 Immatics Biotechnologies Gmbh Novel Peptides and combination of peptides for use in immunotherapy against various tumors
GB201505585D0 (en) 2015-03-31 2015-05-13 Immatics Biotechnologies Gmbh Novel peptides and combination of peptides and scaffolds for use in immunotherapy against renal cell carinoma (RCC) and other cancers
TN2017000328A1 (en) 2015-04-24 2019-01-16 Ferring Bv Method of production of gonadotrophin
US11377651B2 (en) 2016-10-19 2022-07-05 Flodesign Sonics, Inc. Cell therapy processes utilizing acoustophoresis
US11708572B2 (en) 2015-04-29 2023-07-25 Flodesign Sonics, Inc. Acoustic cell separation techniques and processes
US11021699B2 (en) 2015-04-29 2021-06-01 FioDesign Sonics, Inc. Separation using angled acoustic waves
CN104878091B (zh) * 2015-04-30 2019-05-17 北京大北农科技集团股份有限公司 用于检测玉米植物dbn9978的核酸序列及其检测方法
US20180346988A1 (en) * 2015-05-04 2018-12-06 The Brigham And Women's Hospital, Inc. Znf532 for diagnosis and treatment of cancer
DK3294885T3 (da) * 2015-05-08 2020-08-10 Curevac Real Estate Gmbh Fremgangsmåde til at fremstille rna
US10808020B2 (en) * 2015-05-12 2020-10-20 Sangamo Therapeutics, Inc. Nuclease-mediated regulation of gene expression
WO2016197133A1 (en) * 2015-06-04 2016-12-08 Protiva Biotherapeutics, Inc. Delivering crispr therapeutics with lipid nanoparticles
WO2016197132A1 (en) * 2015-06-04 2016-12-08 Protiva Biotherapeutics Inc. Treating hepatitis b virus infection using crispr
AR105319A1 (es) 2015-06-05 2017-09-27 Sanofi Sa Profármacos que comprenden un conjugado agonista dual de glp-1 / glucagón conector ácido hialurónico
EP3304082B1 (en) 2015-06-08 2020-05-13 Arquer Diagnostics Limited Methods for analysing a urine sample
ES2911415T3 (es) 2015-06-08 2022-05-19 Arquer Diagnostics Ltd Métodos y kits
IL316159A (en) 2015-06-15 2024-12-01 Mpeg La Llc Defined Oligonucleotide Multimers and Methods for Manufacture Thereof
US9597274B2 (en) 2015-06-17 2017-03-21 Avon Products, Inc. Peptides and their use in the treatment of skin
WO2016205759A1 (en) 2015-06-18 2016-12-22 The Broad Institute Inc. Engineering and optimization of systems, methods, enzymes and guide scaffolds of cas9 orthologs and variants for sequence manipulation
GB201510771D0 (en) 2015-06-19 2015-08-05 Immatics Biotechnologies Gmbh Novel peptides and combination of peptides for use in immunotherapy and methods for generating scaffolds for the use against pancreatic cancer
AU2016280839B2 (en) 2015-06-19 2020-07-16 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy and methods for generating scaffolds for the use against pancreatic cancer and other cancers
TW201706291A (zh) 2015-07-10 2017-02-16 賽諾菲公司 作為選擇性肽雙重ｇｌｐ－１／升糖素受體促效劑之新毒蜥外泌肽（ｅｘｅｎｄｉｎ－４）衍生物
US12404552B2 (en) * 2015-07-17 2025-09-02 Allele Biotechnology & Pharmaceuticals, Inc. Methods of selecting antibodies and antibody fragments
US11007260B2 (en) 2015-07-21 2021-05-18 Modernatx, Inc. Infectious disease vaccines
US11364292B2 (en) 2015-07-21 2022-06-21 Modernatx, Inc. CHIKV RNA vaccines
US11474085B2 (en) 2015-07-28 2022-10-18 Flodesign Sonics, Inc. Expanded bed affinity selection
US11459540B2 (en) 2015-07-28 2022-10-04 Flodesign Sonics, Inc. Expanded bed affinity selection
US10800843B2 (en) 2015-07-29 2020-10-13 Ngm Biopharmaceuticals, Inc. Beta klotho-binding proteins
EP3328394A4 (en) 2015-07-30 2019-03-13 ModernaTX, Inc. CONCATEMEE peptide epitope RNAs
GB201513921D0 (en) 2015-08-05 2015-09-23 Immatics Biotechnologies Gmbh Novel peptides and combination of peptides for use in immunotherapy against prostate cancer and other cancers
WO2017031232A1 (en) 2015-08-17 2017-02-23 Modernatx, Inc. Methods for preparing particles and related compositions
EP4029522B1 (en) * 2015-08-28 2025-08-13 BioNTech SE Method for reducing immunogenicity of rna
US12258567B2 (en) * 2015-08-28 2025-03-25 CureVac SE Artificial nucleic acid molecules
EP3347376B1 (en) * 2015-09-07 2021-01-06 Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Novel igfr-like receptor and uses thereof
GB201516066D0 (en) * 2015-09-10 2015-10-28 Young & Co Llp D Treatment of retinitis pigmentosa
WO2017049074A1 (en) * 2015-09-18 2017-03-23 Moderna Therapeutics, Inc. Polynucleotide formulations for use in the treatment of renal diseases
HUE064227T2 (hu) * 2015-09-21 2024-02-28 Trilink Biotechnologies Llc Módszer 5'-sapkával ellátott rns-ek szintetizálására
DK3353196T5 (da) * 2015-09-22 2024-09-30 Inst Nat Sante Rech Med Polypeptider, der er i stand til at inhibere bindingen mellem leptin og neuropilin-1
PH12022551111A1 (en) 2015-10-05 2023-08-23 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against small cell lung cancer and other cancers
CA3001312A1 (en) 2015-10-08 2017-04-13 Dna2.0, Inc. Dna vectors, transposons and transposases for eukaryotic genome modification
CN108368505B (zh) * 2015-10-09 2023-02-21 建新公司 改善的flare(流式细胞术减弱报道蛋白表达)技术用于快速批量分选
EP3365026B1 (en) 2015-10-19 2021-09-22 University of Massachusetts Anti-cancer and anti-inflammatory therapeutics and methods thereof
CN108431216B (zh) 2015-10-21 2022-08-05 美国政府(由卫生和人类服务部的部长所代表) 经密码子优化的尺寸减小的atp7a cdna及用于治疗铜转运障碍的用途
WO2017070613A1 (en) 2015-10-22 2017-04-27 Modernatx, Inc. Human cytomegalovirus vaccine
MD3718565T2 (ro) 2015-10-22 2022-09-30 Modernatx Inc Vaccinuri împotriva virusului respirator
BR112018008102A2 (pt) * 2015-10-22 2018-11-06 Modernatx Inc vacina de vírus sincicial respiratório
EA201891001A1 (ru) 2015-10-22 2018-11-30 МОДЕРНАТиЭкс, ИНК. Вакцины на основе нуклеиновых кислот против вируса ветряной оспы (vzv)
WO2017070624A1 (en) 2015-10-22 2017-04-27 Modernatx, Inc. Tropical disease vaccines
EA201890999A1 (ru) * 2015-10-22 2018-12-28 МОДЕРНАТиЭкс, ИНК. Вакцина против вируса простого герпеса
CA3003090A1 (en) * 2015-10-22 2017-04-27 Modernatx, Inc. Cancer vaccines
AU2016342376A1 (en) 2015-10-22 2018-06-07 Modernatx, Inc. Sexually transmitted disease vaccines
GB201518792D0 (en) * 2015-10-23 2015-12-09 Univ Manchester Production of proteins
CA3041130A1 (en) * 2015-10-30 2017-05-04 The University Of Melbourne Methods and compositions for improving glucose metabolism
AU2016353988B2 (en) 2015-11-09 2019-09-26 Ngm Biopharmaceuticals, Inc. Methods for treatment of bile acid-related disorders
KR102821290B1 (ko) 2015-11-12 2025-06-18 더 리서치 인스티튜트 앳 네이션와이드 칠드런스 하스피탈 근이영양증을 치료하는 방법
EP3386533A1 (en) 2015-12-09 2018-10-17 ModernaTX, Inc. Modified mrna encoding a uridine diphopsphate glucuronosyl transferase and uses thereof
PT3386484T (pt) 2015-12-10 2022-08-01 Modernatx Inc Composições e métodos para entrega de agentes terapêuticos
HK1255541A1 (zh) * 2015-12-11 2019-08-23 Immatics Biotechnologies Gmbh 用於多种癌症免疫治疗的新型肽和肽组合物
US11241506B2 (en) 2015-12-14 2022-02-08 The Trustees Of The University Of Pennsylvania Composition for treatment of Crigler-Najjar syndrome
EP3390630B1 (en) 2015-12-17 2025-01-22 ModernaTX, Inc. Polynucleotides encoding methylmalonyl-coa mutase
US10465190B1 (en) 2015-12-23 2019-11-05 Modernatx, Inc. In vitro transcription methods and constructs
PT3394093T (pt) 2015-12-23 2022-05-30 Modernatx Inc Métodos de utilização de polinucleotídeos que codificam ligandos ox40
US20190241658A1 (en) 2016-01-10 2019-08-08 Modernatx, Inc. Therapeutic mRNAs encoding anti CTLA-4 antibodies
KR20180095720A (ko) * 2016-01-13 2018-08-27 메리얼 인코포레이티드 포유동물에서 골관절염 및 관련 관절 병태의 치료에 유용한, ｈａｓ２ 및 루브리신을 포함하는, 골보호성 유전자를 발현하는 재조합 ａａｖ 벡터
EP3405579A1 (en) * 2016-01-22 2018-11-28 Modernatx, Inc. Messenger ribonucleic acids for the production of intracellular binding polypeptides and methods of use thereof
WO2017136399A1 (en) * 2016-02-02 2017-08-10 Idera Pharmaceuticals, Inc. POTENTIATION OF mmRNA THERAPEUTICS
EP3410849B1 (en) 2016-02-05 2023-07-05 Institut Pasteur Use of inhibitors of adam12 as adjuvants in tumor therapies
EP3427060B1 (en) 2016-03-07 2025-08-13 Father Flanagan's Boys' Home doing Business as Boys Town National Research Hospital Noninvasive molecular controls
PT3436048T (pt) * 2016-03-31 2025-08-06 Biontech Us Inc Neoantigénios e métodos da sua utilização
KR20180134385A (ko) * 2016-04-15 2018-12-18 노파르티스 아게 선택적 단백질 발현을 위한 조성물 및 방법
BR112018070873A2 (pt) 2016-04-21 2019-02-05 Immatics Biotechnologies Gmbh imunoterapia contra melanoma e outros cânceres
CR20200608A (es) 2016-04-21 2021-01-20 Immatics Biotechnologies Gmbh INMUNOTERAPIA CONTRA EL MELANOMA Y OTROS TIPOS DE CÁNCER (Divisional 2018-0551)
WO2017186928A1 (en) * 2016-04-29 2017-11-02 Curevac Ag Rna encoding an antibody
GB2549798A (en) 2016-04-29 2017-11-01 Univ Bradford Peptides and nanoparticle formulations thereof
US11214789B2 (en) 2016-05-03 2022-01-04 Flodesign Sonics, Inc. Concentration and washing of particles with acoustics
US11085035B2 (en) 2016-05-03 2021-08-10 Flodesign Sonics, Inc. Therapeutic cell washing, concentration, and separation utilizing acoustophoresis
US20180126003A1 (en) * 2016-05-04 2018-05-10 Curevac Ag New targets for rna therapeutics
US20190298657A1 (en) 2016-05-18 2019-10-03 Modernatx, Inc. Polynucleotides Encoding Acyl-CoA Dehydrogenase, Very Long-Chain for the Treatment of Very Long-Chain Acyl-CoA Dehydrogenase Deficiency
US12123030B2 (en) 2016-05-18 2024-10-22 Modernatx, Inc. Polynucleotides encoding lipoprotein lipase for the treatment of hyperlipidemia
SG11201809381XA (en) 2016-05-18 2018-12-28 Modernatx Inc Polynucleotides encoding interleukin-12 (il12) and uses thereof
KR20230074598A (ko) 2016-05-18 2023-05-30 모더나티엑스, 인크. 릴랙신을 인코딩하는 폴리뉴클레오타이드
EP3458104A1 (en) 2016-05-18 2019-03-27 Modernatx, Inc. Polynucleotides encoding porphobilinogen deaminase for the treatment of acute intermittent porphyria
ES2973443T3 (es) 2016-05-18 2024-06-20 Modernatx Inc Polinucleótidos que codifican galactosa-1-fosfato uridililtransferasa para el tratamiento de galactosemia de tipo 1
EP4137509A1 (en) 2016-05-18 2023-02-22 ModernaTX, Inc. Combinations of mrnas encoding immune modulating polypeptides and uses thereof
EP3458108A4 (en) 2016-05-18 2020-04-22 ModernaTX, Inc. POLYNUCLEOTIDES ENCODING A CYSTIC FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR FOR THE TREATMENT OF CYSTIC FIBROSIS
US12128113B2 (en) 2016-05-18 2024-10-29 Modernatx, Inc. Polynucleotides encoding JAGGED1 for the treatment of Alagille syndrome
KR20220120711A (ko) 2016-05-26 2022-08-30 유니버시티 오브 피츠버그 - 오브 더 커먼웰쓰 시스템 오브 하이어 에듀케이션 폐혈관 질환 치료용 조성물 및 방법
EP3971204A1 (en) 2016-06-07 2022-03-23 Modernatx, Inc. Modified rna encoding vegf-a polypeptides, formulations, and uses relating thereto
US11235036B2 (en) 2016-06-17 2022-02-01 Alexion Pharmaceuticals, Inc. Lysosomal acid lipase deficiency compositions and methods
PT109480B (pt) 2016-06-22 2020-03-13 Inst Superior Tecnico Polímero de polibenzimidazolo com cadeia espaçadora funcionalizada e seu método de obtenção para remoção de impurezas genotóxicas
EP3481943A1 (en) 2016-07-07 2019-05-15 Rubius Therapeutics, Inc. Compositions and methods related to therapeutic cell systems expressing exogenous rna
CN108699589B (zh) 2016-07-08 2021-08-13 花王株式会社 核酸样品的制备方法
CA3030534A1 (en) 2016-07-11 2018-01-18 The National Institute For Biotechnology In The Negev, Ltd. Fusion proteins with extended serum half life
US20190248893A1 (en) 2016-07-14 2019-08-15 Bristol-Myers Squibb Company Antibodies against tim3 and uses thereof
WO2018022511A1 (en) * 2016-07-25 2018-02-01 The Trustees Of The University Of Pennsylvania Compositions comprising a lecithin cholesterol acyltransferase variant and uses thereof
EP3493834A1 (en) 2016-08-07 2019-06-12 Novartis AG Mrna-mediated immunization methods
BR112019002586A2 (pt) 2016-08-09 2019-05-21 Syngenta Participations Ag proteínas inseticidas
US20190175690A1 (en) * 2016-08-16 2019-06-13 Children's Medical Center Corporation Compositions and methods for cardiac repair
JP2019528284A (ja) 2016-08-17 2019-10-10 ファクター バイオサイエンス インコーポレイテッド 核酸産物およびその投与方法
ES2982489T3 (es) 2016-08-19 2024-10-16 Univ Florida Composiciones para el tratamiento de afecciones que utilizan virus adeno-asociados recombinantes autocomplementarios
AU2017315459B2 (en) 2016-08-26 2023-06-29 Ngm Biopharmaceuticals, Inc. Methods of treating fibroblast growth factor 19-mediated cancers and tumors
EP3293259A1 (en) * 2016-09-12 2018-03-14 Genethon Acid-alpha glucosidase variants and uses thereof
CA3035868A1 (en) 2016-09-12 2018-03-15 Genethon Acid-alpha glucosidase variants and uses thereof
CA3036831A1 (en) 2016-09-14 2018-03-22 Modernatx, Inc. High purity rna compositions and methods for preparation thereof
WO2018057727A1 (en) * 2016-09-21 2018-03-29 David Weiner Optimized synthetic consensus inmunogenic compositions targeting fibroblast activation protein
SG10202103545PA (en) 2016-10-07 2021-05-28 Genzyme Corp Early post-transfection isolation of cells (epic) for biologics production
AU2017338911B2 (en) 2016-10-07 2021-09-30 Board Of Regents, The University Of Texas System HLA-restricted VGLL1 peptides and use thereof
US10633705B2 (en) 2016-10-14 2020-04-28 Alexion Pharmaceuticals, Inc. N-acetyl-alpha-D-glucosaminidase deficiency compositions and methods
KR101837856B1 (ko) 2016-10-18 2018-03-13 단국대학교 산학협력단 뎅기바이러스 혈청형 2 및 3의 메틸트랜스퍼라제 활성을 억제하는 rna 앱타머
EP3529347A1 (en) 2016-10-19 2019-08-28 Flodesign Sonics, Inc. Affinity cell extraction by acoustics
EP3528821A4 (en) 2016-10-21 2020-07-01 ModernaTX, Inc. HUMAN CYTOMEGALOVIRUS VACCINE
MX2019004810A (es) * 2016-10-26 2019-10-15 Modernatx Inc Ácidos ribonucleicos mensajeros para aumentar respuestas inmunes y métodos para usarlos.
AR109844A1 (es) * 2016-10-27 2019-01-30 Syngenta Participations Ag Proteínas insecticidas
WO2018089851A2 (en) 2016-11-11 2018-05-17 Modernatx, Inc. Influenza vaccine
EP3323827A1 (en) * 2016-11-21 2018-05-23 Christian-Albrechts-Universität zu Kiel Cationic intrinsically disordered antimicrobial peptides
EP3973955B1 (en) 2016-11-23 2025-05-21 Mayo Foundation for Medical Education and Research Particle-mediated delivery of inhibitory rna
KR20190088561A (ko) * 2016-12-07 2019-07-26 유니버시티 오브 플로리다 리서치 파운데이션, 인코포레이티드 인터류킨-1 수용체 길항제(IL-1RA) cDNA
US11542490B2 (en) 2016-12-08 2023-01-03 CureVac SE RNAs for wound healing
WO2018107088A2 (en) 2016-12-08 2018-06-14 Modernatx, Inc. Respiratory virus nucleic acid vaccines
JP2020501545A (ja) 2016-12-08 2020-01-23 キュアバック アーゲー 肝疾患の処置または予防のためのｒｎａ
WO2018111967A1 (en) 2016-12-13 2018-06-21 Modernatx, Inc. Rna affinity purification
CN106771190B (zh) * 2016-12-26 2018-11-13 中国农业科学院兰州兽医研究所 一种羊无浆体病间接elisa诊断试剂盒及其制备方法
WO2018126084A1 (en) 2016-12-30 2018-07-05 Phaserx, Inc. Branched peg molecules and related compositions and methods
WO2018126112A1 (en) * 2016-12-30 2018-07-05 The Trustees Of The University Of Pennsylvania Gene therapy for treating phenylketonuria
EP4361277A3 (en) * 2016-12-30 2024-07-31 The Trustees of The University of Pennsylvania Gene therapy for treating wilson's disease
EP3574007A1 (en) 2017-01-30 2019-12-04 Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Novel igfr-like 2 receptor and uses thereof
EP3576751A4 (en) * 2017-02-01 2021-08-04 ModernaTX, Inc. RNA ANTI-CANCER VACCINES
MX2019009070A (es) 2017-02-01 2019-10-30 Modernatx Inc Composiciones de arnm terapeuticas inmunomoduladoras que codifican peptidos de mutacion de oncogenes de activacion.
MA47515A (fr) 2017-02-16 2019-12-25 Modernatx Inc Compositions immunogènes très puissantes
WO2018157009A1 (en) * 2017-02-24 2018-08-30 Modernatx, Inc. Nucleic acid-based therapy of muscular dystrophies
DK3585892T3 (da) * 2017-02-27 2022-08-22 Translate Bio Inc Fremgangsmåder til oprensning af messenger-rna
JP7674077B2 (ja) 2017-02-28 2025-05-09 アークトゥラス・セラピューティクス・インコーポレイテッド 翻訳可能分子およびその合成
JOP20190200A1 (ar) * 2017-02-28 2019-08-27 Univ Pennsylvania تركيبات نافعة في معالجة ضمور العضل النخاعي
SG11201907846VA (en) * 2017-02-28 2019-09-27 Sanofi Sa Therapeutic rna
CN110520112A (zh) 2017-03-14 2019-11-29 贝勒医学院 作为Hippo效应子的显性活性Yap诱导染色质可及性和心肌细胞更新
EP3595713A4 (en) 2017-03-15 2021-01-13 ModernaTX, Inc. Respiratory syncytial virus vaccine
WO2018170256A1 (en) 2017-03-15 2018-09-20 Modernatx, Inc. Herpes simplex virus vaccine
WO2018170270A1 (en) 2017-03-15 2018-09-20 Modernatx, Inc. Varicella zoster virus (vzv) vaccine
EP3609534A4 (en) 2017-03-15 2021-01-13 ModernaTX, Inc. WIDE SPECTRUM INFLUENZA VIRUS VACCINE
GB201704192D0 (en) * 2017-03-16 2017-05-03 Nightstarx Ltd Treatment of Retinitis Pigmentosa
WO2018170347A1 (en) 2017-03-17 2018-09-20 Modernatx, Inc. Zoonotic disease rna vaccines
CA3057768A1 (en) * 2017-03-31 2018-10-04 Accanis Biotech F&E Gmbh & Co Kg Prevention and treatment of non-melanoma skin cancer (nmsc)
WO2018187231A2 (en) 2017-04-03 2018-10-11 American Gene Technologies International Inc. Compositions and methods for treating phenylketonuria
US12303561B2 (en) 2017-04-03 2025-05-20 Biontech Us Inc. Protein antigens and uses thereof
US11905525B2 (en) 2017-04-05 2024-02-20 Modernatx, Inc. Reduction of elimination of immune responses to non-intravenous, e.g., subcutaneously administered therapeutic proteins
EA038300B1 (ru) * 2017-04-18 2021-08-06 Юниверсити Оф Флорида Рисерч Фаундейшен, Инкорпорейтед Кднк il-1ra
EP3635100A4 (en) 2017-05-05 2021-03-24 University of Florida Research Foundation, Incorporated COMPOSITIONS AND METHOD OF EXPRESSION OF OTOFERLIN
WO2018209205A1 (en) 2017-05-11 2018-11-15 The Trustees Of The University Of Pennsylvania Gene therapy for neuronal ceroid lipofuscinoses
WO2018209182A2 (en) * 2017-05-11 2018-11-15 The Research Foundation For The State University Of New York Compositions and methods for loading extracellular vesicles with chemical and biological agents/molecules
CA3061656A1 (en) 2017-05-17 2018-11-22 The General Hospital Corporation Gene therapy for tuberous sclerosis
JP7285220B2 (ja) 2017-05-18 2023-06-01 モデルナティエックス インコーポレイテッド 連結したインターロイキン－１２（ｉｌ１２）ポリペプチドをコードするポリヌクレオチドを含む脂質ナノ粒子
US20180338929A1 (en) * 2017-05-23 2018-11-29 Soon Kap Hahn Method and Compounds for Treating Peripheral Neuropathy
ES3039647T3 (en) 2017-05-31 2025-10-23 Arcturus Therapeutics Inc Synthesis and structure of high potency rna therapeutics
KR102636537B1 (ko) * 2017-05-31 2024-02-15 울트라제닉스 파마수티컬 인코포레이티드 글리코겐 축적 질환 유형 iii에 대한 치료제
WO2018222925A1 (en) 2017-05-31 2018-12-06 Ultragenyx Pharmaceutical Inc. Therapeutics for phenylketonuria
WO2018231990A2 (en) 2017-06-14 2018-12-20 Modernatx, Inc. Polynucleotides encoding methylmalonyl-coa mutase
MA49395A (fr) 2017-06-14 2020-04-22 Modernatx Inc Polynucléotides codant pour le facteur viii de coagulation
GB201709551D0 (en) * 2017-06-15 2017-08-02 Ucl Business Plc Expression vectors comprising engineered genes
US11786607B2 (en) * 2017-06-15 2023-10-17 Modernatx, Inc. RNA formulations
US10034951B1 (en) 2017-06-21 2018-07-31 New England Biolabs, Inc. Use of thermostable RNA polymerases to produce RNAs having reduced immunogenicity
KR102675270B1 (ko) 2017-06-22 2024-06-17 버텍스 파마슈티칼스 인코포레이티드 변형된 막 유형 세린 프로테아제 １(ｍｔｓｐ－１) 폴리펩티드 및 사용 방법
JP2020529836A (ja) * 2017-07-03 2020-10-15 ユニヴェルシテ・ドゥ・ストラスブール ミオパチーの処置における使用のためのｍｔｍｒ２−ｓポリペプチド
CN107333755B (zh) * 2017-07-04 2021-03-16 南开大学 具有g-四链体结构的水凝胶制备方法及其在杀灭金黄色葡萄球菌和大肠杆菌中的应用
US11628227B2 (en) * 2017-07-05 2023-04-18 Wisconsin Alumni Research Foundation Mineral coated microparticles for gene delivery in chronic wound therapy
US10800823B2 (en) 2017-07-07 2020-10-13 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against lung cancer, including NSCLC, SCLC and other cancers
EP3648790A1 (en) 2017-07-07 2020-05-13 Immatics Biotechnologies GmbH Novel peptides and combination of peptides for use in immunotherapy against lung cancer, including nsclc, sclc and other cancers
US11261447B2 (en) 2017-07-13 2022-03-01 Alnylam Pharmaceuticals, Inc. Methods for inhibition of HAO1 (hydroxyacid oxidase 1 (glycolate oxidase)) gene expression
EP3652203B1 (en) * 2017-07-14 2025-07-02 The Johns Hopkins University Engineered tsc2
US20200165593A1 (en) 2017-07-21 2020-05-28 Modernatx, Inc. Modified mRNA Encoding a Propionyl-CoA Carboxylase and Uses Thereof
EP3658672A1 (en) 2017-07-24 2020-06-03 Modernatx, Inc. Modified mrna encoding a glucose-6-phosphatase and uses thereof
WO2019036484A1 (en) * 2017-08-15 2019-02-21 The Trustees Of The University Of Pennsylvania COMPOSITIONS AND METHODS FOR THE TREATMENT OF ARGININOSUCCINIC ACIDURIA
WO2019036683A1 (en) 2017-08-18 2019-02-21 Modernatx, Inc. ANALYTICAL METHODS BY HPLC
EP3668971B8 (en) 2017-08-18 2024-05-29 ModernaTX, Inc. Rna polymerase variants
US11912982B2 (en) 2017-08-18 2024-02-27 Modernatx, Inc. Methods for HPLC analysis
WO2019040367A1 (en) * 2017-08-19 2019-02-28 Ohio State Innovation Foundation NEW CANCER IMAGING AGENTS BASED ON PEPTIDES
HRP20240485T1 (hr) 2017-08-24 2024-07-05 Novo Nordisk A/S Pripravci glp-1 i njihova upotreba
JP7275111B2 (ja) 2017-08-31 2023-05-17 モデルナティエックス インコーポレイテッド 脂質ナノ粒子の生成方法
US20200407421A1 (en) 2017-09-05 2020-12-31 GLAdiator Biosciences, Inc. Delivery of payloads to stem cells
JP2020534352A (ja) 2017-09-07 2020-11-26 キュー バイオファーマ，インコーポレーテッド コンジュゲーション部位を有するｔ細胞調節多量体ポリペプチド及びその使用方法
US10653767B2 (en) 2017-09-14 2020-05-19 Modernatx, Inc. Zika virus MRNA vaccines
MX2020004005A (es) 2017-10-03 2020-10-05 Prevail Therapeutics Inc Terapias genicas para los trastornos lisosomales.
MX2020003965A (es) * 2017-10-03 2020-10-05 Prevail Therapeutics Inc Terapias genicas para los trastornos lisosomales.
JP7367988B2 (ja) * 2017-10-18 2023-10-24 ワシントン・ユニバーシティ 神経変性の疾患または障害のための治療戦略としてのドミナントネガティブｓａｒｍ１分子
DK3703658T3 (da) * 2017-10-31 2022-07-18 Astrazeneca Ab Lipidnanopartikler til administration af modificeret rna, der koder for et vegf-a-polypeptid
EP3713569B1 (en) * 2017-11-22 2024-03-13 University of Pittsburgh- Of the Commonwealth System of Higher Education Therapeutic particle comprising a yap1/wwrt1 inhibiting agent and the glutaminase inhibiting agent 2-cyclopropyl-n-[5-(4-{ [5-(2-phenylacetamido)-1,3,4-thiadiazol-2-yl]amino}piperidin-1-yl)-1,3,4-thiadiazol-2-yl] acetamide and use thereof for treating a pulmonary disease
JP7424976B2 (ja) * 2017-11-22 2024-01-30 モダーナティエックス・インコーポレイテッド プロピオン酸血症の治療用のプロピオニルＣｏＡカルボキシラーゼアルファ及びベータサブユニットをコードするポリヌクレオチド
MA50803A (fr) * 2017-11-22 2020-09-30 Modernatx Inc Polynucléotides codant pour l'ornithine transcarbamylase pour le traitement de troubles du cycle de l'urée
EP3714047A2 (en) 2017-11-22 2020-09-30 ModernaTX, Inc. Polynucleotides encoding phenylalanine hydroxylase for the treatment of phenylketonuria
JP2021505144A (ja) 2017-12-05 2021-02-18 シンセティック ジェノミクス インコーポレーテッド シグナル伝達タンパク質の遺伝子改変を介した藻類脂質生産性の改善方法
GB201720224D0 (en) * 2017-12-05 2018-01-17 Royal Holloway & Bedford New College Treatment of muscular dystrophies
WO2019118766A2 (en) 2017-12-13 2019-06-20 Inovio Pharmaceuticals, Inc. Cancer vaccines targeting survivin and uses thereof
KR102673699B1 (ko) 2017-12-13 2024-06-17 이노비오 파마수티컬즈, 인크. Lemd1을 표적화하는 암 백신 및 이의 용도
KR20220066413A (ko) 2017-12-14 2022-05-24 프로디자인 소닉스, 인크. 음향 트랜스듀서 구동기 및 제어기
CN111819185A (zh) 2017-12-15 2020-10-23 旗舰创业创新第六有限责任公司 包含环状多核糖核苷酸的组合物及其用途
WO2019126186A1 (en) 2017-12-18 2019-06-27 Neon Therapeutics, Inc. Neoantigens and uses thereof
MA51523A (fr) 2018-01-05 2020-11-11 Modernatx Inc Polynucléotides codant pour des anticorps anti-virus du chikungunya
GB201800620D0 (en) 2018-01-15 2018-02-28 Univ Manchester C3b Binding Polypeptide
MA54676A (fr) 2018-01-29 2021-11-17 Modernatx Inc Vaccins à base d'arn contre le vrs
CN111971397A (zh) * 2018-02-14 2020-11-20 耶鲁大学 用于调节trem或treml蛋白的组合物及其使用方法
WO2019158745A1 (de) * 2018-02-16 2019-08-22 Bontana Therapies Gmbh Nukleinsäure-basiertes botulinum neurotoxin zur therapeutischen anwendung
JP7266611B2 (ja) * 2018-02-26 2023-04-28 アブリンクス・エヌ・フェー ペプチドリンカーをコードする改良されたヌクレオチド配列
US20210000975A1 (en) * 2018-03-07 2021-01-07 Icahn School Of Medicine At Mount Sinai Modrna encoding sphingolipid-metabolizing proteins
US20210002668A1 (en) * 2018-03-07 2021-01-07 Icahn School Of Medicine At Mount Sinai Sphingolipid-metabolizing proteins enhance the efficiency of gene editing in cells
US12194108B2 (en) 2018-03-23 2025-01-14 University Of Massachusetts Gene therapeutics for treating bone disorders
WO2019195580A1 (en) * 2018-04-04 2019-10-10 North Carolina State University Fibrin-specific materials and methods of using thereof
US12122811B2 (en) 2018-04-06 2024-10-22 Northwestern University BDNF mimetic peptide amphiphiles
DK3773689T5 (da) 2018-04-11 2024-08-19 Enterome S A Antigene peptider til forebyggelse og behandling af kræft
CN119523873A (zh) * 2018-04-27 2025-02-28 克里斯托生物技术股份有限公司 用于美容性应用的编码一种或多种美容蛋白的重组核酸
GB201807831D0 (en) * 2018-05-15 2018-06-27 Univ College Cardiff Consultants Ltd Cancer Vaccine
MY207355A (en) 2018-05-16 2025-02-21 Spark Therapeutics Inc Codon-optimized acid lpha-glucosidase expression cassettes and methods of using same
MX421685B (es) * 2018-06-05 2025-03-14 Univ Pennsylvania Composiciones y metodos de celulas del receptor de autoanticuerpos quimericos de quinasa especifica del musculo
TW202015719A (zh) 2018-06-19 2020-05-01 美商尼恩醫療公司 新抗原及其用途
WO2020001657A1 (en) 2018-06-29 2020-01-02 Wuhan Neurophth Biological Technology Limited Company Compositions and methods for treating leber's hereditary optic neuropathy
EP3813871A4 (en) 2018-06-29 2022-10-12 Icahn School of Medicine at Mount Sinai SPHINGOLIPID METABOLIZING PROTEINS ENCODING FOR ANC80
CN111073899B (zh) * 2018-10-19 2021-01-01 武汉纽福斯生物科技有限公司 一种编码人nadh脱氢酶亚单位4蛋白的核酸及其应用
JP2021529001A (ja) * 2018-06-29 2021-10-28 ウーハン ニューロフス バイオテクノロジー リミテッド カンパニーＷｕｈａｎ Ｎｅｕｒｏｐｈｔｈ Ｂｉｏｔｅｃｈｎｏｌｏｇｙ Ｌｉｍｉｔｅｄ Ｃｏｍｐａｎｙ レーベル遺伝性視神経症を治療するための組成物及び方法
WO2020010007A1 (en) 2018-07-02 2020-01-09 Siemens Healthcare Diagnostics Inc. Novel thyroid peroxidase autoantibody immunoassay
EP3818146A4 (en) * 2018-07-04 2022-10-19 Cytoimmune Therapeutics, Inc. COMPOSITIONS AND METHODS OF IMMUNOTHERAPY TARGETING FLT3, PD-1 AND/OR PD-L1
CN110699367B (zh) * 2018-07-09 2021-06-11 武汉纽福斯生物科技有限公司 编码人nadh脱氢酶亚单位4蛋白的核酸及其应用
US11524986B2 (en) 2018-07-11 2022-12-13 Ohio University Peptide-based inhibitors of growth hormone action and methods of use thereof
CA3106838A1 (en) * 2018-07-20 2020-01-23 University Of Utah Research Foundation Gene therapy for macular degeneration
US20220184185A1 (en) 2018-07-25 2022-06-16 Modernatx, Inc. Mrna based enzyme replacement therapy combined with a pharmacological chaperone for the treatment of lysosomal storage disorders
TWI764022B (zh) * 2018-07-30 2022-05-11 中央研究院 凝聚複合物的治療性奈米粒子及其治療細菌的用途
EP3829605A4 (en) 2018-08-01 2022-10-19 ImmunityBio, Inc. QUADRICISTRONIC SYSTEM COMPRISING A homing or CYTOKINE RECEPTOR, AND CHIMERIC ANTIGEN RECEPTOR FOR GENETIC MODIFICATION OF IMMUNOTHERAPIES
EP3837357A1 (en) * 2018-08-13 2021-06-23 Aarhus Universitet Genetically altered lysm receptors with altered agonist specificity and affinity
WO2020041500A1 (en) * 2018-08-21 2020-02-27 Georgia State University Research Foundation, Inc. Treatment of flavivirus infections in humans using mus musculus resistant 2'-5' oligoadenylate synthetase 1b
US20210268126A1 (en) * 2018-08-23 2021-09-02 Rutgers, The State University Of New Jersey Treating spinal cord injury (sci) and brain injury using gsx1
CA3110563A1 (en) * 2018-08-31 2020-03-05 University Of Florida Research Foundation, Incorporated Adeno-associated viral vectors for the treatment of best disease
MA53545A (fr) 2018-09-02 2021-07-14 Modernatx Inc Polynucléotides codant pour l'acyl-coa déshydrogénase à très longue chaîne pour le traitement de l'insuffisance en acyl-coa déshydrogénase à très longue chaîne
WO2020056155A2 (en) 2018-09-13 2020-03-19 Modernatx, Inc. Polynucleotides encoding branched-chain alpha-ketoacid dehydrogenase complex e1-alpha, e1-beta, and e2 subunits for the treatment of maple syrup urine disease
US20230009009A1 (en) 2018-09-13 2023-01-12 Modernatx, Inc. Polynucleotides encoding glucose-6-phosphatase for the treatment of glycogen storage disease
EP3850102A1 (en) 2018-09-14 2021-07-21 ModernaTX, Inc. Polynucleotides encoding uridine diphosphate glycosyltransferase 1 family, polypeptide a1 for the treatment of crigler-najjar syndrome
AU2019343045A1 (en) 2018-09-18 2021-05-13 Vnv Newco Inc. ARC-based capsids and uses thereof
JP7526168B2 (ja) 2018-09-19 2024-07-31 モデルナティエックス インコーポレイテッド Ｐｅｇ脂質及びそれらの使用
CN109106948B (zh) * 2018-09-19 2022-03-29 天康制药(苏州)有限公司 一种口蹄疫抗原保护剂及其应用
EP4509118A3 (en) 2018-09-19 2025-05-14 ModernaTX, Inc. High-purity peg lipids and uses thereof
WO2020061457A1 (en) 2018-09-20 2020-03-26 Modernatx, Inc. Preparation of lipid nanoparticles and methods of administration thereof
US20220152225A1 (en) 2018-09-27 2022-05-19 Modernatx, Inc. Polynucleotides encoding arginase 1 for the treatment of arginase deficiency
WO2020072914A1 (en) 2018-10-04 2020-04-09 New England Biolabs, Inc. Methods and compositions for increasing capping efficiency of transcribed rna
US11072808B2 (en) 2018-10-04 2021-07-27 New England Biolabs, Inc. Methods and compositions for increasing capping efficiency of transcribed RNA
EA202190688A1 (ru) 2018-10-09 2021-06-07 Дзе Юниверсити Оф Бритиш Коламбиа Композиции и системы, содержащие трансфекционно-компетентные везикулы, не содержащие органических растворителей и детергентов, и связанные с ними способы
US12331320B2 (en) 2018-10-10 2025-06-17 The Research Foundation For The State University Of New York Genome edited cancer cell vaccines
BR112021006881A2 (pt) * 2018-10-12 2021-07-13 Vivet Therapeutics transgene otimizado por códon para o tratamento de colestase intra-hepática familiar progressiva tipo 3 (pfic3)
CN111118016B (zh) 2018-10-30 2022-04-15 上海朗昇生物科技有限公司 治疗视网膜色素变性疾病的基因治疗载体
WO2020093018A1 (en) * 2018-11-01 2020-05-07 University Of Florida Research Foundation, Incorporated A codon optimized otoferlin aav dual vector gene therapy
BR112021006074A2 (pt) * 2018-11-05 2021-07-20 The University Of North Carolina At Chapel Hill genes e cassetes de expressão fig4 otimizados e seu uso
CN112955186A (zh) * 2018-11-07 2021-06-11 维韦特治疗公司 用于治疗进行性家族性肝内胆汁淤积症2型(pfic2)的密码子优化的abcb11转基因
WO2020097511A2 (en) * 2018-11-09 2020-05-14 Translate Bio, Inc. Messenger rna therapy for treatment of ocular diseases
WO2020100089A2 (en) 2018-11-14 2020-05-22 Urovant Sciences Gmbh Compositions and methods for the treatment of smooth muscle dysfunction
JP7558167B2 (ja) 2018-12-03 2024-09-30 ボード オブ リージェンツ，ザ ユニバーシティ オブ テキサス システム オリゴベンズアミド類似体およびがん処置におけるそれらの使用
EP3884057A4 (en) * 2018-12-21 2022-09-07 The University of North Carolina at Chapel Hill OPTIMIZED GALC GENES AND EXPRESSION CASSETTE AND THEIR USE
GB201821089D0 (en) * 2018-12-21 2019-02-06 Gyroscope Therapeutics Ltd Codon-optimised complement factor I
WO2020132789A1 (zh) 2018-12-24 2020-07-02 黄海东 突变的人2Ig-B7-H3蛋白编码基因、重组载体、包含其的宿主细胞、药物组合物及其应用
US11562809B2 (en) * 2018-12-25 2023-01-24 Shenzhen Jingtai Technology Co., Ltd. Method for automatically generating universal set of stereoisomers of organic molecule
PT3906066T (pt) 2019-01-04 2024-02-06 Ultragenyx Pharmaceutical Inc Constructos de terapia génica para o tratamento da doença de wilson
US20220118017A1 (en) * 2019-01-09 2022-04-21 The Johns Hopkins University Engineered tuberous sclerosis complex 2 polypeptides
TWI852977B (zh) 2019-01-10 2024-08-21 美商健生生物科技公司 前列腺新抗原及其用途
US20220119478A1 (en) * 2019-01-15 2022-04-21 Caerus Therapeutics, Corp. Advanced chimeric antigen receptor vectors for targeting solid tumors
EP3920887B1 (en) * 2019-02-04 2024-08-14 The Regents of the University of California A phosphatidylinositol-glycan-specific phospholipase d1 (gpld1) polypeptide for use in a method of treating or preventing age-related cognitive dysfunction
KR20210148101A (ko) * 2019-02-04 2021-12-07 프리라인 테라퓨틱스 리미티드 폴리뉴클레오티드
EP3693457A1 (en) * 2019-02-05 2020-08-12 Pharmaq AS Novel fish totivirus
WO2020163743A1 (en) 2019-02-08 2020-08-13 Decibel Therapeutics, Inc. Compositions and methods for treating sensorineural hearing loss using otoferlin dual vector systems
US11351242B1 (en) 2019-02-12 2022-06-07 Modernatx, Inc. HMPV/hPIV3 mRNA vaccine composition
GB201902068D0 (en) * 2019-02-14 2019-04-03 Cambridge Entpr Ltd Methods of reactivating proliferative capacity non-proliferative tissues
US11851694B1 (en) 2019-02-20 2023-12-26 Modernatx, Inc. High fidelity in vitro transcription
EP3927821A4 (en) 2019-02-20 2023-01-25 ModernaTX, Inc. RNA POLYMERASE VARIANTS FOR CO-STRANSCRIPTION CAPTING
WO2020172537A1 (en) * 2019-02-22 2020-08-27 University Of Massachusetts Oxr1 gene therapy
US20220142896A1 (en) * 2019-03-01 2022-05-12 Flagship Pioneering Innovations Vi, Llc Polyribonucleotides and cosmetic uses thereof
JP2022526089A (ja) 2019-03-11 2022-05-23 モデルナティエックス インコーポレイテッド 流加バッチインビトロ転写プロセス
WO2020190750A1 (en) 2019-03-15 2020-09-24 Modernatx, Inc. Hiv rna vaccines
CA3131319A1 (en) 2019-03-25 2020-10-01 Avak Kahvejian Compositions comprising modified circular polyribonucleotides and uses thereof
AU2020248101A1 (en) * 2019-03-27 2021-09-16 Sigilon Therapeutics, Inc. Compositions, devices and methods for factor VII therapy
US10967119B1 (en) 2019-04-01 2021-04-06 Azizi Bilal Wearable medication injecting device
CN109998055B (zh) * 2019-04-09 2022-03-25 黑龙江省科学院大庆分院 一种汉麻籽抗氧化多肽咀嚼片及其制备方法
WO2020214694A1 (en) * 2019-04-15 2020-10-22 The Regents Of The University Of California Treatment for restoring ureagenesis in carbamoyl phosphate synthetase 1 deficiency
AU2020259449A1 (en) 2019-04-17 2021-12-09 Aadigen, Llc Peptides and nanoparticles for intracellular delivery of molecules
CN114072129A (zh) 2019-05-03 2022-02-18 宾夕法尼亚州大学信托人 可用于治疗异染性脑白质营养不良的组合物
WO2020227194A1 (en) * 2019-05-08 2020-11-12 The Feinstein Institutes For Medical Research Interferon regulatory factor 5 inhibitors and uses thereof
WO2020227542A1 (en) * 2019-05-08 2020-11-12 The Regents Of The University Of California A method to prevent the myelin abnormalites associated with arginase deficiency
EP3965797A1 (en) 2019-05-08 2022-03-16 AstraZeneca AB Compositions for skin and wounds and methods of use thereof
BR112021022951A2 (pt) * 2019-05-14 2022-01-25 Univ Duke Composições e métodos para o tratamento de doenças mediadas por atpase
JP7578619B2 (ja) * 2019-05-21 2024-11-06 リジェネロン・ファーマシューティカルズ・インコーポレイテッド ホスト細胞タンパク質の同定および定量方法
CA3137698A1 (en) * 2019-05-31 2020-12-03 Tyler LAHUSEN Optimized phenylalanine hydroxylase expression
JP2022536364A (ja) 2019-06-13 2022-08-15 ザ ジェネラル ホスピタル コーポレイション 操作されたヒト内在性ウイルス様粒子および細胞への送達のためのその使用方法
CN110256578B (zh) * 2019-06-24 2021-04-23 王跃驹 植物生产人霍乱毒素b亚基(ctb)与胰岛素原的融合蛋白速效口服降糖胶囊的应用
CN110327307B (zh) * 2019-06-26 2020-06-23 浙江大学 一种丝素载药纳米微囊的制备方法及产品
WO2021003300A1 (en) 2019-07-02 2021-01-07 Chien Kenneth R Mesenchymal stem cells or stromal cells harboring modified rnas encoding vegf and bmp polypeptides
CN114450265B (zh) 2019-07-03 2024-12-24 菲克特生物科学股份有限公司 阳离子脂质及其用途
CA3147042A1 (en) * 2019-07-11 2021-01-14 University Of Utah Research Foundation Compositions and methods for treating peroxisomal biogenesis disorders
US11377655B2 (en) 2019-07-16 2022-07-05 Pacific Biosciences Of California, Inc. Synthetic nucleic acids having non-natural structures
US10501404B1 (en) 2019-07-30 2019-12-10 Factor Bioscience Inc. Cationic lipids and transfection methods
US11644463B2 (en) 2019-08-30 2023-05-09 Euroimmun Medizinische Labordiagnostika Ag Detection of an autoantibody
EP4021407A1 (en) 2019-08-30 2022-07-06 GlaxoSmithKline Biologicals S.A. Jet mixing lipid nanoparticle manufacturing process
GB2605276B (en) * 2019-09-03 2024-08-07 Myeloid Therapeutics Inc Methods and compositions for genomic integration
AU2020346056A1 (en) * 2019-09-13 2022-03-31 Regeneron Pharmaceuticals, Inc. Transcription modulation in animals using CRISPR/Cas systems delivered by lipid nanoparticles
AU2020366209A1 (en) * 2019-10-15 2022-05-19 Board Of Regents Of The University Of Nebraska mRNA encoding granulocyte-macrophage colony stimulating factor for treating Parkinson's disease
MX2022004812A (es) * 2019-10-22 2023-02-23 Applied Genetic Tech Corporation Sistemas de virus adeno-asociados (aav) para el tratamiento de enfermedades o trastornos neurodegenerativos asociados a la progranulina.
CN110684751B (zh) * 2019-10-23 2021-06-25 江南大学 一种催化能力提高的淀粉分支酶突变体
WO2021081217A1 (en) * 2019-10-23 2021-04-29 The Trustees Of The University Of Pennsylvania Compositions for drg-specific reduction of transgene expression
CN110669104B (zh) * 2019-10-30 2021-11-05 上海交通大学 一组来源于人外周血单核细胞的标志物及其应用
CN114929288A (zh) * 2019-11-07 2022-08-19 西奈山伊坎医学院 合成的修饰的rna及其用途
PL4021487T3 (pl) 2019-11-15 2024-04-15 Enterome S.A. Peptydy antygenowe do zapobiegania i leczenia nowotworów złośliwych wywodzących się z limfocytów b
WO2021097552A1 (en) * 2019-11-22 2021-05-27 Critical Outcome Technologies Inc. Peptides, compounds, compositions and methods for inhibiting sox9 dimerization
EP4069291A1 (en) 2019-12-03 2022-10-12 Evotec International GmbH Interferon-associated antigen binding proteins and uses thereof
CN113025633B (zh) * 2019-12-09 2024-08-27 武汉纽福斯生物科技有限公司 编码人nadh脱氢酶亚单位1蛋白的核酸及其应用
US11904006B2 (en) 2019-12-11 2024-02-20 University Of Iowa Research Foundation Poly(diaminosulfide) particle-based vaccine
KR20220119085A (ko) 2019-12-20 2022-08-26 남미 테라퓨틱스, 인크. 암의 치료에 유용한 톨-유사 수용체 (“tlr”) 효능제 전구약물을 함유하는 제제화된 및/또는 공동-제제화된 리포솜 조성물 및 그의 방법
JP7500193B2 (ja) * 2019-12-27 2024-06-17 小林製薬株式会社 乳化組成物
CN113115821B (zh) * 2019-12-30 2024-07-05 丰益(上海)生物技术研发中心有限公司 含多肽的结构化乳液
CN111004787B (zh) * 2020-01-06 2022-05-10 江南大学 一种链霉菌磷脂酶d突变体、改造方法及其应用
US20230054941A1 (en) * 2020-01-13 2023-02-23 University Of Kentucky Research Foundation Inhibition of dennd5b expression for treating hepatic steatosis
CN111166884B (zh) * 2020-01-15 2021-12-03 广州中医药大学第一附属医院 Foxf1基因在制备用于骨质疏松症药物中的应用
KR102114880B1 (ko) * 2020-01-15 2020-05-26 서울대학교병원 코돈 최적화된 TIF1γ 폴리뉴클레오티드를 포함하는 재조합 벡터 및 이의 용도
JP2023510588A (ja) * 2020-01-17 2023-03-14 ニューヨーク ユニバーシティ アデノ随伴ウイルスベクター、組成物、筋再生を促進する方法、及び治療方法
WO2021151001A1 (en) 2020-01-22 2021-07-29 Outpace Bio, Inc. Chimeric polypeptides
US11230699B2 (en) 2020-01-28 2022-01-25 Immunitybio, Inc. Chimeric antigen receptor-modified NK-92 cells targeting EGFR super-family receptors
US12194089B2 (en) 2020-02-04 2025-01-14 CureVac SE Coronavirus vaccine
US20230093542A1 (en) 2020-02-18 2023-03-23 Novo Nordisk A/S Glp-1 compositions and uses thereof
WO2021183433A1 (en) * 2020-03-09 2021-09-16 University Of Massachusetts Gene replacement therapy for foxg1 syndrome
KR20220154740A (ko) 2020-03-17 2022-11-22 제네반트 사이언시즈 게엠베하 간 성상 세포로 치료제의 지질 나노입자 전달을 위한 양이온성 지질
JP2021147353A (ja) * 2020-03-19 2021-09-27 国立大学法人信州大学 組成物、脂質粒子製造用キット、物質送達方法及び検出方法
AU2021247172A1 (en) 2020-04-01 2022-09-15 University Of Florida Research Foundation, Incorporated Dual AAV-MY07A vectors with improved safety for the treatment of USH1B
BR112022019182A2 (pt) * 2020-04-06 2022-11-29 Homology Medicines Inc Composições de vírus adeno-associadas para transferência do gene ids e métodos de uso da mesma
AU2021261471B2 (en) 2020-04-22 2024-10-24 BioNTech SE Coronavirus vaccine
KR102854745B1 (ko) 2020-04-23 2025-09-04 진크래프트 주식회사 R-point 조절 단백질 복합체를 유효성분으로 포함하는 폐암 치료용 약학적 조성물, 상기 복합체의 형성 여부를 이용한 폐암 치료제 스크리닝 방법 및 폐암 진단 방법
CN111665361B (zh) * 2020-04-29 2023-02-28 中南林业科技大学 一种溶酶体标记磁性荧光淀粉纳米颗粒及其制备方法
US12070509B2 (en) * 2020-05-01 2024-08-27 Arcturus Therapeutics, Inc. Nucleic acids and methods of treatment for cystic fibrosis
AU2021268634A1 (en) * 2020-05-04 2022-11-24 The Board Of Trustees Of The Leland Stanford Junior University Compositions, systems, and methods for the generation, identification, and characterization of effector domains for activating and silencing gene expression
EP4146807A4 (en) * 2020-05-08 2024-09-04 Takeda Pharmaceuticals U.S.A., Inc. METHODS OF TREATING NUCLEOTIDE AMPLIFICATION DISEASES ASSOCIATED WITH MSH3 ACTIVITY
US20240043835A1 (en) * 2020-05-11 2024-02-08 The Board Of Trustees Of The Leland Stanford Junior University Systems and Methods for Enhancing Gene Expression
WO2021229502A1 (en) 2020-05-15 2021-11-18 Crispr Therapeutics Ag Messenger rna encoding cas9 for use in genome-editing systems
US11129892B1 (en) 2020-05-18 2021-09-28 Vnv Newco Inc. Vaccine compositions comprising endogenous Gag polypeptides
US20230190883A1 (en) * 2020-05-29 2023-06-22 Bessor Pharma, Llc Stable peptides having renalase agonist activity
AU2021285812A1 (en) 2020-06-01 2023-01-05 Modernatx, Inc. Phenylalanine hydroxylase variants and uses thereof
EP4162047A1 (en) * 2020-06-09 2023-04-12 Roche Innovation Center Copenhagen A/S Guanosine analogues for use in therapeutic polynucleotides
CN116194755A (zh) * 2020-06-23 2023-05-30 总医院公司 隧道纳米管细胞及其用于递送生物分子的方法
WO2022009049A1 (en) * 2020-07-06 2022-01-13 Janssen Biotech, Inc. Prostate neoantigens and their uses
US12295997B2 (en) 2020-07-06 2025-05-13 Janssen Biotech, Inc. Prostate neoantigens and their uses
US11857551B1 (en) 2020-07-10 2024-01-02 Ting Therapeutics Llc Methods for the prevention and treatment of hearing loss
JP2023536067A (ja) * 2020-07-23 2023-08-23 ザ ユニバーシティ オブ ノース カロライナ アット チャペル ヒル 最適化されたｓｌｃ１３ａ５遺伝子および発現カセットならびにそれらの使用
KR20230043151A (ko) 2020-07-24 2023-03-30 더 제너럴 하스피탈 코포레이션 증강된 바이러스-유사 입자 및 세포에의 전달을 위한 그의 사용 방법
EP4189095A1 (en) * 2020-07-27 2023-06-07 Voyager Therapeutics, Inc. Compositions and methods for the treatment of neurological disorders related to glucosylceramidase beta deficiency
CN116322744A (zh) * 2020-07-29 2023-06-23 自由行疗法有限公司 稳定性提高的突变的β-葡糖脑苷脂酶
TWI784298B (zh) * 2020-08-06 2022-11-21 大江生醫股份有限公司 生物活性物質用於製備促進肌膚膠原蛋白質生成及提升肌膚膠原蛋白質密度的組合物的用途
CN114053165B (zh) * 2020-08-06 2023-10-20 大江生医股份有限公司 生物活性物质用于制备改善皮肤状态的组合物的用途
WO2022040275A1 (en) * 2020-08-19 2022-02-24 University Of Massachusetts Development of novel gene therapeutics inflammation-induced bone loss
US11406703B2 (en) 2020-08-25 2022-08-09 Modernatx, Inc. Human cytomegalovirus vaccine
US20230302135A1 (en) * 2020-08-26 2023-09-28 Arizona Board Of Regents On Behalf Of The University Of Arizona Hybrid allosteric receptor-engineered stem cells
US12419948B2 (en) 2020-08-31 2025-09-23 The Broad Institute, Inc. Immunogenic compositions and use thereof
EP4217377A4 (en) * 2020-09-23 2024-11-27 Myeloid Therapeutics, Inc. Improved methods and compositions for expression of nucleic acids in cells
CN112063625A (zh) * 2020-09-24 2020-12-11 武汉纽福斯生物科技有限公司 编码arl2bp的核酸及其应用
TW202229228A (zh) 2020-10-14 2022-08-01 喬治梅森研究基金會 可離子化脂質及其製造和使用方法
EP4237556A2 (en) * 2020-10-28 2023-09-06 Children's Medical Center Corporation Truncated modified recombinant adamts13 and uses thereof
TW202233232A (zh) 2020-11-06 2022-09-01 法商賽諾菲公司 遞送mRNA疫苗的脂質奈米顆粒
US20220145302A1 (en) * 2020-11-09 2022-05-12 Battle Biotech, LLC Targets and methods for treating epstein-barr virus mediated neurodegeneration
WO2022104131A1 (en) 2020-11-13 2022-05-19 Modernatx, Inc. Polynucleotides encoding cystic fibrosis transmembrane conductance regulator for the treatment of cystic fibrosis
CN112480242B (zh) * 2020-12-04 2023-06-06 中国人民解放军陆军军医大学 Spink7蛋白在制备预防和/或治疗溃疡性结肠炎的药物中的应用
CN112402592B (zh) * 2020-12-04 2023-06-02 中国人民解放军陆军军医大学 Spink7蛋白在制备促进过度炎症创面愈合的药物中的应用
CN112552375B (zh) * 2020-12-11 2022-12-23 中国水产科学研究院南海水产研究所 一种罗非鱼副产物抗菌肽及其筛选方法和应用
CN112592902B (zh) * 2020-12-16 2022-03-29 熊猫乳品集团股份有限公司 一种生物活性肽aseppvldvkrpflc及其制备方法和应用
AU2021403156A1 (en) 2020-12-18 2023-07-13 Genevant Sciences Gmbh Peg lipids and lipid nanoparticles
US11596589B2 (en) 2020-12-19 2023-03-07 Purvala Bioscience, Inc. Compositions and method of use for hair straightening and shaping
BR112023012303A2 (pt) 2020-12-22 2024-02-15 CureVac SE Vacina de rna contra variantes de sars-cov-2
EP4274607A1 (en) 2021-01-11 2023-11-15 ModernaTX, Inc. Seasonal rna influenza virus vaccines
CA3208153A1 (en) * 2021-01-14 2022-07-21 Spark Therapeutics, Inc. Compositions and methods for treating fabry disease
CN112725346A (zh) * 2021-01-22 2021-04-30 青岛大学 一种增加尿酸排泄的修饰mRNA序列及其应用
US20250283044A1 (en) * 2021-01-22 2025-09-11 HigherSteaks Limited Products for cell conversion
EP4284417A4 (en) * 2021-01-27 2024-12-25 Spark Therapeutics, Inc. COMPOSITIONS AND METHODS FOR THE TREATMENT OF HEREDITARY ANGIOEDEMA
US20240123040A1 (en) * 2021-02-05 2024-04-18 Sigilon Therapeutics, Inc. Compositions, devices and methods for treating mps vi disease
US11524023B2 (en) 2021-02-19 2022-12-13 Modernatx, Inc. Lipid nanoparticle compositions and methods of formulating the same
WO2022178093A1 (en) * 2021-02-19 2022-08-25 New England Biolabs, Inc. Compositions and methods for labeling modified nucleotides in nucleic acids
AU2022226655A1 (en) 2021-02-25 2023-07-27 Lyell Immunopharma, Inc. Codon-optimized nucleotide sequences encoding an ap-1 transcription factor
KR20230148837A (ko) 2021-02-25 2023-10-25 라이엘 이뮤노파마, 인크. Ror1 표적화 키메라 항원 수용체
JP2024509934A (ja) * 2021-03-08 2024-03-05 アイジーン インコーポレイテッド Ｒｎａの体内伝達用組成物及びその製造方法
WO2022198099A1 (en) * 2021-03-19 2022-09-22 Recode Therapeutics, Inc. Polynucleotide compositions, related formulations, and methods of use thereof
AU2022237643A1 (en) * 2021-03-19 2023-09-28 Generation Bio Co. Non-viral dna vectors and uses thereof for expressing pfic therapeutics
US20240294587A1 (en) * 2021-03-22 2024-09-05 The Johns Hopkins University K-ras inhibitor
EP4314290A4 (en) 2021-03-23 2025-01-15 Recode Therapeutics, Inc. POLYNUCLEOTIDE COMPOSITIONS, RELATED FORMULATIONS AND METHODS OF USE THEREOF
WO2022204371A1 (en) 2021-03-24 2022-09-29 Modernatx, Inc. Lipid nanoparticles containing polynucleotides encoding glucose-6-phosphatase and uses thereof
EP4314260A1 (en) 2021-03-24 2024-02-07 Modernatx, Inc. Lipid nanoparticles and polynucleotides encoding ornithine transcarbamylase for the treatment of ornithine transcarbamylase deficiency
US20240207444A1 (en) 2021-03-24 2024-06-27 Modernatx, Inc. Lipid nanoparticles containing polynucleotides encoding phenylalanine hydroxylase and uses thereof
US20240216288A1 (en) 2021-03-24 2024-07-04 Modernatx, Inc. Lipid nanoparticles containing polynucleotides encoding propionyl-coa carboxylase alpha and beta subunits and uses thereof
WO2022204369A1 (en) 2021-03-24 2022-09-29 Modernatx, Inc. Polynucleotides encoding methylmalonyl-coa mutase for the treatment of methylmalonic acidemia
CN115385998B (zh) * 2021-04-13 2025-08-05 杭州先为达生物科技股份有限公司 稳定的iii型干扰素蛋白及其融合蛋白
IL307770A (en) * 2021-04-20 2023-12-01 Walking Fish Therapeutics Inc Engineering B-cells based on protein production for the treatment of serious diseases
CN115025247A (zh) * 2021-04-23 2022-09-09 上海交通大学医学院 包载促血小板生成素mRNA的组合物及其用途
US12064466B2 (en) * 2021-04-27 2024-08-20 Academia Sinica Methods of treating hypertriglyceridemia or hypertriglyceridemia-related diseases
EP4085932A1 (en) * 2021-05-03 2022-11-09 H.M.Z. Privatstiftung Stabilized, modified rna for use in the treatment of a disease associated with the cystic fibrosis transmembrane conductance regulator (cftr) gene
AU2022270607A1 (en) * 2021-05-03 2023-11-23 North Carolina State University Compositions and methods related to the treatment of ocular diseases in equines
US20220363937A1 (en) 2021-05-14 2022-11-17 Armstrong World Industries, Inc. Stabilization of antimicrobial coatings
WO2022251096A1 (en) * 2021-05-23 2022-12-01 Oregon Health & Science University Promoter sequence and related products and uses thereof
WO2022251644A1 (en) 2021-05-28 2022-12-01 Lyell Immunopharma, Inc. Nr4a3-deficient immune cells and uses thereof
EP4347826A1 (en) 2021-06-02 2024-04-10 Lyell Immunopharma, Inc. Nr4a3-deficient immune cells and uses thereof
WO2022271776A1 (en) 2021-06-22 2022-12-29 Modernatx, Inc. Polynucleotides encoding uridine diphosphate glycosyltransferase 1 family, polypeptide a1 for the treatment of crigler-najjar syndrome
CN113577303B (zh) * 2021-07-05 2023-06-02 四川大学 三分枝rgd修饰的脑胶质瘤靶向脂质材料的制备和应用
WO2023288325A2 (en) * 2021-07-16 2023-01-19 Ptc Therapeutics Inc. Recombinant reelin gene therapy
KR102818854B1 (ko) * 2021-07-29 2025-06-13 주식회사 에스엠엘바이오팜 발현 시스템 및 이를 이용한 핵산 기반 백신
US20230280334A1 (en) * 2021-07-30 2023-09-07 Whitehead Institute For Biomedical Research Cdc20 variants resistant to anti-mitotic drugs and related methods and compositions
AU2022335593A1 (en) * 2021-08-25 2024-03-14 Canbridge Pharmaceuticals, Inc. Aav particles comprising liver-tropic capsid protein and acid alpha-glucosidase and use to treat pompe disease
AU2022336209B2 (en) 2021-09-03 2025-10-16 CureVac SE Novel lipid nanoparticles for delivery of nucleic acids
BR102021018527A2 (pt) * 2021-09-17 2023-03-28 Fundação Oswaldo Cruz Aptâmero de ácido nucleico, composição, uso de um aptâmero, kit diagnóstico, método para detectar ou diagnosticar um tumor, e, método para tratamento de câncer
US20240384245A1 (en) * 2021-09-29 2024-11-21 Sirt6 Ltd Method for treating a disease
US20250017867A1 (en) 2021-10-01 2025-01-16 Modernatx, Inc. Polynucleotides encoding relaxin for the treatment of fibrosis and/or cardiovascular disease
WO2023060059A2 (en) * 2021-10-05 2023-04-13 The Board Of Trustees Of The Leland Stanford Junior University Treatment of polycythemia vera via cr1spr/aav6 genome editing
AU2022361486A1 (en) * 2021-10-06 2024-05-16 Dana-Farber Cancer Institute, Inc. Engineered cytokine receptors for tunable adoptive cell therapy
WO2023061985A2 (en) 2021-10-12 2023-04-20 Modernatx, Inc. Compositions comprising modified rna encoding vegf-a and methods of use
TW202330928A (zh) * 2021-10-18 2023-08-01 美商邏輯生物療法公司 用於治療ｈｔ１之基因療法
JP2024539512A (ja) 2021-10-22 2024-10-28 セイル バイオメディシンズ インコーポレイテッド Ｍｒｎａワクチン組成物
EP4422698A1 (en) 2021-10-29 2024-09-04 CureVac SE Improved circular rna for expressing therapeutic proteins
EP4426340A1 (en) 2021-11-01 2024-09-11 ModernaTX, Inc. Polynucleotides encoding integrin beta-6 and methods of use thereof
CA3237598A1 (en) * 2021-11-08 2023-05-11 Boston Medical Center Corporation Nucleoside modified mrna and uses thereof
US20250120997A1 (en) * 2021-11-09 2025-04-17 The Trustees Of The University Of Pennsylvania Intraspinal delivery of therapeutic agents
WO2023084013A1 (en) 2021-11-12 2023-05-19 Modernatx, Inc. Compositions comprising modified rna encoding vegf-a and methods of use
WO2023091907A1 (en) * 2021-11-16 2023-05-25 Mayo Foundation For Medical Education And Research Methods and materials for assessing and treating neurologic autoimmune disorders and/or cancer
KR20240107356A (ko) 2021-11-23 2024-07-09 세일 바이오메디슨스, 인크. 박테리아-유래 지질 조성물 및 이의 용도
US12186387B2 (en) 2021-11-29 2025-01-07 BioNTech SE Coronavirus vaccine
AU2022421841A1 (en) 2021-12-20 2024-06-27 Sail Biomedicines, Inc. Mrna therapeutic compositions
JP7684523B2 (ja) * 2021-12-21 2025-05-27 エスアールアイ インターナショナル 中枢神経系への細胞特異的輸送のための二重標的化
WO2023133575A2 (en) * 2022-01-10 2023-07-13 Mahana Therapeutics, Inc. Methods and systems for treating chronic itch conditions using digital therapeutics in combination with other therapies
WO2023141376A2 (en) * 2022-01-20 2023-07-27 Mahana Therapeutics, Inc. Methods and systems for treating respiratory conditions using digital therapeutics in combination with other therapies
US20250099614A1 (en) 2022-01-28 2025-03-27 CureVac SE Nucleic acid encoded transcription factor inhibitors
WO2023144798A1 (en) 2022-01-31 2023-08-03 Genevant Sciences Gmbh Ionizable cationic lipids for lipid nanoparticles
US20250269063A2 (en) * 2022-02-07 2025-08-28 Aavogen Inc. Codon-optimized smad7 gene therapy to treat and prevent muscle wasting and to enhance muscle mass
CN114533569B (zh) * 2022-02-16 2023-08-25 杭州诺莘科技有限责任公司 适用于眼部皮肤的细胞穿膜肽/磷脂聚合物修饰的脂质体乳液及其制备和应用
TW202345864A (zh) 2022-02-18 2023-12-01 美商現代公司 編碼檢查點癌症疫苗之ｍＲＮＡ及其用途
CA3245352A1 (en) * 2022-03-04 2023-09-14 Proof Diagnostics, Inc. METHODS AND COMPONENTS FOR DIAGNOSING DISEASES
WO2023177904A1 (en) 2022-03-18 2023-09-21 Modernatx, Inc. Sterile filtration of lipid nanoparticles and filtration analysis thereof for biological applications
WO2023183909A2 (en) 2022-03-25 2023-09-28 Modernatx, Inc. Polynucleotides encoding fanconi anemia, complementation group proteins for the treatment of fanconi anemia
AU2023246941A1 (en) 2022-03-31 2024-10-24 Enterome S.A. Antigenic peptides for prevention and treatment of cancer.
KR20240167063A (ko) 2022-04-01 2024-11-26 나노베이션 테라퓨틱스 인크. mRNA 전달 방법 및 이의 조성물
WO2023196399A1 (en) 2022-04-06 2023-10-12 Modernatx, Inc. Lipid nanoparticles and polynucleotides encoding argininosuccinate lyase for the treatment of argininosuccinic aciduria
CN119278205A (zh) * 2022-04-07 2025-01-07 得克萨斯大学体系董事会 用靶向CIDEB的siRNA治疗肝病的组合物和方法
WO2023212654A2 (en) * 2022-04-27 2023-11-02 The Regents Of The University Of Colorado A Body Corporate Non-endogenous protein production in plant systems
WO2023220428A1 (en) * 2022-05-12 2023-11-16 Wave Life Sciences Ltd. Compositions for editing ass1 transcripts and methods thereof
TW202408594A (zh) 2022-05-12 2024-03-01 瑞士商優洛凡特科學公司 用於膀胱過動之長期基因療法
CN119013405A (zh) 2022-05-13 2024-11-22 上海瑞宏迪医药有限公司 包含utr的核酸构建体及其应用
AU2023273885A1 (en) 2022-05-19 2024-12-05 Lyell Immunopharma, Inc. Polynucleotides targeting nr4a3 and uses thereof
CA3248209A1 (en) 2022-05-25 2023-11-30 CureVac SE Escherichia coli Antigenic Polypeptide-Based Nucleic Acid Vaccine (FIMH)
CN114920806B (zh) * 2022-06-07 2023-09-12 中南大学 多肽及其抗体、以及检测它们的试剂在制备鼻咽癌诊断、预后或治疗制剂中的应用
WO2024002985A1 (en) 2022-06-26 2024-01-04 BioNTech SE Coronavirus vaccine
PT118087A (pt) 2022-07-06 2024-01-08 I3S Instituto De Investig E Inovacao Em Saude Associacao Supressores de ttl e mcak para uso no tratamento do cancro através da sensibilização à resposta ao taxol
CN117264096A (zh) * 2022-07-21 2023-12-22 杭州诺莘科技有限责任公司 一种超分子聚集体及其制备方法和应用
WO2024026295A1 (en) * 2022-07-27 2024-02-01 Aera Therapeutics, Inc. Endogenous gag-based and pnma family capsids and uses thereof
EP4562132A2 (en) * 2022-07-29 2025-06-04 Adicet Therapeutics, Inc. Affinity binding entities directed to cd70 and methods of use thereof
WO2024040212A2 (en) * 2022-08-19 2024-02-22 Staidson Biopharma Inc. Antibodies specifically recognizing programmed cell death 1 ligand 1 and uses thereof
WO2024044147A1 (en) 2022-08-23 2024-02-29 Modernatx, Inc. Methods for purification of ionizable lipids
AU2023274159A1 (en) * 2022-09-07 2024-03-21 Eyegene Inc. COMPOSITION FOR IN-VIVO DELIVERING mRNA CONTAINING MODIFIED NUCLEOTIDE
KR102785258B1 (ko) * 2022-09-07 2025-03-26 아이진 주식회사 변형핵산 함유 mRNA의 체내 전달용 조성물
TW202426652A (zh) * 2022-09-14 2024-07-01 美商奧伊斯特普安生物製藥公司 編碼氧化還原酶之aav載體及其用途
WO2024091694A1 (en) * 2022-10-28 2024-05-02 Mary Hitchcock Memorial Hospital, For Itself And On Behalf Of Dartmouth-Hitchcock Clinic Chimeric human receptor for pathogenic viruses
EP4608442A1 (en) 2022-10-28 2025-09-03 GlaxoSmithKline Biologicals S.A. Nucleic acid based vaccine
WO2024097521A2 (en) * 2022-11-03 2024-05-10 University Of Massachusetts Compositions for treatment of osteogenesis imperfecta
WO2024102434A1 (en) 2022-11-10 2024-05-16 Senda Biosciences, Inc. Rna compositions comprising lipid nanoparticles or lipid reconstructed natural messenger packs
WO2024121378A1 (en) * 2022-12-09 2024-06-13 Institut National de la Santé et de la Recherche Médicale Novel human antiviral genes related to the eleos and lamassu prokaryotic systems
WO2024130158A1 (en) 2022-12-16 2024-06-20 Modernatx, Inc. Lipid nanoparticles and polynucleotides encoding extended serum half-life interleukin-22 for the treatment of metabolic disease
KR20250133812A (ko) * 2022-12-16 2025-09-08 더 클리브랜드 클리닉 파운데이션 Sfts 바이러스 백신
WO2024159172A1 (en) 2023-01-27 2024-08-02 Senda Biosciences, Inc. A modified lipid composition and uses thereof
WO2024163335A2 (en) * 2023-01-30 2024-08-08 The Board Of Regents Of The University Of Texas System Pten gene therapy vectors and uses thereof
EP4410316A1 (en) * 2023-02-01 2024-08-07 4basebio UK Ltd Nanoparticles for delivery of nucleic acid cargos
EP4410828A1 (en) 2023-02-02 2024-08-07 Eberhard-Karls-Universität Tübingen Oligonucleotide encoding a tissue inhibitor of metalloproteases protein for medical use in mammals
WO2024171063A1 (en) * 2023-02-13 2024-08-22 AstraZeneca Ireland Limited Nucleic acids encoding bcl2-associated athanogene 3 (bag3) for gene therapy
WO2024182301A2 (en) 2023-02-27 2024-09-06 Modernatx, Inc. Lipid nanoparticles and polynucleotides encoding galactose-1-phosphate uridylyltransferase (galt) for the treatment of galactosemia
JPWO2024185696A1 (enExample) 2023-03-03 2024-09-12
DE112024001143T5 (de) 2023-03-08 2025-12-18 CureVac SE Neue lipid-nanopartikel-formeln für die abgabe von nukleinsäuren
CN121263528A (zh) * 2023-03-22 2026-01-02 九天生物医药(上海)有限公司 用于威尔逊病基因治疗的重组aav
EP4434534A1 (en) 2023-03-22 2024-09-25 ADvantage Therapeutics, Inc. Klotho mrna
WO2024206329A1 (en) 2023-03-27 2024-10-03 Modernatx, Inc. Nucleic acid molecules encoding bi-specific secreted engagers and uses thereof
WO2024220378A2 (en) * 2023-04-17 2024-10-24 University Of Massachusetts Raav vector for the treatment of cox20 deficiency
WO2024220752A2 (en) 2023-04-19 2024-10-24 Sail Biomedicines, Inc. Rna therapeutic compositions
WO2024220625A1 (en) 2023-04-19 2024-10-24 Sail Biomedicines, Inc. Delivery of polynucleotides from lipid nanoparticles comprising rna and ionizable lipids
WO2024220712A2 (en) 2023-04-19 2024-10-24 Sail Biomedicines, Inc. Vaccine compositions
WO2024223948A1 (en) * 2023-04-28 2024-10-31 Ospedale San Raffaele S.R.L. Vector production
AU2024265267A1 (en) 2023-05-03 2025-11-20 Modernatx, Inc. Polynucleotides encoding cystic fibrosis transmembrane conductance regulator for the treatment of cystic fibrosis
AU2024264943A1 (en) * 2023-05-03 2025-11-13 Monash University Nampt fusion proteins
US12502424B2 (en) 2023-05-05 2025-12-23 Sanofi Pasteur Inc. Compositions for use in treatment of acne
WO2024230934A1 (en) 2023-05-11 2024-11-14 CureVac SE Therapeutic nucleic acid for the treatment of ophthalmic diseases
WO2024236504A1 (en) * 2023-05-15 2024-11-21 Takeda Pharmaceutical Company Limited Sequences and methods for delivery of dna and rna
WO2024238726A1 (en) 2023-05-16 2024-11-21 Omega Therapeutics, Inc. Methods and compositions for modulating methylation of a target gene
WO2024238723A1 (en) 2023-05-16 2024-11-21 Omega Therapeutics, Inc. Methods and compositions for modulating pcsk9 expression
WO2024240962A1 (en) * 2023-05-25 2024-11-28 Ethris Gmbh Gm-csf-encoding nucleic acids, pharmaceutical compositions, methods and uses thereof
CN119264236A (zh) * 2023-07-05 2025-01-07 中国医学科学院药物研究所 一种角蛋白cf2、制法和其药物组合物与用途
CN117069821B (zh) * 2023-07-14 2024-07-19 中山大学肿瘤防治中心（中山大学附属肿瘤医院、中山大学肿瘤研究所） 靶向人pkm1蛋白的nudt13多肽及其在制备药物中的应用
CN119320441A (zh) * 2023-07-17 2025-01-17 中国医学科学院药物研究所 一种角蛋白cf5、制法和其药物组合物与用途
WO2025019742A1 (en) 2023-07-19 2025-01-23 Omega Therapeutics, Inc. Methods and compositions for modulating ctnnb1 expression
WO2025052278A1 (en) 2023-09-05 2025-03-13 Genevant Sciences Gmbh Pyrrolidine based cationic lipids for lipid nanoparticle delivery of therapeutics to hepatic stellate cells
WO2025059215A1 (en) 2023-09-12 2025-03-20 Aadigen, Llc Methods and compositions for treating or preventing cancer
WO2025072383A1 (en) 2023-09-25 2025-04-03 The Broad Institute, Inc. Viral open reading frames, uses thereof, and methods of detecting the same
WO2025072675A1 (en) * 2023-09-29 2025-04-03 Siemens Healthcare Diagnostics Inc. COMPOSITIONS AND METHODS FOR REVERSE TRANSCRIBING MATURE miRNA FOR qPCR
CN119841928A (zh) * 2023-10-18 2025-04-18 中国医学科学院药物研究所 一种角蛋白cf6、制法和其药物组合物与用途
WO2025097055A2 (en) 2023-11-02 2025-05-08 The Broad Institute, Inc. Compositions and methods of use of t cells in immunotherapy
US12364773B2 (en) 2023-12-01 2025-07-22 Recode Therapeutics, Inc. Lipid nanoparticle compositions and uses thereof
CN117471107B (zh) * 2023-12-27 2024-04-26 湖南家辉生物技术有限公司 检测先天性无毛症的hr突变基因、蛋白、试剂、试剂盒及应用
CN117959323B (zh) * 2024-01-12 2025-01-21 南方医科大学南方医院 环状rna在制备防治放射性肝纤维化的药物中的应用
WO2025155751A1 (en) * 2024-01-17 2025-07-24 Nutcracker Therapeutics, Inc. Improved method for isolating and characterizing proteins
TW202530250A (zh) * 2024-01-25 2025-08-01 大陸商四川至善唯新生物科技有限公司 編碼卵泡抑素的核酸及其用途
WO2025178388A1 (ko) * 2024-02-20 2025-08-28 가천대학교 산학협력단 통증 치료용 의약 조성물
WO2025194138A1 (en) 2024-03-14 2025-09-18 Tessera Therapeutics, Inc. St1cas9 compositions and methods for modulating a genome
WO2025212858A1 (en) * 2024-04-03 2025-10-09 Children's Hospital Medical Center Ivt messenger rna and methods of treating or preventing pfic type iv
WO2025235563A1 (en) 2024-05-07 2025-11-13 Omega Therapeutics, Inc. Epigenetic modulation for upregulation of genes
WO2025233431A1 (en) 2024-05-07 2025-11-13 Immatics Biotechnologies Gmbh Heteromeric proteins comprising three heteromerization improving substitution, production, combinations and applications thereof
CN118406133B (zh) * 2024-05-30 2025-02-28 徐州医科大学 一种多肽5-HT4R-peptide及其应用
WO2025255199A1 (en) 2024-06-05 2025-12-11 Modernatx, Inc. Argininosuccinate synthase 1 and argininosuccinate lyase polypeptides and polynucleotides and uses thereof
CN119345218A (zh) * 2024-10-18 2025-01-24 中南大学湘雅医院 腺苷在治疗蛇毒神经毒性中的应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090286852A1 (en) * 2005-08-23 2009-11-19 Katalin Kariko RNA containing modified nucleosides and methods of use thereof
WO2010144740A1 (en) * 2009-06-10 2010-12-16 Alnylam Pharmaceuticals, Inc. Improved lipid formulation
US20130115274A1 (en) * 2011-11-04 2013-05-09 Nitto Denko Corporation Method of producing lipid nanoparticles for drug delivery

Family Cites Families (1470)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2008526A (en) 1932-11-03 1935-07-16 Wappler Frederick Charles Method and means for treating living tissue
US3467096A (en) 1966-04-12 1969-09-16 Ferrell S Horn Multiple hypodermic syringe arrangement
BE757653A (fr) 1969-10-21 1971-04-16 Ugine Kuhlmann Nouveaux medicaments derives d'acides nucleiques et procedes pour leur preparation
BE786542A (fr) 1971-07-22 1973-01-22 Dow Corning Dispositif d'aspiration permettant d'obtenir des echantillons de cellules
US3906092A (en) 1971-11-26 1975-09-16 Merck & Co Inc Stimulation of antibody response
US4399216A (en) 1980-02-25 1983-08-16 The Trustees Of Columbia University Processes for inserting DNA into eucaryotic cells and for producing proteinaceous materials
US5132418A (en) 1980-02-29 1992-07-21 University Patents, Inc. Process for preparing polynucleotides
US4500707A (en) 1980-02-29 1985-02-19 University Patents, Inc. Nucleosides useful in the preparation of polynucleotides
US4458066A (en) 1980-02-29 1984-07-03 University Patents, Inc. Process for preparing polynucleotides
US4411657A (en) 1980-05-19 1983-10-25 Anibal Galindo Hypodermic needle
US4973679A (en) 1981-03-27 1990-11-27 University Patents, Inc. Process for oligonucleo tide synthesis using phosphormidite intermediates
US4668777A (en) 1981-03-27 1987-05-26 University Patents, Inc. Phosphoramidite nucleoside compounds
US4415732A (en) 1981-03-27 1983-11-15 University Patents, Inc. Phosphoramidite compounds and processes
US4401796A (en) 1981-04-30 1983-08-30 City Of Hope Research Institute Solid-phase synthesis of polynucleotides
US4373071A (en) 1981-04-30 1983-02-08 City Of Hope Research Institute Solid-phase synthesis of polynucleotides
US4474569A (en) 1982-06-28 1984-10-02 Denver Surgical Developments, Inc. Antenatal shunt
JPS5927900A (ja) 1982-08-09 1984-02-14 Wakunaga Seiyaku Kk 固定化オリゴヌクレオチド
US4737462A (en) 1982-10-19 1988-04-12 Cetus Corporation Structural genes, plasmids and transformed cells for producing cysteine depleted muteins of interferon-β
US4588585A (en) 1982-10-19 1986-05-13 Cetus Corporation Human recombinant cysteine depleted interferon-β muteins
FR2540122B1 (fr) 1983-01-27 1985-11-29 Centre Nat Rech Scient Nouveaux composes comportant une sequence d'oligonucleotide liee a un agent d'intercalation, leur procede de synthese et leur application
US4605735A (en) 1983-02-14 1986-08-12 Wakunaga Seiyaku Kabushiki Kaisha Oligonucleotide derivatives
US4948882A (en) 1983-02-22 1990-08-14 Syngene, Inc. Single-stranded labelled oligonucleotides, reactive monomers and methods of synthesis
US4824941A (en) 1983-03-10 1989-04-25 Julian Gordon Specific antibody to the native form of 2'5'-oligonucleotides, the method of preparation and the use as reagents in immunoassays or for binding 2'5'-oligonucleotides in biological systems
US4816567A (en) 1983-04-08 1989-03-28 Genentech, Inc. Recombinant immunoglobin preparations
US4587044A (en) 1983-09-01 1986-05-06 The Johns Hopkins University Linkage of proteins to nucleic acids
US5118800A (en) 1983-12-20 1992-06-02 California Institute Of Technology Oligonucleotides possessing a primary amino group in the terminal nucleotide
US5118802A (en) 1983-12-20 1992-06-02 California Institute Of Technology DNA-reporter conjugates linked via the 2' or 5'-primary amino group of the 5'-terminal nucleoside
US4579849A (en) 1984-04-06 1986-04-01 Merck & Co., Inc. N-alkylguanine acyclonucleosides as antiviral agents
US4957735A (en) 1984-06-12 1990-09-18 The University Of Tennessee Research Corporation Target-sensitive immunoliposomes- preparation and characterization
FR2567892B1 (fr) 1984-07-19 1989-02-17 Centre Nat Rech Scient Nouveaux oligonucleotides, leur procede de preparation et leurs applications comme mediateurs dans le developpement des effets des interferons
US5430136A (en) 1984-10-16 1995-07-04 Chiron Corporation Oligonucleotides having selectably cleavable and/or abasic sites
US5258506A (en) 1984-10-16 1993-11-02 Chiron Corporation Photolabile reagents for incorporation into oligonucleotide chains
US4828979A (en) 1984-11-08 1989-05-09 Life Technologies, Inc. Nucleotide analogs for nucleic acid labeling and detection
US4959314A (en) 1984-11-09 1990-09-25 Cetus Corporation Cysteine-depleted muteins of biologically active proteins
US5036006A (en) 1984-11-13 1991-07-30 Cornell Research Foundation, Inc. Method for transporting substances into living cells and tissues and apparatus therefor
US5116943A (en) 1985-01-18 1992-05-26 Cetus Corporation Oxidation-resistant muteins of Il-2 and other protein
CA1288073C (en) 1985-03-07 1991-08-27 Paul G. Ahlquist Rna transformation vector
US5034506A (en) 1985-03-15 1991-07-23 Anti-Gene Development Group Uncharged morpholino-based polymers having achiral intersubunit linkages
EP0204401A1 (en) 1985-04-09 1986-12-10 Biogen, Inc. Method of improving the yield of polypeptides produced in a host cell by stabilizing mRNA
US4762779A (en) 1985-06-13 1988-08-09 Amgen Inc. Compositions and methods for functionalizing nucleic acids
US5017691A (en) 1986-07-03 1991-05-21 Schering Corporation Mammalian interleukin-4
US5317098A (en) 1986-03-17 1994-05-31 Hiroaki Shizuya Non-radioisotope tagging of fragments
US5153319A (en) 1986-03-31 1992-10-06 University Patents, Inc. Process for preparing polynucleotides
US4879111A (en) 1986-04-17 1989-11-07 Cetus Corporation Treatment of infections with lymphokines
JPS638396A (ja) 1986-06-30 1988-01-14 Wakunaga Pharmaceut Co Ltd ポリ標識化オリゴヌクレオチド誘導体
US4904582A (en) 1987-06-11 1990-02-27 Synthetic Genetics Novel amphiphilic nucleic acid conjugates
IE72468B1 (en) 1987-07-31 1997-04-09 Univ Leland Stanford Junior Selective amplification of target polynucleotide sequences
US6090591A (en) 1987-07-31 2000-07-18 The Board Of Trustees Of The Leland Stanford Junior University Selective amplification of target polynucleotide sequences
US5585481A (en) 1987-09-21 1996-12-17 Gen-Probe Incorporated Linking reagents for nucleotide probes
US5525465A (en) 1987-10-28 1996-06-11 Howard Florey Institute Of Experimental Physiology And Medicine Oligonucleotide-polyamide conjugates and methods of production and applications of the same
DE3738460A1 (de) 1987-11-12 1989-05-24 Max Planck Gesellschaft Modifizierte oligonukleotide
CA1327358C (en) 1987-11-17 1994-03-01 Morio Fujiu Fluoro cytidine derivatives
DE68908054T2 (de) 1988-01-21 1994-03-10 Genentech Inc Verstärkung und nachweis von nukleinsäuresequenzen.
JP2650159B2 (ja) 1988-02-24 1997-09-03 アクゾ・ノベル・エヌ・ベー 核酸増幅方法
CA1340807C (en) 1988-02-24 1999-11-02 Lawrence T. Malek Nucleic acid amplification process
US5082830A (en) 1988-02-26 1992-01-21 Enzo Biochem, Inc. End labeled nucleotide probe
DE68923027D1 (de) 1988-03-04 1995-07-20 Cancer Res Campaign Tech Antigene.
JPH02503867A (ja) 1988-04-15 1990-11-15 プロテイン　デザイン　ラブズ　インコーポレーテッド Ｉｌ‐２レセプター特異的キメラ抗体
US5109124A (en) 1988-06-01 1992-04-28 Biogen, Inc. Nucleic acid probe linked to a label having a terminal cysteine
US5168038A (en) 1988-06-17 1992-12-01 The Board Of Trustees Of The Leland Stanford Junior University In situ transcription in cells and tissues
US5021335A (en) 1988-06-17 1991-06-04 The Board Of Trustees Of The Leland Stanford Junior University In situ transcription in cells and tissues
US5130238A (en) 1988-06-24 1992-07-14 Cangene Corporation Enhanced nucleic acid amplification process
US5262536A (en) 1988-09-15 1993-11-16 E. I. Du Pont De Nemours And Company Reagents for the preparation of 5'-tagged oligonucleotides
US5759802A (en) 1988-10-26 1998-06-02 Tonen Corporation Production of human serum alubumin A
US5512439A (en) 1988-11-21 1996-04-30 Dynal As Oligonucleotide-linked magnetic particles and uses thereof
US5221732A (en) 1988-12-06 1993-06-22 The United States Of America As Represented By The Department Of Health And Human Services Antimicrobial magainin modified peptides
US5047524A (en) 1988-12-21 1991-09-10 Applied Biosystems, Inc. Automated system for polynucleotide synthesis and purification
US5262530A (en) 1988-12-21 1993-11-16 Applied Biosystems, Inc. Automated system for polynucleotide synthesis and purification
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5599923A (en) 1989-03-06 1997-02-04 Board Of Regents, University Of Tx Texaphyrin metal complexes having improved functionalization
US5457183A (en) 1989-03-06 1995-10-10 Board Of Regents, The University Of Texas System Hydroxylated texaphyrins
US5703055A (en) 1989-03-21 1997-12-30 Wisconsin Alumni Research Foundation Generation of antibodies through lipid mediated DNA delivery
DK0737750T3 (da) 1989-03-21 2003-09-01 Vical Inc Ekspression af exogene polynucleotidsekvenser i vertebrater
US6214804B1 (en) 1989-03-21 2001-04-10 Vical Incorporated Induction of a protective immune response in a mammal by injecting a DNA sequence
US6867195B1 (en) 1989-03-21 2005-03-15 Vical Incorporated Lipid-mediated polynucleotide administration to reduce likelihood of subject's becoming infected
US6673776B1 (en) 1989-03-21 2004-01-06 Vical Incorporated Expression of exogenous polynucleotide sequences in a vertebrate, mammal, fish, bird or human
US5693622A (en) 1989-03-21 1997-12-02 Vical Incorporated Expression of exogenous polynucleotide sequences cardiac muscle of a mammal
US5012818A (en) 1989-05-04 1991-05-07 Joishy Suresh K Two in one bone marrow surgical needle
IE66597B1 (en) 1989-05-10 1996-01-24 Akzo Nv Method for the synthesis of ribonucleic acid (RNA)
US5332671A (en) 1989-05-12 1994-07-26 Genetech, Inc. Production of vascular endothelial cell growth factor and DNA encoding same
US5240855A (en) 1989-05-12 1993-08-31 Pioneer Hi-Bred International, Inc. Particle gun
US5391723A (en) 1989-05-31 1995-02-21 Neorx Corporation Oligonucleotide conjugates
US4958013A (en) 1989-06-06 1990-09-18 Northwestern University Cholesteryl modified oligonucleotides
CA2020958C (en) 1989-07-11 2005-01-11 Daniel L. Kacian Nucleic acid sequence amplification methods
US5451463A (en) 1989-08-28 1995-09-19 Clontech Laboratories, Inc. Non-nucleoside 1,3-diol reagents for labeling synthetic oligonucleotides
US5254469A (en) 1989-09-12 1993-10-19 Eastman Kodak Company Oligonucleotide-enzyme conjugate that can be used as a probe in hybridization assays and polymerase chain reaction procedures
US5591722A (en) 1989-09-15 1997-01-07 Southern Research Institute 2'-deoxy-4'-thioribonucleosides and their antiviral activity
US5545522A (en) 1989-09-22 1996-08-13 Van Gelder; Russell N. Process for amplifying a target polynucleotide sequence using a single primer-promoter complex
KR0185192B1 (ko) 1989-10-05 1999-04-01 제임스 더블유. 데이비 신규의 유전자 및 폴리펩티드의 무세포 합성 및 분리
DE69034150T2 (de) 1989-10-24 2005-08-25 Isis Pharmaceuticals, Inc., Carlsbad 2'-Modifizierte Oligonukleotide
US5208020A (en) 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
NO904633L (no) 1989-11-09 1991-05-10 Molecular Diagnostics Inc Amplifikasjon av nukleinsyrer ved transkriberbar haarnaalsprobe.
US5215899A (en) 1989-11-09 1993-06-01 Miles Inc. Nucleic acid amplification employing ligatable hairpin probe and transcription
US5292873A (en) 1989-11-29 1994-03-08 The Research Foundation Of State University Of New York Nucleic acids labeled with naphthoquinone probe
US5633076A (en) 1989-12-01 1997-05-27 Pharming Bv Method of producing a transgenic bovine or transgenic bovine embryo
US5697901A (en) 1989-12-14 1997-12-16 Elof Eriksson Gene delivery by microneedle injection
US5486603A (en) 1990-01-08 1996-01-23 Gilead Sciences, Inc. Oligonucleotide having enhanced binding affinity
US5646265A (en) 1990-01-11 1997-07-08 Isis Pharmceuticals, Inc. Process for the preparation of 2'-O-alkyl purine phosphoramidites
US7037646B1 (en) 1990-01-11 2006-05-02 Isis Pharmaceuticals, Inc. Amine-derivatized nucleosides and oligonucleosides
US5670633A (en) 1990-01-11 1997-09-23 Isis Pharmaceuticals, Inc. Sugar modified oligonucleotides that detect and modulate gene expression
US6783931B1 (en) 1990-01-11 2004-08-31 Isis Pharmaceuticals, Inc. Amine-derivatized nucleosides and oligonucleosides
US5578718A (en) 1990-01-11 1996-11-26 Isis Pharmaceuticals, Inc. Thiol-derivatized nucleosides
US5214136A (en) 1990-02-20 1993-05-25 Gilead Sciences, Inc. Anthraquinone-derivatives oligonucleotides
AU7579991A (en) 1990-02-20 1991-09-18 Gilead Sciences, Inc. Pseudonucleosides and pseudonucleotides and their polymers
CA2028849A1 (en) 1990-03-08 1991-09-09 Michinao Mizugaki Monoclonal antibodies, assay method, reagent kit, sarching method and drug missiles using them
US5264618A (en) 1990-04-19 1993-11-23 Vical, Inc. Cationic lipids for intracellular delivery of biologically active molecules
GB9009980D0 (en) 1990-05-03 1990-06-27 Amersham Int Plc Phosphoramidite derivatives,their preparation and the use thereof in the incorporation of reporter groups on synthetic oligonucleotides
DK0455905T3 (da) 1990-05-11 1998-12-07 Microprobe Corp Dipsticks til nukleinsyrehybridiseringsassays og fremgangsmåde til kovalent immobilisering af oligonukleotider
US5194370A (en) 1990-05-16 1993-03-16 Life Technologies, Inc. Promoter ligation activated transcription amplification of nucleic acid sequences
CA2042448A1 (en) 1990-06-05 1991-12-06 Jonathan P. Duvick Antimicrobial peptides and plant disease resistance based thereon
US5637459A (en) 1990-06-11 1997-06-10 Nexstar Pharmaceuticals, Inc. Systematic evolution of ligands by exponential enrichment: chimeric selex
US5447914A (en) 1990-06-21 1995-09-05 Emory University Antimicrobial peptides
AU649066B2 (en) 1990-07-25 1994-05-12 Syngene, Inc. Circular extension for generating multiple nucleic acid complements
US5489677A (en) 1990-07-27 1996-02-06 Isis Pharmaceuticals, Inc. Oligonucleoside linkages containing adjacent oxygen and nitrogen atoms
US5688941A (en) 1990-07-27 1997-11-18 Isis Pharmaceuticals, Inc. Methods of making conjugated 4' desmethyl nucleoside analog compounds
US5602240A (en) 1990-07-27 1997-02-11 Ciba Geigy Ag. Backbone modified oligonucleotide analogs
US5608046A (en) 1990-07-27 1997-03-04 Isis Pharmaceuticals, Inc. Conjugated 4'-desmethyl nucleoside analog compounds
US5138045A (en) 1990-07-27 1992-08-11 Isis Pharmaceuticals Polyamine conjugated oligonucleotides
US5218105A (en) 1990-07-27 1993-06-08 Isis Pharmaceuticals Polyamine conjugated oligonucleotides
US5245022A (en) 1990-08-03 1993-09-14 Sterling Drug, Inc. Exonuclease resistant terminally substituted oligonucleotides
US5512667A (en) 1990-08-28 1996-04-30 Reed; Michael W. Trifunctional intermediates for preparing 3'-tailed oligonucleotides
US6140496A (en) 1990-10-09 2000-10-31 Benner; Steven Albert Precursors for deoxyribonucleotides containing non-standard nucleosides
DE69132510T2 (de) 1990-11-08 2001-05-03 Hybridon, Inc. Verbindung von mehrfachreportergruppen auf synthetischen oligonukleotiden
US5527288A (en) 1990-12-13 1996-06-18 Elan Medical Technologies Limited Intradermal drug delivery device and method for intradermal delivery of drugs
AU648140B2 (en) 1991-02-01 1994-04-14 Virtual Drug Development, Inc. Reverse antimicrobial peptides and antimicrobial compositions
US6100024A (en) 1991-02-08 2000-08-08 Promega Corporation Methods and compositions for nucleic acid detection by target extension and probe amplification
EP1905782A1 (en) 1991-03-18 2008-04-02 New York University Monoclonal and chimeric antibodies specific for human tumor necrosis factor
US5426180A (en) 1991-03-27 1995-06-20 Research Corporation Technologies, Inc. Methods of making single-stranded circular oligonucleotides
ES2134212T3 (es) 1991-04-25 1999-10-01 Chugai Pharmaceutical Co Ltd Anticuerpo humano reconstituido contra el receptor de la interleuquina 6 humano.
US5539082A (en) 1993-04-26 1996-07-23 Nielsen; Peter E. Peptide nucleic acids
US5714331A (en) 1991-05-24 1998-02-03 Buchardt, Deceased; Ole Peptide nucleic acids having enhanced binding affinity, sequence specificity and solubility
US5719262A (en) 1993-11-22 1998-02-17 Buchardt, Deceased; Ole Peptide nucleic acids having amino acid side chains
US5169766A (en) 1991-06-14 1992-12-08 Life Technologies, Inc. Amplification of nucleic acid molecules
US5371241A (en) 1991-07-19 1994-12-06 Pharmacia P-L Biochemicals Inc. Fluorescein labelled phosphoramidites
US5199441A (en) 1991-08-20 1993-04-06 Hogle Hugh H Fine needle aspiration biopsy apparatus and method
EP0538194B1 (de) 1991-10-17 1997-06-04 Novartis AG Bicyclische Nukleoside, Oligonukleotide, Verfahren zu deren Herstellung und Zwischenprodukte
US5298422A (en) 1991-11-06 1994-03-29 Baylor College Of Medicine Myogenic vector systems
US5359044A (en) 1991-12-13 1994-10-25 Isis Pharmaceuticals Cyclobutyl oligonucleotide surrogates
US5824307A (en) 1991-12-23 1998-10-20 Medimmune, Inc. Human-murine chimeric antibodies against respiratory syncytial virus
US5565552A (en) 1992-01-21 1996-10-15 Pharmacyclics, Inc. Method of expanded porphyrin-oligonucleotide conjugate synthesis
US5595726A (en) 1992-01-21 1997-01-21 Pharmacyclics, Inc. Chromophore probe for detection of nucleic acid
EP0625049A4 (en) 1992-01-23 1995-07-12 Vical Inc EX VIVO GENTRANSFER.
FR2687679B1 (fr) 1992-02-05 1994-10-28 Centre Nat Rech Scient Oligothionucleotides.
JP3368603B2 (ja) 1992-02-28 2003-01-20 オリンパス光学工業株式会社 遺伝子治療用処置具
DK0563475T3 (da) 1992-03-25 2000-09-18 Immunogen Inc Konjugater af cellebindende midler og derivater af CC-1065
US6174666B1 (en) 1992-03-27 2001-01-16 The United States Of America As Represented By The Department Of Health And Human Services Method of eliminating inhibitory/instability regions from mRNA
US6132419A (en) 1992-05-22 2000-10-17 Genetronics, Inc. Electroporetic gene and drug therapy
US5514545A (en) 1992-06-11 1996-05-07 Trustees Of The University Of Pennsylvania Method for characterizing single cells based on RNA amplification for diagnostics and therapeutics
EP0577558A2 (de) 1992-07-01 1994-01-05 Ciba-Geigy Ag Carbocyclische Nukleoside mit bicyclischen Ringen, Oligonukleotide daraus, Verfahren zu deren Herstellung, deren Verwendung und Zwischenproduckte
US6670178B1 (en) 1992-07-10 2003-12-30 Transkaryotic Therapies, Inc. In Vivo production and delivery of insulinotropin for gene therapy
US5272250A (en) 1992-07-10 1993-12-21 Spielvogel Bernard F Boronated phosphoramidate compounds
DE69310179T2 (de) 1992-07-31 1997-07-31 Behringwerke Ag Verfahren zur einführung von definierten sequenzen am 3' ende von polynukleotiden
US5273525A (en) 1992-08-13 1993-12-28 Btx Inc. Injection and electroporation apparatus for drug and gene delivery
US5240885A (en) 1992-09-21 1993-08-31 Corning Incorporated Rare earth-doped, stabilized cadmium halide glasses
AU5665694A (en) 1992-11-04 1994-05-24 Denver Biomaterials Inc. Apparatus for removal of pleural effusion fluid
WO1994011026A2 (en) 1992-11-13 1994-05-26 Idec Pharmaceuticals Corporation Therapeutic application of chimeric and radiolabeled antibodies to human b lymphocyte restricted differentiation antigen for treatment of b cell lymphoma
US5736137A (en) 1992-11-13 1998-04-07 Idec Pharmaceuticals Corporation Therapeutic application of chimeric and radiolabeled antibodies to human B lymphocyte restricted differentiation antigen for treatment of B cell lymphoma
US5429923A (en) * 1992-12-11 1995-07-04 President And Fellows Of Harvard College Method for detecting hypertrophic cardiomyophathy associated mutations
US5574142A (en) 1992-12-15 1996-11-12 Microprobe Corporation Peptide linkers for improved oligonucleotide delivery
AU688751B2 (en) 1993-01-12 1998-03-19 Biogen Idec Ma Inc. Recombinant anti-VLA4 antibody molecules
US5607914A (en) 1993-01-13 1997-03-04 Pioneer Hi-Bred International, Inc. Synthetic antimicrobial peptides
US5459235A (en) 1993-03-19 1995-10-17 The Regents Of The University Of California Antimicrobial peptides antibodies and nucleic acid molecules from bovine neutrophils
FR2703253B1 (fr) 1993-03-30 1995-06-23 Centre Nat Rech Scient Applicateur d'impulsions electriques pour traitement de tissus biologiques.
EP0691968B1 (en) 1993-03-30 1997-07-16 Sanofi Acyclic nucleoside analogs and oligonucleotide sequences containing them
DE4311944A1 (de) 1993-04-10 1994-10-13 Degussa Umhüllte Natriumpercarbonatpartikel, Verfahren zu deren Herstellung und sie enthaltende Wasch-, Reinigungs- und Bleichmittelzusammensetzungen
US7135312B2 (en) 1993-04-15 2006-11-14 University Of Rochester Circular DNA vectors for synthesis of RNA and DNA
US5773244A (en) 1993-05-19 1998-06-30 Regents Of The University Of California Methods of making circular RNA
US6541498B2 (en) 1993-05-20 2003-04-01 Texas Biotechnology Benzenesulfonamides and the use thereof to modulate the activity of endothelin
US5851829A (en) 1993-07-16 1998-12-22 Dana-Farber Cancer Institute Method of intracellular binding of target molecules
US6294664B1 (en) 1993-07-29 2001-09-25 Isis Pharmaceuticals, Inc. Synthesis of oligonucleotides
US5672491A (en) 1993-09-20 1997-09-30 The Leland Stanford Junior University Recombinant production of novel polyketides
US6432711B1 (en) 1993-11-03 2002-08-13 Diacrin, Inc. Embryonic stem cells capable of differentiating into desired cell lines
US6096503A (en) 1993-11-12 2000-08-01 The Scripps Research Institute Method for simultaneous identification of differentially expresses mRNAs and measurement of relative concentrations
US5446137B1 (en) 1993-12-09 1998-10-06 Behringwerke Ag Oligonucleotides containing 4'-substituted nucleotides
US5519134A (en) 1994-01-11 1996-05-21 Isis Pharmaceuticals, Inc. Pyrrolidine-containing monomers and oligomers
US5840299A (en) 1994-01-25 1998-11-24 Athena Neurosciences, Inc. Humanized antibodies against leukocyte adhesion molecule VLA-4
US7435802B2 (en) 1994-01-25 2008-10-14 Elan Pharaceuticals, Inc. Humanized anti-VLA4 immunoglobulins
ATE272113T1 (de) 1994-02-16 2004-08-15 Crucell Holland Bv Melanoma-assoziierte antigene, epitope davon und impstoffe gegen melanoma
IL112820A0 (en) 1994-03-07 1995-05-26 Merck & Co Inc Coordinate in vivo gene expression
EP0754242A4 (en) 1994-03-18 1997-06-11 Lynx Therapeutics Inc SYNTHESIS AND SUBSTANCE, HYBRIDIZATION AND NUCLEASE-RESISTANT PROPERTIES OF OLIGONUCLEOTID-N3'-m (7) P5'-PHOSPHORAMIDATE
US5457041A (en) 1994-03-25 1995-10-10 Science Applications International Corporation Needle array and method of introducing biological substances into living cells using the needle array
WO1995026204A1 (en) 1994-03-25 1995-10-05 Isis Pharmaceuticals, Inc. Immune stimulation by phosphorothioate oligonucleotide analogs
US5627053A (en) 1994-03-29 1997-05-06 Ribozyme Pharmaceuticals, Inc. 2'deoxy-2'-alkylnucleotide containing nucleic acid
US6074642A (en) 1994-05-02 2000-06-13 Alexion Pharmaceuticals, Inc. Use of antibodies specific to human complement component C5 for the treatment of glomerulonephritis
AU699552B2 (en) 1994-05-18 1998-12-10 Bayer Cropscience Aktiengesellschaft DNA sequences coding for enzymes capable of facilitating the synthesis of linear alpha-1,4 glucans in plants, fungi and microorganisms
US5550109A (en) 1994-05-24 1996-08-27 Magainin Pharmaceuticals Inc. Inducible defensin peptide from mammalian epithelia
EP0802980A1 (en) 1994-06-02 1997-10-29 Chiron Corporation Nucleic acid immunization using a virus-based infection/transfection system
GB9412230D0 (en) 1994-06-17 1994-08-10 Celltech Ltd Interleukin-5 specific recombiant antibodies
US6239116B1 (en) 1994-07-15 2001-05-29 University Of Iowa Research Foundation Immunostimulatory nucleic acid molecules
US5597696A (en) 1994-07-18 1997-01-28 Becton Dickinson And Company Covalent cyanine dye oligonucleotide conjugates
AU3272695A (en) 1994-08-12 1996-03-07 Immunomedics Inc. Immunoconjugates and humanized antibodies specific for b-cell lymphoma and leukemia cells
US5597909A (en) 1994-08-25 1997-01-28 Chiron Corporation Polynucleotide reagents containing modified deoxyribose moieties, and associated methods of synthesis and use
US5580731A (en) 1994-08-25 1996-12-03 Chiron Corporation N-4 modified pyrimidine deoxynucleotides and oligonucleotide probes synthesized therewith
US5665545A (en) 1994-11-28 1997-09-09 Akzo Nobel N.V. Terminal repeat amplification method
US5641665A (en) 1994-11-28 1997-06-24 Vical Incorporated Plasmids suitable for IL-2 expression
US5588960A (en) 1994-12-01 1996-12-31 Vidamed, Inc. Transurethral needle delivery device with cystoscope and method for treatment of urinary incontinence
US5807718A (en) 1994-12-02 1998-09-15 The Scripps Research Institute Enzymatic DNA molecules
US5585108A (en) 1994-12-30 1996-12-17 Nanosystems L.L.C. Formulations of oral gastrointestinal therapeutic agents in combination with pharmaceutically acceptable clays
PT795018E (pt) 1995-01-06 2007-12-21 Plant Res Int Bv Sequências de adn codificando enzimas de síntese de polímeros de hidratos de carbono e método para a produção de plantas transgénicas
US5795587A (en) 1995-01-23 1998-08-18 University Of Pittsburgh Stable lipid-comprising drug delivery complexes and methods for their production
US5824497A (en) 1995-02-10 1998-10-20 Mcmaster University High efficiency translation of mRNA molecules
EP0727187B1 (en) 1995-02-15 2003-08-06 Joseph Eldor Multiple hole spinal needle
DE69621507T2 (de) 1995-03-28 2003-01-09 Japan Science And Technology Corp., Kawaguchi Verfahren zur molekularen Indexierung von Genen unter Verwendung von Restriktionsenzymen
US5869230A (en) 1995-03-30 1999-02-09 Beth Israel Hospital Association Gene transfer into the kidney
US6020139A (en) * 1995-04-25 2000-02-01 Oridigm Corporation S-adenosyl methionine regulation of metabolic pathways and its use in diagnosis and therapy
US5986054A (en) 1995-04-28 1999-11-16 The Hospital For Sick Children, Hsc Research And Development Limited Partnership Genetic sequences and proteins related to alzheimer's disease
FR2733762B1 (fr) 1995-05-02 1997-08-01 Genset Sa Methode de couplage specifique de la coiffe de l'extremite 5' d'un fragment d'arnm et preparation d'arnm et d'adnc complet
US5700642A (en) 1995-05-22 1997-12-23 Sri International Oligonucleotide sizing using immobilized cleavable primers
US6057291A (en) 1995-06-02 2000-05-02 University Of British Columbia Antimicrobial cationic peptides
US6111095A (en) 1995-06-07 2000-08-29 Merck & Co., Inc. Capped synthetic RNA, analogs, and aptamers
US6051429A (en) 1995-06-07 2000-04-18 Life Technologies, Inc. Peptide-enhanced cationic lipid transfections
US5889136A (en) 1995-06-09 1999-03-30 The Regents Of The University Of Colorado Orthoester protecting groups in RNA synthesis
US5734015A (en) 1995-06-19 1998-03-31 Magainin Pharmaceuticals Inc. Family of linear antimicrobial peptides from hagfish intestine
US5766903A (en) 1995-08-23 1998-06-16 University Technology Corporation Circular RNA and uses thereof
ATE412668T1 (de) 1995-08-23 2008-11-15 Univ British Columbia Antimikrobielle kationische peptide und methoden zu ihrer identifizierung
US6265389B1 (en) 1995-08-31 2001-07-24 Alkermes Controlled Therapeutics, Inc. Microencapsulation and sustained release of oligonucleotides
WO1997011085A1 (en) 1995-09-19 1997-03-27 University Of Massachusetts Inhibited biological degradation of oligodeoxynucleotides
US5830879A (en) 1995-10-02 1998-11-03 St. Elizabeth's Medical Center Of Boston, Inc. Treatment of vascular injury using vascular endothelial growth factor
US6265387B1 (en) 1995-10-11 2001-07-24 Mirus, Inc. Process of delivering naked DNA into a hepatocyte via bile duct
US5871697A (en) 1995-10-24 1999-02-16 Curagen Corporation Method and apparatus for identifying, classifying, or quantifying DNA sequences in a sample without sequencing
EP0771873A3 (en) 1995-10-27 1998-03-04 Takeda Chemical Industries, Ltd. Neuronal cell-specific receptor protein
CU22584A1 (es) 1995-11-17 1999-11-03 Centro Inmunologia Molecular Composiciones farmacéuticas que contienen un anticuerpo monoclonal que reconoce el antígeno de diferenciación leucocitario humano cd6 y sus usos para el diagnóstico y tratamiento de la psoriasis
US6090382A (en) 1996-02-09 2000-07-18 Basf Aktiengesellschaft Human antibodies that bind human TNFα
BR9612011A (pt) 1995-12-13 1999-05-18 Zeneca Ltd Peptídeo antifungico sequencia de dna recombinante vetor sistema biológico planta composição antifúngica e processo para o combate a fungos ou a bacterias
US5962271A (en) 1996-01-03 1999-10-05 Cloutech Laboratories, Inc. Methods and compositions for generating full-length cDNA having arbitrary nucleotide sequence at the 3'-end
US5789578A (en) 1996-01-11 1998-08-04 Massey University Methods for the preparation of resins with ligands attached thereto through a linking group comprising sulfide, sulfoxide or sulfone functionality
US7291463B2 (en) 1996-01-23 2007-11-06 Affymetrix, Inc. Nucleic acid labeling compounds
US5714577A (en) 1996-01-26 1998-02-03 University Of Pittsburgh Antimicrobial peptides
US6261584B1 (en) 1996-02-02 2001-07-17 Alza Corporation Sustained delivery of an active agent using an implantable system
US6395292B2 (en) 1996-02-02 2002-05-28 Alza Corporation Sustained delivery of an active agent using an implantable system
AU1874397A (en) 1996-02-16 1997-09-02 Stichting Rega Vzw Hexitol containing oligonucleotides and their use in antisense strategies
US6534312B1 (en) 1996-02-22 2003-03-18 Merck & Co., Inc. Vaccines comprising synthetic genes
US6090391A (en) 1996-02-23 2000-07-18 Aviron Recombinant tryptophan mutants of influenza
US5994308A (en) 1996-02-28 1999-11-30 Board Of Trustees Of Southern Illinois University Broad spectrum antimicrobial peptides containing a tryptophan triplet and methods of use
US6300487B1 (en) 1996-03-19 2001-10-09 Cell Therapuetics, Inc. Mammalian lysophosphatidic acid acyltransferase
SE9601245D0 (sv) 1996-03-29 1996-03-29 Pharmacia Ab Chimeric superantigens and their use
US5773696A (en) 1996-03-29 1998-06-30 Monsanto Company Antifungal polypeptide and methods for controlling plant pathogenic fungi
TW517061B (en) 1996-03-29 2003-01-11 Pharmacia & Amp Upjohn Ab Modified/chimeric superantigens and their use
JPH09278726A (ja) * 1996-04-11 1997-10-28 Takeshi Imanishi 新規リポソーム
US5712127A (en) 1996-04-29 1998-01-27 Genescape Inc. Subtractive amplification
US5853719A (en) 1996-04-30 1998-12-29 Duke University Methods for treating cancers and pathogen infections using antigen-presenting cells loaded with RNA
US7329741B2 (en) 1996-06-05 2008-02-12 Chiron Corporation Polynucleotides that hybridize to DP-75 and their use
DE69739524D1 (de) 1996-06-05 2009-09-17 Novartis Vaccines & Diagnostic Dp-75 kodierende dna und verfahren zu ihrer verwendung
WO1997048370A2 (en) 1996-06-21 1997-12-24 Merck & Co., Inc. Vaccines comprising synthetic genes
US6234990B1 (en) 1996-06-28 2001-05-22 Sontra Medical, Inc. Ultrasound enhancement of transdermal transport
US5677124A (en) 1996-07-03 1997-10-14 Ambion, Inc. Ribonuclease resistant viral RNA standards
US5939262A (en) 1996-07-03 1999-08-17 Ambion, Inc. Ribonuclease resistant RNA preparation and utilization
US5856127A (en) 1996-07-26 1999-01-05 The Research Foundation Of State University Of New York Antimicrobial peptides
US7288266B2 (en) 1996-08-19 2007-10-30 United States Of America As Represented By The Secretary, Department Of Health And Human Services Liposome complexes for increased systemic delivery
AU741663B2 (en) 1996-08-22 2001-12-06 Magainin Pharmaceuticals, Inc. Compositions and methods for use of defensin
US5849546A (en) 1996-09-13 1998-12-15 Epicentre Technologies Corporation Methods for using mutant RNA polymerases with reduced discrimination between non-canonical and canonical nucleoside triphosphates
US6114148C1 (en) 1996-09-20 2012-05-01 Gen Hospital Corp High level expression of proteins
CA2266325C (en) 1996-09-24 2012-07-17 Lxr Biotechnology, Inc. A family of genes encoding apoptosis-related peptides, peptides encoded thereby and methods of use thereof
US6214966B1 (en) 1996-09-26 2001-04-10 Shearwater Corporation Soluble, degradable poly(ethylene glycol) derivatives for controllable release of bound molecules into solution
CA2268825C (en) 1996-10-11 2006-04-18 The Regents Of The University Of California Immunostimulatory polynucleotide/immunomodulatory molecule conjugates
EP0839912A1 (en) 1996-10-30 1998-05-06 Instituut Voor Dierhouderij En Diergezondheid (Id-Dlo) Infectious clones of RNA viruses and vaccines and diagnostic assays derived thereof
GB9623051D0 (en) 1996-11-06 1997-01-08 Schacht Etienne H Delivery of DNA to target cells in biological systems
US5980887A (en) 1996-11-08 1999-11-09 St. Elizabeth's Medical Center Of Boston Methods for enhancing angiogenesis with endothelial progenitor cells
US6121436A (en) 1996-12-13 2000-09-19 Monsanto Company Antifungal polypeptide and methods for controlling plant pathogenic fungi
US5759179A (en) 1996-12-31 1998-06-02 Johnson & Johnson Medical, Inc. Needle and valve assembly for use with a catheter
CA2278786C (en) 1997-01-21 2010-07-20 The General Hospital Corporation Selection of proteins using rna-protein fusions
EP0855184A1 (en) 1997-01-23 1998-07-29 Grayson B. Dr. Lipford Pharmaceutical composition comprising a polynucleotide and an antigen especially for vaccination
IL131131A0 (en) 1997-02-07 2001-01-28 Merck & Co Inc Synthetic hiv gag genes
US6228640B1 (en) 1997-02-07 2001-05-08 Cem Cezayirli Programmable antigen presenting cell of CD34 lineage
US6251665B1 (en) 1997-02-07 2001-06-26 Cem Cezayirli Directed maturation of stem cells and production of programmable antigen presenting dentritic cells therefrom
US6696291B2 (en) 1997-02-07 2004-02-24 Merck & Co., Inc. Synthetic HIV gag genes
US6576752B1 (en) 1997-02-14 2003-06-10 Isis Pharmaceuticals, Inc. Aminooxy functionalized oligomers
US5998374A (en) 1997-02-28 1999-12-07 The Regents Of University Of California Clavaspirins
US5837860A (en) 1997-03-05 1998-11-17 Molecular Tool, Inc. Covalent attachment of nucleic acid molecules onto solid-phases via disulfide bonds
JP3756313B2 (ja) 1997-03-07 2006-03-15 武 今西 新規ビシクロヌクレオシド及びオリゴヌクレオチド類縁体
US6406705B1 (en) 1997-03-10 2002-06-18 University Of Iowa Research Foundation Use of nucleic acids containing unmethylated CpG dinucleotide as an adjuvant
US6306393B1 (en) 1997-03-24 2001-10-23 Immunomedics, Inc. Immunotherapy of B-cell malignancies using anti-CD22 antibodies
US6261281B1 (en) 1997-04-03 2001-07-17 Electrofect As Method for genetic immunization and introduction of molecules into skeletal muscle and immune cells
US5914269A (en) 1997-04-04 1999-06-22 Isis Pharmaceuticals, Inc. Oligonucleotide inhibition of epidermal growth factor receptor expression
GB2324370B (en) 1997-04-14 1999-03-03 Stuart Harbron Detection of hybrid double-stranded DNA with antibody after enzyme degradation of excess single-standed DNA
WO1998047913A2 (en) 1997-04-18 1998-10-29 The University Of Medicine And Dentistry Of New Jersey Inhibition of hiv-1 replication by a tat rna-binding domain peptide analog
US5958688A (en) 1997-04-28 1999-09-28 The Trustees Of The University Of Pennsylvania Characterization of mRNA patterns in neurites and single cells for medical diagnosis and therapeutics
US6235883B1 (en) 1997-05-05 2001-05-22 Abgenix, Inc. Human monoclonal antibodies to epidermal growth factor receptor
US5989911A (en) 1997-05-09 1999-11-23 University Of Massachusetts Site-specific synthesis of pseudouridine in RNA
EP2113247A3 (en) * 1997-05-14 2010-05-05 The University Of British Columbia High efficiency encapsulation of nucleic acids in lipid vesicles
WO1998054302A2 (en) * 1997-05-27 1998-12-03 Icos Corporation Human lysophosphatidic acid acyltransferase
NL1006164C2 (nl) 1997-05-29 1998-12-01 Univ Leiden Antimicrobiële peptiden.
US6124091A (en) 1997-05-30 2000-09-26 Research Corporation Technologies, Inc. Cell growth-controlling oligonucleotides
US6589940B1 (en) 1997-06-06 2003-07-08 Dynavax Technologies Corporation Immunostimulatory oligonucleotides, compositions thereof and methods of use thereof
ATE252596T1 (de) 1997-06-06 2003-11-15 Dynavax Tech Corp Immunstimulierende oligonucleotide, zusammensetzungen davon, und verfahren zur verwendung davon
DE19726167B4 (de) * 1997-06-20 2008-01-24 Sanofi-Aventis Deutschland Gmbh Insulin, Verfahren zu seiner Herstellung und es enthaltende pharmazeutische Zubereitung
JP2002510319A (ja) 1997-07-01 2002-04-02 アイシス・ファーマシューティカルス・インコーポレーテッド オリゴヌクレオチドの消化管を介したデリバリーのための組成物及び方法
US5994511A (en) 1997-07-02 1999-11-30 Genentech, Inc. Anti-IgE antibodies and methods of improving polypeptides
FR2766191B1 (fr) 1997-07-21 2000-11-10 Ifremer Peptides anti-microbiens de crustaces
KR20010022075A (ko) 1997-07-21 2001-03-15 존 헤덴스트룀 T세포활성화를유도하는슈퍼항원접합체에의한표적세포의세포용해
US20030073640A1 (en) 1997-07-23 2003-04-17 Ribozyme Pharmaceuticals, Inc. Novel compositions for the delivery of negatively charged molecules
WO1999006073A1 (en) 1997-07-31 1999-02-11 St. Elizabeth's Medical Center Of Boston, Inc. Method for the treatment of grafts
EP0988314B1 (en) 1997-07-31 2006-07-19 Philip Richard Abraham Synthetic peptides with antimicrobial and endotoxin neutralizing properties for management of the sepsis syndrome
GB9718908D0 (en) * 1997-09-05 1997-11-12 Rowett Research Services Limit Proteins
US6576755B1 (en) 1997-09-10 2003-06-10 Zymogenetics, Inc. Beta-defensins
US6794499B2 (en) 1997-09-12 2004-09-21 Exiqon A/S Oligonucleotide analogues
EP1015009A4 (en) 1997-09-18 2001-11-07 Univ Pennsylvania GENETIC MATERIAL IN THE FORM OF MITIGATED IMMUNIZATION CASSETTES BASED ON LIVER DNA FOR GENETIC VACCINES
EP1021549A2 (en) 1997-09-19 2000-07-26 Sequitur, Inc. SENSE mRNA THERAPY
AU9747698A (en) 1997-09-25 1999-04-12 Academisch Ziekenhuis Bij De Universiteit Van Amsterdam Isolated and recombinant antimicrobial peptides thrombocidin-1 (tc-1) and thrombocidin-2 (tc-2) or variants thereof
US6004573A (en) 1997-10-03 1999-12-21 Macromed, Inc. Biodegradable low molecular weight triblock poly(lactide-co-glycolide) polyethylene glycol copolymers having reverse thermal gelation properties
AU750106B2 (en) 1997-10-07 2002-07-11 University Of Maryland Biotechnology Institute Method for introducing and expressing RNA in animal cells
AP1219A (en) 1997-10-20 2003-10-22 Gtc Biotherapeutics Inc Novel modified MSP-1 nucleic acid sequences and methods for increasing mRNA levels and protein expression in cell systems.
US6019747A (en) 1997-10-21 2000-02-01 I-Flow Corporation Spring-actuated infusion syringe
CA2348675A1 (en) 1997-10-24 1999-05-06 Warren Dang Methods for preparing polynucleotide transfection complexes
EP1030927A1 (en) 1997-11-12 2000-08-30 Valentis Inc. Expression plasmids for multiepitope nucleic acid-based vaccines
US6548633B1 (en) 1998-12-22 2003-04-15 Genset, S.A. Complementary DNA's encoding proteins with signal peptides
DE69815707T2 (de) 1997-11-20 2004-07-01 Vical, Inc., San Diego Behandlung von krebs durch verwendung von zytokin-exprimierender polynukleotiden und zusammensetzungen dafür
US7655777B2 (en) 1997-11-24 2010-02-02 Monsanto Technology Llc Nucleic acid molecules associated with the tocopherol pathway
AR014940A1 (es) 1997-12-12 2001-04-11 Expression Genetics Inc Un portador para la liberacion de un agente bioactivo, un polimero poliester biodegradable, copolimeros y composiciones farmaceuticas que loscontienen.
US6517869B1 (en) 1997-12-12 2003-02-11 Expression Genetics, Inc. Positively charged poly(alpha-(omega-aminoalkyl)lycolic acid) for the delivery of a bioactive agent via tissue and cellular uptake
JP2002500010A (ja) 1997-12-23 2002-01-08 カイロン コーポレイション ヒト遺伝子および遺伝子発現産物ｉ
US6320017B1 (en) 1997-12-23 2001-11-20 Inex Pharmaceuticals Corp. Polyamide oligomers
US6383811B2 (en) 1997-12-30 2002-05-07 Mirus Corporation Polyampholytes for delivering polyions to a cell
ATE443528T1 (de) 1998-01-05 2009-10-15 Univ Washington Erhöhter transport unter benutzung membranzerstörender stoffe
JP2002500075A (ja) 1998-01-08 2002-01-08 ソントラ メディカル， インコーポレイテッド 超音波伝達で増強される経皮輸送
US8287483B2 (en) 1998-01-08 2012-10-16 Echo Therapeutics, Inc. Method and apparatus for enhancement of transdermal transport
NL1008139C2 (nl) 1998-01-27 1999-07-28 Stichting Tech Wetenschapp Antimicrobiële peptiden.
US6365346B1 (en) 1998-02-18 2002-04-02 Dade Behring Inc. Quantitative determination of nucleic acid amplification products
JP2002503701A (ja) 1998-02-18 2002-02-05 ハーバー−ユーシーエルエイ リサーチ アンド エデュケーション インスティテュート 抗菌性ペプチドおよび誘導したメタペプチド
US5888793A (en) * 1998-02-25 1999-03-30 Incyte Pharmaceuticals, Inc. Human lysophosphatidic acid acyltransferase
US5955310A (en) 1998-02-26 1999-09-21 Novo Nordisk Biotech, Inc. Methods for producing a polypeptide in a bacillus cell
US6849417B1 (en) * 1998-04-06 2005-02-01 The United States Of America As Represented By The Department Of Health And Human Services Mammalian selenoprotein differentially expressed in tumor cells
WO1999051637A1 (en) * 1998-04-06 1999-10-14 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Mammalian selenoprotein differentially expressed in tumor cells
US6432925B1 (en) 1998-04-16 2002-08-13 John Wayne Cancer Institute RNA cancer vaccine and methods for its use
US6429301B1 (en) 1998-04-17 2002-08-06 Whitehead Institute For Biomedical Research Use of a ribozyme to join nucleic acids and peptides
GB9808327D0 (en) 1998-04-20 1998-06-17 Chiron Spa Antidiotypic compounds
AU3534199A (en) 1998-04-23 1999-11-08 Takara Shuzo Co., Ltd. Method For Synthesizing DNA
US6395253B2 (en) 1998-04-23 2002-05-28 The Regents Of The University Of Michigan Microspheres containing condensed polyanionic bioactive agents and methods for their production
US20020064517A1 (en) 1998-04-30 2002-05-30 Stewart A. Cederholm-Williams Fibrin sealant as a transfection/transformation vehicle for gene therapy
US20090208418A1 (en) 2005-04-29 2009-08-20 Innexus Biotechnology Internaltional Ltd. Superantibody synthesis and use in detection, prevention and treatment of disease
US6177274B1 (en) 1998-05-20 2001-01-23 Expression Genetics, Inc. Hepatocyte targeting polyethylene glyco-grafted poly-L-lysine polymeric gene carrier
US6503231B1 (en) 1998-06-10 2003-01-07 Georgia Tech Research Corporation Microneedle device for transport of molecules across tissue
US7091192B1 (en) 1998-07-01 2006-08-15 California Institute Of Technology Linear cyclodextrin copolymers
KR20010079526A (ko) 1998-07-13 2001-08-22 추후제출 용해성 생분해 유전자 전달 담체인 폴리-ｌ-리신의폴리에스테르 유사체
US6222030B1 (en) 1998-08-03 2001-04-24 Agilent Technologies, Inc. Solid phase synthesis of oligonucleotides using carbonate protecting groups and alpha-effect nucleophile deprotection
EP1974747B1 (en) 1998-08-11 2012-06-27 Biogen Idec Inc. Combination therapies for B-cell lymphomas comprising administration of anti-CD20 antibody
US6476189B1 (en) 1998-08-12 2002-11-05 National Institute Of Agrobiological Sciences Antibacterial peptides and antibacterial agents containing such peptides as an effective ingredient
GB9817662D0 (en) 1998-08-13 1998-10-07 Crocker Peter J Substance delivery
US6288212B1 (en) 1998-08-28 2001-09-11 The University Of British Columbia Anti-endotoxic, antimicrobial cationic peptides and methods of use therefor
US20020065236A1 (en) * 1998-09-09 2002-05-30 Yew Nelson S. CpG reduced plasmids and viral vectors
US20090042283A1 (en) 1998-09-29 2009-02-12 Shire Human Genetic Therapies, Inc., A Delaware Corporation Optimized messenger rna
US6924365B1 (en) 1998-09-29 2005-08-02 Transkaryotic Therapies, Inc. Optimized messenger RNA
CA2348779A1 (en) 1998-11-03 2000-05-11 Yale University Multidomain polynucleotide molecular sensors
DE69941903D1 (de) 1998-11-09 2010-02-25 Biogen Idec Inc Behandlung von patienten die eine knochenmarktransplantation oder eine transplantation peripherer blutstammzellen erhalten mit anti-cd20 antikörpern
EP1949912A3 (en) 1998-11-09 2008-08-13 Biogen Idec, Inc. Treatment of chronic lymphcytic leukemia (CLL) using chimeric anti-CD20 antibody
WO2000027340A2 (en) 1998-11-12 2000-05-18 The Children's Medical Center Corporation USE OF t-RNA AND FRAGMENTS FOR INHIBITING ANGIOGENESIS AND COMPOSITIONS THEREOF
US6248268B1 (en) 1998-11-16 2001-06-19 Xc Corporation Process of making microparticles of a thermally-gelled polysaccharide
JP3141107B2 (ja) * 1998-11-16 2001-03-05 工業技術院長 ヒト由来ブラディオン蛋白質、それをコードするｄｎａ及びそれらの使用
US6210931B1 (en) 1998-11-30 2001-04-03 The United States Of America As Represented By The Secretary Of Agriculture Ribozyme-mediated synthesis of circular RNA
JP2000175684A (ja) * 1998-12-14 2000-06-27 Eiken Chem Co Ltd 新規アシルトランスフェラーゼをコードする遺伝子
US20040171980A1 (en) 1998-12-18 2004-09-02 Sontra Medical, Inc. Method and apparatus for enhancement of transdermal transport
EP1141376A4 (en) 1998-12-23 2002-03-13 Human Genome Sciences PEPTIDOGLYCANE RECOGNITION PROTEINS
AU776150B2 (en) 1999-01-28 2004-08-26 Medical College Of Georgia Research Institute, Inc. Composition and method for (in vivo) and (in vitro) attenuation of gene expression using double stranded RNA
GB9902000D0 (en) * 1999-01-30 1999-03-17 Delta Biotechnology Ltd Process
EP1155124A2 (en) 1999-02-22 2001-11-21 European Molecular Biology Laboratory In vitro translation system
US6255476B1 (en) 1999-02-22 2001-07-03 Pe Corporation (Ny) Methods and compositions for synthesis of labelled oligonucleotides and analogs on solid-supports
US7629311B2 (en) 1999-02-24 2009-12-08 Edward Lewis Tobinick Methods to facilitate transmission of large molecules across the blood-brain, blood-eye, and blood-nerve barriers
CA2689696C (en) 1999-02-26 2013-08-06 Novartis Vaccines And Diagnostics, Inc. Microemulsions with adsorbed macromolecules and microparticles
US6107460A (en) 1999-03-01 2000-08-22 The Board Of Regents Of The University Of Oklahoma Antimicrobial peptides and methods of use thereof
US8410248B2 (en) 1999-03-12 2013-04-02 Human Genome Sciences Inc. HWBAO62 polypeptides
US7084125B2 (en) 1999-03-18 2006-08-01 Exiqon A/S Xylo-LNA analogues
US7244710B2 (en) 2002-05-21 2007-07-17 Zengen, Inc. Treatment of ophthalmic infections using antimicrobial peptides
CA2369119A1 (en) 1999-03-29 2000-05-25 Statens Serum Institut Nucleotide construct with optimised codons for an hiv genetic vaccine based on a primary, early hiv isolate and synthetic envelope
CN1311005C (zh) 1999-04-09 2007-04-18 迪纳尔生物技术公司 用于制备单分散聚合物颗粒的方法
KR100782896B1 (ko) 1999-05-04 2007-12-06 엑시콘 에이/에스 Ｌ-리보-ｌｎａ 유사체
US8663692B1 (en) 1999-05-07 2014-03-04 Pharmasol Gmbh Lipid particles on the basis of mixtures of liquid and solid lipids and method for producing same
IL146005A0 (en) 1999-05-07 2002-07-25 Genentech Inc Treatment of autoimmune diseases with antagonists which bind to b cell surface markers
ES2185595T5 (es) 1999-05-17 2009-12-17 Conjuchem Biotechnologies Inc. Peptidos antivirales modificados y sus composiciones para la prevencion y/o el tratamiento de infecciones viricas.
US6346382B1 (en) 1999-06-01 2002-02-12 Vanderbilt University Human carbamyl phosphate synthetase I polymorphism and diagnostic methods related thereto
US6611707B1 (en) 1999-06-04 2003-08-26 Georgia Tech Research Corporation Microneedle drug delivery device
AU4332399A (en) 1999-06-04 2000-12-28 Cheng-Ming Chuong Rna polymerase chain reaction
US6743211B1 (en) 1999-11-23 2004-06-01 Georgia Tech Research Corporation Devices and methods for enhanced microneedle penetration of biological barriers
US6303573B1 (en) 1999-06-07 2001-10-16 The Burnham Institute Heart homing peptides and methods of using same
EP1196558A1 (fr) 1999-06-08 2002-04-17 Aventis Pasteur Oligonucleotide immunostimulant
DE60042785D1 (de) 1999-06-09 2009-10-01 Immunomedics Inc Immuntherapie von autoimmunerkrankungen durch die verwendung von b-zell spezifischen antikörpern
US6949245B1 (en) 1999-06-25 2005-09-27 Genentech, Inc. Humanized anti-ErbB2 antibodies and treatment with anti-ErbB2 antibodies
US20030153050A1 (en) 1999-06-28 2003-08-14 Conklin Darrell C. Helical polypeptide zalpha29
BR0012099A (pt) 1999-06-30 2003-07-29 Advanced Cell Tech Inc Transferência citoplásmica para de-diferenciar células recipientes
US6514948B1 (en) 1999-07-02 2003-02-04 The Regents Of The University Of California Method for enhancing an immune response
FR2796072B1 (fr) 1999-07-08 2003-09-19 Centre Nat Rech Scient Peptides anti-microbiens de mollusques
BR0012325A (pt) 1999-07-09 2002-05-21 American Home Prod Métodos e composições para prevenção da formação de rna anormal durante a transcrição de uma sequência de plasmìdeo
CA2311201A1 (en) 1999-08-05 2001-02-05 Genset S.A. Ests and encoded human proteins
US8557244B1 (en) 1999-08-11 2013-10-15 Biogen Idec Inc. Treatment of aggressive non-Hodgkins lymphoma with anti-CD20 antibody
US7071293B1 (en) 1999-08-18 2006-07-04 The University Of Iowa Research Foundation Alpha helical peptides with broad spectrum antimicrobial activity that are insensitive to salt
JP2002300878A (ja) 1999-08-19 2002-10-15 Chugai Pharmaceut Co Ltd 新規ｂＨＬＨ型転写因子遺伝子、ＤＥＣ２
DK1212422T3 (da) 1999-08-24 2007-07-02 Medarex Inc Humane CTLA-4-antistoffer og anvendelserne deraf
US20050112141A1 (en) 2000-08-30 2005-05-26 Terman David S. Compositions and methods for treatment of neoplastic disease
US20040106567A1 (en) 1999-09-07 2004-06-03 Hagstrom James E. Intravascular delivery of non-viral nucleic acid
DE69943068D1 (de) 1999-09-09 2011-02-03 Curevac Gmbh Transfer von mRNA unter Verwendung von polykationischen Verbindungen
WO2001021810A1 (en) 1999-09-17 2001-03-29 Aventis Pasteur Limited Chlamydia antigens and corresponding dna fragments and uses thereof
US6623457B1 (en) 1999-09-22 2003-09-23 Becton, Dickinson And Company Method and apparatus for the transdermal administration of a substance
WO2002064799A2 (en) 1999-09-28 2002-08-22 Transkaryotic Therapies, Inc. Optimized messenger rna
AU7863200A (en) 1999-10-06 2001-05-10 Quark Biotech, Inc. Method for enrichment of natural antisense messenger rna
US6511832B1 (en) 1999-10-06 2003-01-28 Texas A&M University System In vitro synthesis of capped and polyadenylated mRNAs using baculovirus RNA polymerase
EP1101771A1 (en) 1999-11-15 2001-05-23 Korea Kumho Petrochemical Co. Ltd. Pathogen-induced genes from Capsicum annuum
US7060291B1 (en) 1999-11-24 2006-06-13 Transave, Inc. Modular targeted liposomal delivery system
US6573361B1 (en) 1999-12-06 2003-06-03 Monsanto Technology Llc Antifungal proteins and methods for their use
US6613026B1 (en) 1999-12-08 2003-09-02 Scimed Life Systems, Inc. Lateral needle-less injection apparatus and method
US6277974B1 (en) 1999-12-14 2001-08-21 Cogent Neuroscience, Inc. Compositions and methods for diagnosing and treating conditions, disorders, or diseases involving cell death
US6794490B2 (en) 1999-12-15 2004-09-21 Cubist Pharmaceuticals, Inc. Lipopeptides as antibacterial agents
US6245929B1 (en) 1999-12-20 2001-06-12 General Electric Company Catalyst composition and method for producing diaryl carbonates, using bisphosphines
ATE280188T1 (de) 1999-12-22 2004-11-15 Basell Poliolefine Spa Alpha-olefin enthaltendes polymerisationskatalysatorsystem, das ein aromatisches silan enthält
WO2001051092A2 (en) 2000-01-07 2001-07-19 University Of Washington Enhanced transport of agents using membrane disruptive agents
WO2001051661A2 (en) 2000-01-13 2001-07-19 Amsterdam Support Diagnostics B.V. A universal nucleic acid amplification system for nucleic acids in a sample
DE10001377A1 (de) * 2000-01-14 2001-08-02 Univ Mainz Johannes Gutenberg bHLH-Transkriptionsfaktor ASCL3 und diesen enthaltendes Arzneimittel
WO2001055306A2 (en) 2000-01-31 2001-08-02 Human Genome Sciences, Inc. Nucleic acids, proteins, and antibodies
CA2398756A1 (en) 2000-01-31 2001-08-02 Eyal Raz Immunomodulatory polynucleotides in treatment of an infection by an intracellular pathogen
US7491805B2 (en) 2001-05-18 2009-02-17 Sirna Therapeutics, Inc. Conjugates and compositions for cellular delivery
US7833992B2 (en) 2001-05-18 2010-11-16 Merck Sharpe & Dohme Conjugates and compositions for cellular delivery
AU2001238595A1 (en) 2000-02-22 2001-09-03 Shearwater Corporation N-maleimidyl polymer derivatives
EP1257584B2 (en) 2000-02-24 2013-03-06 Washington University St. Louis Humanized antibodies that sequester amyloid beta peptide
EP1130091A3 (en) 2000-03-01 2001-11-14 Message Pharmaceuticals, Inc. Bacterial RNaseP Proteins and their use in identifying antibacterial compounds
ATE511400T1 (de) 2000-03-03 2011-06-15 Genetronics Inc Nukleinsäure-fomulierungen zur genverabreichung
GB0006572D0 (en) 2000-03-17 2000-05-10 Isis Innovation Novel transcription transactivator protein
AU2001249727A1 (en) * 2000-03-31 2001-10-15 Genentech, Inc. Compositions and methods for detecting and quantifying gene expression
AU8729101A (en) 2000-03-31 2001-10-15 Idec Pharma Corp Combined use of anti-cytokine antibodies or antagonists and anti-CD20 for the treatment of B cell lymphoma
US6565572B2 (en) 2000-04-10 2003-05-20 Sdgi Holdings, Inc. Fenestrated surgical screw and method
WO2001079444A2 (en) 2000-04-12 2001-10-25 Human Genome Sciences, Inc Albumin fusion proteins
US6368801B1 (en) 2000-04-12 2002-04-09 Molecular Staging, Inc. Detection and amplification of RNA using target-mediated ligation of DNA by RNA ligase
US20010046496A1 (en) 2000-04-14 2001-11-29 Brettman Lee R. Method of administering an antibody
US6375972B1 (en) 2000-04-26 2002-04-23 Control Delivery Systems, Inc. Sustained release drug delivery devices, methods of use, and methods of manufacturing thereof
US7871598B1 (en) 2000-05-10 2011-01-18 Novartis Ag Stable metal ion-lipid powdered pharmaceutical compositions for drug delivery and methods of use
US20040229271A1 (en) 2000-05-19 2004-11-18 Williams Richard B. Compositions and methods for the identification and selection of nucleic acids and polypeptides
WO2001092523A2 (en) 2000-05-30 2001-12-06 Curagen Corporation Human polynucleotides and polypeptides encoded thereby
US20040052763A1 (en) 2000-06-07 2004-03-18 Mond James J. Immunostimulatory RNA/DNA hybrid molecules
MXPA02012256A (es) 2000-06-23 2003-04-25 American Cyanamid Co Proteinas v de morbillivirus modificados.
US6337317B1 (en) 2000-06-27 2002-01-08 The University Of British Columbia Antimicrobial peptides and methods of use thereof
US6492328B2 (en) 2000-06-28 2002-12-10 The University Of Iowa Research Foundation Novispirins: antimicrobial peptides
EP2166019A3 (en) 2000-07-03 2010-06-09 Novartis Vaccines and Diagnostics S.r.l. Immunisation against Chlamydia Pneumoniae
US6440096B1 (en) 2000-07-14 2002-08-27 Becton, Dickinson And Co. Microdevice and method of manufacturing a microdevice
ES2277605T3 (es) 2000-07-21 2007-07-16 Glaxo Group Limited Secuencias de papilomavirus de codones optimizados.
US6727066B2 (en) 2000-07-28 2004-04-27 Incyte Corporation Genes expressed in treated human C3A liver cell cultures
WO2002009738A1 (en) 2000-07-28 2002-02-07 Murphy Christopher J Transplant media
US6902734B2 (en) 2000-08-07 2005-06-07 Centocor, Inc. Anti-IL-12 antibodies and compositions thereof
WO2002016592A2 (en) * 2000-08-21 2002-02-28 Millennium Pharmaceuticals, Inc. Atcr-1, a human acyltransferase and uses thereof
US6875907B2 (en) 2000-09-13 2005-04-05 Pioneer Hi-Bred International, Inc. Antimicrobial peptides and methods of use
US20040142474A1 (en) 2000-09-14 2004-07-22 Expression Genetics, Inc. Novel cationic lipopolymer as a biocompatible gene delivery agent
US6696038B1 (en) 2000-09-14 2004-02-24 Expression Genetics, Inc. Cationic lipopolymer as biocompatible gene delivery agent
AU2001290078A1 (en) 2000-09-20 2002-04-02 Ruggero Della Bitta Stem cell therapy
US6998484B2 (en) 2000-10-04 2006-02-14 Santaris Pharma A/S Synthesis of purine locked nucleic acid analogues
CA2425152A1 (en) 2000-10-04 2002-04-11 The Trustees Of The University Of Pennsylvania Highly expressible genes
DE10050274A1 (de) * 2000-10-09 2002-04-18 Henkel Kgaa Verfahren zur in vitro Bestimmung der Hautalterung
US6998115B2 (en) 2000-10-10 2006-02-14 Massachusetts Institute Of Technology Biodegradable poly(β-amino esters) and uses thereof
US6649138B2 (en) 2000-10-13 2003-11-18 Quantum Dot Corporation Surface-modified semiconductive and metallic nanoparticles having enhanced dispersibility in aqueous media
US7202226B2 (en) 2000-10-23 2007-04-10 Detroit R & D Augmentation of wound healing by elF-4E mRNA and EGF mRNA
US20030077604A1 (en) 2000-10-27 2003-04-24 Yongming Sun Compositions and methods relating to breast specific genes and proteins
GB0026924D0 (en) 2000-11-03 2000-12-20 Univ Cambridge Tech Antibacterial agents
US20020132788A1 (en) 2000-11-06 2002-09-19 David Lewis Inhibition of gene expression by delivery of small interfering RNA to post-embryonic animal cells in vivo
US7521054B2 (en) 2000-11-17 2009-04-21 The United States Of America As Represented By The Department Of Health And Human Services Reduction of the nonspecific animal toxicity of immunotoxins by mutating the framework regions of the Fv to lower the isoelectric point
AU2002236524A1 (en) 2000-11-28 2002-06-11 Rosetta Inpharmatics, Inc. In vitro transcription method for rna amplification
ES2397627T3 (es) 2000-12-07 2013-03-08 Novartis Vaccines And Diagnostics, Inc. Retrovirus endógenos regulados por aumento en el cáncer de próstata
US20020130430A1 (en) 2000-12-29 2002-09-19 Castor Trevor Percival Methods for making polymer microspheres/nanospheres and encapsulating therapeutic proteins and other products
US7708915B2 (en) 2004-05-06 2010-05-04 Castor Trevor P Polymer microspheres/nanospheres and encapsulating therapeutic proteins therein
EP1224943A1 (en) 2001-01-19 2002-07-24 Crucell Holland B.V. Fibronectin as a tumor marker detected by phage antibodies
CN1524088B (zh) 2001-01-19 2012-11-07 维洛诺瓦蒂夫公司 在易感哺乳动物中引起呼吸道疾病的病毒
US20040110191A1 (en) 2001-01-31 2004-06-10 Winkler Matthew M. Comparative analysis of nucleic acids using population tagging
US20040142433A1 (en) 2001-02-02 2004-07-22 Padgett Hal S. Polynucleotide sequence variants
JP2004527236A (ja) 2001-02-14 2004-09-09 ベイラー　カレッジ　オブ　メディスン Ｒｎａ増幅の方法及び組成物
US6887847B2 (en) 2001-02-16 2005-05-03 University Of Pittsburgh Virus derived antimicrobial peptides
US6835713B2 (en) 2001-02-16 2004-12-28 University Of Pittsburgh Virus derived antimicrobial peptides
US6652886B2 (en) 2001-02-16 2003-11-25 Expression Genetics Biodegradable cationic copolymers of poly (alkylenimine) and poly (ethylene glycol) for the delivery of bioactive agents
DE10109897A1 (de) 2001-02-21 2002-11-07 Novosom Ag Fakultativ kationische Liposomen und Verwendung dieser
US7232425B2 (en) 2001-03-02 2007-06-19 Sorenson Development, Inc. Apparatus and method for specific interstitial or subcutaneous diffusion and dispersion of medication
NZ528000A (en) 2001-03-09 2005-09-30 Gene Stream Pty Ltd A construct comprising in operable linkage a polynucleotide that encodes a polypeptide with a half-life of less than three hours
JP2002262882A (ja) 2001-03-12 2002-09-17 Nisshinbo Ind Inc Ｒｎａの増幅法
FR2822164B1 (fr) 2001-03-19 2004-06-18 Centre Nat Rech Scient Polypeptides derives des arn polymerases, et leurs utilisations
US6520949B2 (en) 2001-04-02 2003-02-18 Martin St. Germain Method and apparatus for administering fluid to animals subcutaneously
WO2003008537A2 (en) * 2001-04-06 2003-01-30 Mannkind Corporation Epitope sequences
US7314858B2 (en) 2001-04-18 2008-01-01 The Regents Of The University Of California Retrocyclins: antiviral and antimicrobial peptides
DE10119005A1 (de) 2001-04-18 2002-10-24 Roche Diagnostics Gmbh Verfahren zur Proteinexpression ausgehend von stabilisierter linearer kurzer DNA in zellfreien in vitro-Transkription/Translations-Systemen mit Exonuklease-haltigen Lysaten oder in einem zellulären System enthaltend Exonukleasen
US20030171253A1 (en) 2001-04-19 2003-09-11 Averil Ma Methods and compositions relating to modulation of A20
EP1383556B9 (de) 2001-04-21 2008-03-19 Curevac GmbH INJEKTIONSGERÄT FÜR mRNA APPLIKATION
US7332332B2 (en) 2001-04-23 2008-02-19 Amaxa Ag Buffer solution for electroporation and a method comprising the use of the same
US7560424B2 (en) 2001-04-30 2009-07-14 Zystor Therapeutics, Inc. Targeted therapeutic proteins
US6777187B2 (en) 2001-05-02 2004-08-17 Rubicon Genomics, Inc. Genome walking by selective amplification of nick-translate DNA library and amplification from complex mixtures of templates
GB0111015D0 (en) * 2001-05-04 2001-06-27 Norsk Hydro As Genetic material
AU2002308623A1 (en) 2001-05-08 2002-11-18 Magnatech International, L.P. Electronic length control wire pay-off system and method
US20050137155A1 (en) 2001-05-18 2005-06-23 Sirna Therapeutics, Inc. RNA interference mediated treatment of Parkinson disease using short interfering nucleic acid (siNA)
US8137911B2 (en) 2001-05-22 2012-03-20 Cellscript, Inc. Preparation and use of single-stranded transcription substrates for synthesis of transcription products corresponding to target sequences
US7514098B2 (en) 2001-05-30 2009-04-07 The Board Of Trustees Of The Leland Stanford Junior University Use of targeted cross-linked nanoparticles for in vivo gene delivery
ATE464317T1 (de) 2001-06-05 2010-04-15 Curevac Gmbh Stabilisierte mrna mit erhöhtem g/c-gehalt für die gentherapie
US7235358B2 (en) 2001-06-08 2007-06-26 Expression Diagnostics, Inc. Methods and compositions for diagnosing and monitoring transplant rejection
EP1402035A2 (en) 2001-06-18 2004-03-31 Novartis AG G-protein coupled receptors and dna sequences thereof
US7785610B2 (en) 2001-06-21 2010-08-31 Dynavax Technologies Corporation Chimeric immunomodulatory compounds and methods of using the same—III
EP1270732A1 (en) 2001-06-21 2003-01-02 Schuler, Gerold Improved transfection of eukaryontic cells with linear polynucleotides by electroporation
US7547551B2 (en) 2001-06-21 2009-06-16 University Of Antwerp. Transfection of eukaryontic cells with linear polynucleotides by electroporation
JP2005503137A (ja) 2001-06-26 2005-02-03 ノバルティス アクチエンゲゼルシャフト Ｇタンパク質共役レセプターおよびそのｄｎａ配列
SE0102327D0 (sv) 2001-06-28 2001-06-28 Active Biotech Ab A novel engineered superantigen for human therapy
US6872705B2 (en) 2001-07-13 2005-03-29 Allergan, Inc. Use of antimicrobial peptides as preservatives in ophthalmic preparations, including solutions, emulsions, and suspensions
WO2003029401A2 (en) * 2001-07-13 2003-04-10 Advanced Research And Technology Institute Peptidoglycan recognition protein encoding nucleic acids and methods of use thereof
US6586524B2 (en) 2001-07-19 2003-07-01 Expression Genetics, Inc. Cellular targeting poly(ethylene glycol)-grafted polymeric gene carrier
IL159895A0 (en) * 2001-07-20 2004-06-20 Technion Res & Dev Foundation Methods of generating human cardiac cells and tissues and uses thereof
ATE502119T1 (de) * 2001-07-25 2011-04-15 Oncomedx Inc Verfahren zur bewertung pathologischer krankheitszustände unter verwendung extrazellulärer rna
US7169750B2 (en) 2001-07-31 2007-01-30 Anormed, Inc. Methods to mobilize progenitor/stem cells
JP2004536614A (ja) 2001-08-01 2004-12-09 ユニバーシティ オブ ユタ Ｐｄｅ３環状ヌクレオチド・ホスホジエステラーゼのアイソフォーム選択的な阻害剤および活性化剤
US6790833B2 (en) 2001-08-08 2004-09-14 The Research Foundation Of The State University Of New York Antifungal and antibacterial agents
US6743598B2 (en) 2001-08-10 2004-06-01 Mycologics, Inc. Methods for the identification of fungal glucose utilization inhibitors and antifungal agents
US6835536B2 (en) 2001-08-21 2004-12-28 Micrologix Biotech Inc. Antimicrobial cationic peptides and formulations thereof
JP2005502344A (ja) 2001-08-27 2005-01-27 ノバルティス アクチエンゲゼルシャフト 新規ｇタンパク質共役受容体およびそのｄｎａ配列
US7456335B2 (en) * 2001-09-03 2008-11-25 Basf Plant Science Gmbh Nucleic acid sequences and their use in methods for achieving pathogen resistance in plants
US20040142325A1 (en) 2001-09-14 2004-07-22 Liat Mintz Methods and systems for annotating biomolecular sequences
WO2003024407A2 (en) 2001-09-21 2003-03-27 Message Pharmaceuticals, Inc. Inhibitors of rnase p proteins as antibacterial compounds
EP2390328A1 (en) 2001-09-28 2011-11-30 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. MicroRNA molecules
AR045702A1 (es) 2001-10-03 2005-11-09 Chiron Corp Composiciones de adyuvantes.
CA2462593A1 (en) 2001-10-03 2003-04-10 Kam W. Leong Compositions for oral gene therapy and methods of using same
DE10148886A1 (de) 2001-10-04 2003-04-30 Avontec Gmbh Inhibition von STAT-1
US7276489B2 (en) 2002-10-24 2007-10-02 Idera Pharmaceuticals, Inc. Modulation of immunostimulatory properties of oligonucleotide-based compounds by optimal presentation of 5′ ends
US7659391B2 (en) 2001-11-05 2010-02-09 Janssen Pharmaceutica N.V. Method for the in vitro synthesis of short double stranded RNAs
US20040076978A1 (en) 2001-11-14 2004-04-22 Catherine Verfaillie Method to identify genes associated with chronic myelogenous leukemia
ATE427992T1 (de) 2001-11-14 2009-04-15 Toyo Boseki Dna-synthesepromotoren, mit dna-polymerase assoziierte faktoren und nutzung davon
WO2003044482A2 (en) 2001-11-16 2003-05-30 The University Of Tennessee Research Corporation Recombinant antibody fusion proteins and methods for detection of apoptotic cells
US6478825B1 (en) 2001-11-28 2002-11-12 Osteotech, Inc. Implant, method of making same and use of the implant for the treatment of bone defects
JP2005510251A (ja) 2001-11-29 2005-04-21 ノバルティス アクチエンゲゼルシャフト サルコイドーシスの評価法と予後判定法
CA2409775C (en) 2001-12-03 2010-07-13 F. Hoffmann-La Roche Ag Reversibly modified thermostable enzymes for dna synthesis and amplification in vitro
EP1521594B1 (en) 2001-12-07 2013-10-02 Novartis Vaccines and Diagnostics, Inc. Endogenous retrovirus polypeptides linked to oncogenic transformation
EP2208736A3 (en) 2001-12-07 2010-10-27 Novartis Vaccines and Diagnostics, Inc. Endogenous retrovirus up-regulated in prostate cancer
US20060275747A1 (en) 2001-12-07 2006-12-07 Hardy Stephen F Endogenous retrovirus up-regulated in prostate cancer
US20050107589A1 (en) 2001-12-17 2005-05-19 Gung-Wei Chirn Novel g-protein coupled receptors and dna sequences thereof
DE10162480A1 (de) 2001-12-19 2003-08-07 Ingmar Hoerr Die Applikation von mRNA für den Einsatz als Therapeutikum gegen Tumorerkrankungen
MXPA04004919A (es) 2001-12-21 2004-08-11 Alcon Inc Uso de nanoparticulas inorganicas sinteticas como vehiculos para farmacos oftalmicos y oticos.
AU2003235707A1 (en) 2002-01-18 2003-07-30 Curevac Gmbh Immunogenic preparations and vaccines on the basis of mrna
EP3020413A1 (en) 2002-01-30 2016-05-18 The Brigham and Women's Hospital, Inc. Compositions and methods related to TIM-3, a TH1-specific cell surface molecule
AU2003203079B9 (en) 2002-02-04 2009-01-15 Oncothyreon Inc. Immunostimulatory, covalently lipidated oligonucleotides
AU2003210802B2 (en) 2002-02-05 2009-09-10 Genentech Inc. Protein purification
FR2835749B1 (fr) 2002-02-08 2006-04-14 Inst Nat Sante Rech Med Composition pharmaceutique ameliorant le transfert de gene in vivo
DE10207178A1 (de) 2002-02-19 2003-09-04 Novosom Ag Komponenten für die Herstellung amphoterer Liposomen
US20050222064A1 (en) 2002-02-20 2005-10-06 Sirna Therapeutics, Inc. Polycationic compositions for cellular delivery of polynucleotides
AR038568A1 (es) 2002-02-20 2005-01-19 Hoffmann La Roche Anticuerpos anti-a beta y su uso
US7354742B2 (en) 2002-02-22 2008-04-08 Ortho-Mcneil Pharmaceutical, Inc. Method for generating amplified RNA
CA2481479C (en) 2002-02-26 2012-12-11 Maxygen, Inc. Novel flavivirus antigens
ES2362931T3 (es) 2002-03-04 2011-07-15 Imclone Llc Anticuerpos humanos específicos contra kdr y usos de los mismos.
CN1653080A (zh) * 2002-03-07 2005-08-10 路德维格癌症研究院 淋巴管和血管的内皮细胞基因
US20050152980A1 (en) 2002-03-13 2005-07-14 Michael Ausborn Pharmeutical microparticles
WO2003078593A2 (en) 2002-03-15 2003-09-25 Epigenomics Ag Discovery and diagnostic methods using 5-methylcytosine dna glycosylase
US7074596B2 (en) 2002-03-25 2006-07-11 Board Of Supervisors Of Louisiana State University And Agricultural And Mechanical College Synthesis and use of anti-reverse mRNA cap analogues
IL164376A0 (en) * 2002-04-03 2005-12-18 Applied Research Systems Ox4or binding agents, their preparation and pharmaceutical compositions containing them
EP3006043B1 (en) 2002-04-04 2019-05-29 Zoetis Belgium S.A. Immunostimulatory g,u-containing oligoribonucleotides
JP4761710B2 (ja) * 2002-04-05 2011-08-31 アムジェン インコーポレイテッド 選択的ｏｐｇｌ経路インヒビターとしてのヒト抗ｏｐｇｌ中和抗体
WO2003087815A2 (en) 2002-04-17 2003-10-23 Novartis Ag Method for the identification of inhibitors of the binding of are-containing mrn a and an hur protein
GB0209539D0 (en) 2002-04-26 2002-06-05 Avecia Ltd Monomer Polymer and process
EP1361277A1 (en) 2002-04-30 2003-11-12 Centre National De La Recherche Scientifique (Cnrs) Optimization of transgene expression in mammalian cells
BR122019027966B8 (pt) 2002-05-02 2021-07-27 Wyeth Corp conjugado monomérico de derivado de caliqueamicina/anti-corpo anti-cd22 e uso dos mesmos
AU2003217531A1 (en) 2002-05-02 2003-11-17 Massachusetts Eye And Ear Infirmary Ocular drug delivery systems and use thereof
US20040018525A1 (en) 2002-05-21 2004-01-29 Bayer Aktiengesellschaft Methods and compositions for the prediction, diagnosis, prognosis, prevention and treatment of malignant neoplasma
US7374930B2 (en) 2002-05-21 2008-05-20 Expression Genetics, Inc. GLP-1 gene delivery for the treatment of type 2 diabetes
DE10224200C1 (de) 2002-05-31 2003-08-21 Artus Ges Fuer Molekularbiolog Vermehrung von Ribonukleinsäuren
AU2003237367A1 (en) 2002-06-03 2003-12-19 Chiron Corporation Use of nrg4, or inhibitors thereof, in the treatment of colon and pancreatic cancer
SE0201907D0 (sv) 2002-06-19 2002-06-19 Atos Medical Ab Plaster for tracheostoma valves
WO2004020575A2 (en) 2002-06-24 2004-03-11 Exiqon A/S Methods and systems for detection and isolation of a nucleotide sequence
US7901708B2 (en) 2002-06-28 2011-03-08 Protiva Biotherapeutics, Inc. Liposomal apparatus and manufacturing methods
BR0312395A (pt) 2002-07-01 2007-06-19 Kenneth S Warren Inst Inc citocina protetora de tecido recombinante de muteìna, célula de mamìfero responsiva à citocina protetora de tecido recombinante, molécula de ácido nucleico isolada, vetor, vetor de expressão, célula geneticamente engenheirada, célula, composição farmacêutica, método para proteger, manter ou realçar a viabilidade de uma célula, tecido ou órgão isolados de um corpo de mamìfero, uso de uma citocina protetora de tecido recombinante, método para facilitar a transcitose de uma molécula através de uma barreira de célula endotelial em um mamìfero, e, composição para transportar uma molécula por intermédio da transcitose através de uma barreira de célula endotelial
DE10229872A1 (de) 2002-07-03 2004-01-29 Curevac Gmbh Immunstimulation durch chemisch modifizierte RNA
GB0215509D0 (en) 2002-07-04 2002-08-14 Novartis Ag Marker genes
US7316925B2 (en) 2002-07-16 2008-01-08 Vgx Pharmaceuticals, Inc. Codon optimized synthetic plasmids
US7927791B2 (en) 2002-07-24 2011-04-19 Ptc Therapeutics, Inc. Methods for identifying small molecules that modulate premature translation termination and nonsense mediated mRNA decay
EP1393745A1 (en) 2002-07-29 2004-03-03 Hybridon, Inc. Modulation of immunostimulatory properties of oligonucleotide-based compounds by optimal presentation of 5'ends
US6653468B1 (en) 2002-07-31 2003-11-25 Isis Pharmaceuticals, Inc. Universal support media for synthesis of oligomeric compounds
EP1386925A1 (en) 2002-07-31 2004-02-04 Girindus AG Method for preparing oligonucleotides
US20040220127A1 (en) 2002-08-09 2004-11-04 Paul Sternberg Methods and compositions relating to 5'-chimeric ribonucleic acids
EP1873180B1 (en) 2002-08-14 2014-05-07 Novartis AG Ophthalmic device made from a radiation-curable prepolymer
ATE533513T1 (de) 2002-09-06 2011-12-15 Cerulean Pharma Inc Polymere auf basis von cyclodextrin zur verabreichung von an diese kovalent gebundene arzneimittel
ES2315526T3 (es) 2002-09-09 2009-04-01 Nektar Therapeutics Al, Corporation Metodo para preparar derivados polimericos solubles en agua que llevan un acido carboxilico terminal.
US7534872B2 (en) 2002-09-27 2009-05-19 Syngen, Inc. Compositions and methods for the use of FMOC derivatives in DNA/RNA synthesis
EA021644B1 (ru) 2002-10-17 2015-08-31 Генмаб А/С Человеческое моноклональное антитело против cd20 и его применение
SG146441A1 (en) 2002-10-22 2008-10-30 Eisai R&D Man Co Ltd Gene specifically expressed in postmitotic dopaminergic neuron precursor cells
US7892793B2 (en) * 2002-11-04 2011-02-22 University Of Massachusetts Allele-specific RNA interference
EP1567169A4 (en) 2002-11-04 2009-10-21 Xenoport Inc GEMCITABINE PROMOTERS, THEIR PHARMACEUTICAL COMPOSITIONS AND USES THEREOF
CN1738914A (zh) 2002-11-21 2006-02-22 震源技术公司 使用编码双链启动子一条链的引物的方法
US7491234B2 (en) 2002-12-03 2009-02-17 Boston Scientific Scimed, Inc. Medical devices for delivery of therapeutic agents
PL212899B1 (pl) 2002-12-16 2012-12-31 Genentech Inc Humanizowane przeciwcialo, kompozycja zawierajaca to przeciwcialo, wyrób fabryczny, przeciwcialo lub jego fragment do zastosowania w sposobie indukowania apoptozy, izolowany kwas nukleinowy, wektor ekspresji, komórka gospodarza, sposób wytwarzania przeciwciala lub jego fragmentu, plynny preparat i zastosowanie przeciwciala do wytwarzania leku
CA2508985A1 (en) 2002-12-23 2004-07-15 Dynavax Technologies Corporation Branched immunomodulatory compounds and methods of using the same
US7169892B2 (en) 2003-01-10 2007-01-30 Astellas Pharma Inc. Lipid-peptide-polymer conjugates for long blood circulation and tumor specific drug delivery systems
EP1601789A4 (en) * 2003-01-16 2007-10-31 Idera Pharmaceuticals Inc MODULATION OF IMMUNOSTIMULATORY PROPERTIES OF OLIGONUCLEOTIDE-BASED COMPOUNDS USING MODIFIED IMMUNOSTIMULATORY DINUCLEOTIDES
WO2004067728A2 (en) 2003-01-17 2004-08-12 Ptc Therapeutics Methods and systems for the identification of rna regulatory sequences and compounds that modulate their function
US8426194B2 (en) 2003-01-21 2013-04-23 Ptc Therapeutics, Inc. Methods and agents for screening for compounds capable of modulating VEGF expression
EP1604011A4 (en) 2003-01-21 2009-12-09 Ptc Therapeutics Inc METHODS FOR IDENTIFYING COMPOUNDS THAT MODULATE THE EXPRESSION OF DEPENDENT GENES FROM A NON-TRANSLATED REGION, AND METHODS OF USING SAME
US9068234B2 (en) 2003-01-21 2015-06-30 Ptc Therapeutics, Inc. Methods and agents for screening for compounds capable of modulating gene expression
US20040147027A1 (en) 2003-01-28 2004-07-29 Troy Carol M. Complex for facilitating delivery of dsRNA into a cell and uses thereof
SI3417875T1 (sl) 2003-02-10 2021-01-29 Biogen Ma Inc. Formulacija imunoglobulina in metode za njegovo pripravo
US20040167090A1 (en) 2003-02-21 2004-08-26 Monahan Sean D. Covalent modification of RNA for in vitro and in vivo delivery
US7091185B2 (en) 2003-02-24 2006-08-15 Dow Global Technologies Inc. Periodic antimicrobial peptides
AU2004215238B2 (en) * 2003-02-27 2009-08-27 Basf Aktiengesellschaft Modified nitrilases and their use in methods for the production of carboxylic acids
CA2450289A1 (en) 2003-03-20 2005-05-19 Imclone Systems Incorporated Method of producing an antibody to epidermal growth factor receptor
US7320961B2 (en) 2003-03-24 2008-01-22 Abbott Laboratories Method for treating a disease, disorder or adverse effect caused by an elevated serum concentration of an UGT1A1 substrate
EP2194123B1 (en) 2003-03-25 2012-08-22 Stratagene California DNA polymerase fusions and uses thereof
WO2004092329A2 (en) 2003-04-08 2004-10-28 Galenica Pharmaceuticals, Inc. Semi-synthetic saponin analogs with carrier and immune stimulatory activities for dna and rna vaccines
HRP20090325T1 (en) 2003-04-09 2009-07-31 Genentech Therapy of autoimmune disease in a patient with an inadequate response to a tnf-alpha inhibitor
JP4991288B2 (ja) * 2003-04-17 2012-08-01 アルナイラム ファーマシューティカルズ， インコーポレイテッド 二本鎖ｉＲＮＡ剤、および二本鎖ｉＲＮＡ剤の対合の安定性を調節する方法。
CN100393367C (zh) 2003-05-05 2008-06-11 宾-古里安尼格夫大学研究及发展部 可注射的交联聚合制剂及其应用
US7348004B2 (en) 2003-05-06 2008-03-25 Syntonix Pharmaceuticals, Inc. Immunoglobulin chimeric monomer-dimer hybrids
EP3002012A1 (en) 2003-05-06 2016-04-06 Biogen Hemophilia Inc. Clotting factor-fc chimeric proteins to treat hemophilia
TWI353991B (en) 2003-05-06 2011-12-11 Syntonix Pharmaceuticals Inc Immunoglobulin chimeric monomer-dimer hybrids
US9567591B2 (en) 2003-05-15 2017-02-14 Mello Biotechnology, Inc. Generation of human embryonic stem-like cells using intronic RNA
GB0313132D0 (en) 2003-06-06 2003-07-09 Ich Productions Ltd Peptide ligands
KR20060054196A (ko) * 2003-06-10 2006-05-22 주식회사 툴젠 전달가능한 ｄｎａ-결합 단백질
WO2005009346A2 (en) 2003-06-24 2005-02-03 Mirus Corporation Inhibition of gene function by delivery of polynucleotide-based gene expression inhibitors to mammalian cells in vivo
GB0316089D0 (en) 2003-07-09 2003-08-13 Xo Bioscience Ltd Differentiation method
KR100992646B1 (ko) 2003-07-09 2010-11-05 제이에스알 가부시끼가이샤 파장판
US8592197B2 (en) 2003-07-11 2013-11-26 Novavax, Inc. Functional influenza virus-like particles (VLPs)
US7575572B2 (en) 2003-07-15 2009-08-18 Spinal Generations, Llc Method and device for delivering medicine to bone
US20050013870A1 (en) 2003-07-17 2005-01-20 Toby Freyman Decellularized extracellular matrix of conditioned body tissues and uses thereof
AU2004265595B2 (en) 2003-07-18 2011-12-08 Amgen Fremont Inc. Specific binding agents to hepatocyte growth factor
DE10334371A1 (de) 2003-07-25 2005-02-17 Bavarian Nordic A/S Reaktorboden eines Reaktors
EP2530157B1 (en) 2003-07-31 2016-09-28 Regulus Therapeutics Inc. Oligomeric compounds and compositions for use in modulation of miRNAs
DE10335833A1 (de) 2003-08-05 2005-03-03 Curevac Gmbh Transfektion von Blutzellen mit mRNA zur Immunstimulation und Gentherapie
CL2004001996A1 (es) 2003-08-08 2005-05-06 Eyetech Pharmaceuticals Inc Aptameros anti-vegf (factor de crecimiento endotelial vascular) con bloqueo nucleotidico 5'-5' o 3'-3' invertido, composicion que lo contiene, util para trastornos de neovascularizacion.
US8668926B1 (en) 2003-09-15 2014-03-11 Shaker A. Mousa Nanoparticle and polymer formulations for thyroid hormone analogs, antagonists, and formulations thereof
US7135010B2 (en) 2003-09-30 2006-11-14 Damage Control Surgical Technologies, Inc. Method and apparatus for rapid deployment chest drainage
US20070155772A1 (en) 2003-10-06 2007-07-05 Susan Ide Use of genetic polymorphisms that associate with efficacy of treatment of inflammatory disease
DE10347710B4 (de) 2003-10-14 2006-03-30 Johannes-Gutenberg-Universität Mainz Rekombinante Impfstoffe und deren Verwendung
US20050130201A1 (en) 2003-10-14 2005-06-16 Dharmacon, Inc. Splint-assisted enzymatic synthesis of polyribounucleotides
RS54450B1 (sr) 2003-11-05 2016-06-30 Roche Glycart Ag Molekuli koji se vezuju za antigen sa povećanim afinitetom vezivanja za fc receptor i efektornom funkcijom
WO2005047536A2 (en) 2003-11-13 2005-05-26 Novartis Ag Detection of genomic amplification and deletion in cancer
US20070054278A1 (en) * 2003-11-18 2007-03-08 Applera Corporation Polymorphisms in nucleic acid molecules encoding human enzyme proteins, methods of detection and uses thereof
US7699852B2 (en) 2003-11-19 2010-04-20 Zimmer Spine, Inc. Fenestrated bone tap and method
US20050153333A1 (en) 2003-12-02 2005-07-14 Sooknanan Roy R. Selective terminal tagging of nucleic acids
WO2007062495A1 (en) 2005-11-30 2007-06-07 Roy Rabindranauth Sooknanan Selective terminal tagging of nucleic acids
EP1691746B1 (en) 2003-12-08 2015-05-27 Gel-Del Technologies, Inc. Mucoadhesive drug delivery devices and methods of making and using thereof
US7674884B2 (en) 2003-12-10 2010-03-09 Novimmune S.A. Neutralizing antibodies and methods of use thereof
US8372966B2 (en) 2003-12-19 2013-02-12 University Of Cincinnati Oligonucleotide decoys and methods of use
JP2005179268A (ja) 2003-12-19 2005-07-07 Gc Corp 口腔用組成物
HRP20120376T1 (hr) 2003-12-23 2012-05-31 Genentech Nova protutijela protiv il-13 i njihove upotrebe
WO2005065721A2 (en) * 2003-12-30 2005-07-21 Board Of Regents, The University Of Texas System Use of an anti-inflammatory compound for the reduction of inflammation secondary to the administration of a lipid-nucleic acid complex
WO2005072710A2 (en) 2004-01-28 2005-08-11 Johns Hopkins University Drugs and gene carrier particles that rapidly move through mucous barriers
EP1716233B1 (en) 2004-01-30 2009-08-26 Maxygen Holdings Ltd. Regulated stop codon readthrough
US7309487B2 (en) * 2004-02-09 2007-12-18 George Inana Methods and compositions for detecting and treating retinal diseases
JP4805848B2 (ja) 2004-02-12 2011-11-02 モルフォテック、インク． 腫瘍抗原の生物活性を特異的に阻止するモノクローナル抗体
US20070265220A1 (en) 2004-03-15 2007-11-15 City Of Hope Methods and compositions for the specific inhibition of gene expression by double-stranded RNA
JPWO2005090405A1 (ja) 2004-03-24 2008-04-17 中外製薬株式会社 インターロイキン−６受容体に対するヒト型化抗体のサブタイプ
WO2005098433A2 (en) 2004-04-01 2005-10-20 Novartis Ag Diagnostic assays for alzheimer’s disease
AU2005329255B2 (en) 2004-04-15 2010-09-30 Chiasma, Inc. Compositions capable of facilitating penetration across a biological barrier
JP5848861B2 (ja) 2004-04-20 2016-01-27 ジェンマブ エー／エスＧｅｎｍａｂ Ａ／Ｓ Ｃｄ２０に対するヒトモノクローナル抗体
ES2246694B1 (es) 2004-04-29 2007-05-01 Instituto Cientifico Y Tecnologico De Navarra, S.A. Nanoparticulas pegiladas.
US20080119645A1 (en) 2004-05-05 2008-05-22 Isis Pharmaceuticals, Inc. Amidites and Methods of Rna Synthesis
ATE409025T1 (de) 2004-05-12 2008-10-15 Baxter Int Nukleinsäure-mikrokügelchen, ihre herstellung und abgabe
US20080103053A1 (en) 2005-11-22 2008-05-01 Helicos Biosciences Corporation Methods and compositions for sequencing a nucleic acid
CA2568772A1 (en) 2004-06-01 2005-12-15 San Diego State University Foundation Expression system based on recombinant vesicular stomatitis virus synthesizing t7 rna polymerase
US20090081243A1 (en) * 2004-06-03 2009-03-26 Athlomics Pty Ltd. Agents and methods for diagnosing stress
EP1781593B1 (en) 2004-06-07 2011-12-14 Protiva Biotherapeutics Inc. Cationic lipids and methods of use
US7799565B2 (en) 2004-06-07 2010-09-21 Protiva Biotherapeutics, Inc. Lipid encapsulated interfering RNA
EP1773240B1 (en) 2004-06-11 2019-11-20 Trustees of the Tufts College Silk-based drug delivery system
US7527947B2 (en) 2004-06-14 2009-05-05 Novozymes A/S Signal peptide for producing a polypeptide
WO2006046978A2 (en) 2004-06-28 2006-05-04 Argos Therapeutics, Inc. Cationic peptide-mediated transformation
WO2006005058A2 (en) 2004-06-30 2006-01-12 Nektar Therapeutics Al, Corporation Polymer-factor ix moiety conjugates
US7700555B2 (en) 2004-07-15 2010-04-20 Joslin Diabetes Center, Inc. Methods of treating diabetes
DE102004035227A1 (de) 2004-07-21 2006-02-16 Curevac Gmbh mRNA-Gemisch zur Vakzinierung gegen Tumorerkrankungen
CA2574088C (en) 2004-07-21 2013-09-17 Alnylam Pharmaceuticals, Inc. Oligonucleotides comprising a modified or non-natural nucleobase
US7603349B1 (en) 2004-07-29 2009-10-13 Yahoo! Inc. User interfaces for search systems using in-line contextual queries
GB0417487D0 (en) 2004-08-05 2004-09-08 Novartis Ag Organic compound
US7968324B2 (en) 2004-08-13 2011-06-28 Barry J Marshall Helicobacter system and uses thereof
US7291208B2 (en) 2004-08-13 2007-11-06 Gore Enterprise Holdings, Inc. Grooved active and passive adsorbent filters
SE0402025D0 (sv) 2004-08-13 2004-08-13 Active Biotech Ab Treatment of hyperproliferative disease with superantigens in combination with another anticancer agent
CA2478458A1 (en) 2004-08-20 2006-02-20 Michael Panzara Treatment of pediatric multiple sclerosis
ES2535235T3 (es) 2004-08-26 2015-05-07 Engeneic Molecular Delivery Pty Ltd Administración de ácidos nucleicos funcionales a células de mamífero a través de minicélulas intactas obtenidas a partir de bacterias
DE102004042546A1 (de) 2004-09-02 2006-03-09 Curevac Gmbh Kombinationstherapie zur Immunstimulation
EP1789460B1 (en) 2004-09-02 2013-01-09 Isis Pharmaceuticals, Inc. Polymeric beads for oligonucleotide synthesis
US7501486B2 (en) 2004-09-07 2009-03-10 Burnham Institute For Medical Research Peptides that selectively home to heart vasculature and related conjugates and methods
CA2583413A1 (en) * 2004-09-21 2006-03-30 Anesiva, Inc. Delivery of polynucleotides
CN101060864A (zh) * 2004-09-21 2007-10-24 阿尼西瓦股份有限公司 多核苷酸的递送
GB0421639D0 (en) * 2004-09-29 2004-10-27 Proteome Sciences Plc Methods and compositions relating to alzheimer's disease
US8663599B1 (en) 2004-10-05 2014-03-04 Gp Medical, Inc. Pharmaceutical composition of nanoparticles
US20080075698A1 (en) 2004-10-12 2008-03-27 Tissue Targeting Japan Inc. Brain-Localizing Bone Marrow Progenitor cells
CA2583177A1 (en) 2004-10-13 2006-04-27 Ptc Therapeutics, Inc. Compounds for nonsense suppression, and methods for their use
US8057821B2 (en) 2004-11-03 2011-11-15 Egen, Inc. Biodegradable cross-linked cationic multi-block copolymers for gene delivery and methods of making thereof
WO2006047842A2 (en) 2004-11-08 2006-05-11 K.U. Leuven Research And Development Modified nucleosides for rna interference
JP2008520740A (ja) 2004-11-23 2008-06-19 ピーティーシー セラピューティクス， インコーポレイテッド Ｖｅｇｆ産生を阻害する活性因子としての置換されたフェノール
US7964571B2 (en) 2004-12-09 2011-06-21 Egen, Inc. Combination of immuno gene therapy and chemotherapy for treatment of cancer and hyperproliferative diseases
US8354476B2 (en) 2004-12-10 2013-01-15 Kala Pharmaceuticals, Inc. Functionalized poly(ether-anhydride) block copolymers
WO2006071903A2 (en) 2004-12-28 2006-07-06 Ptc Therapeutics, Inc. Cell based methods and systems for the identification of rna regulatory sequences and compounds that modulate their functions
US8187570B1 (en) 2005-01-04 2012-05-29 Gp Medical, Inc. Nanoparticles for protein drug delivery
US8192718B1 (en) 2005-01-04 2012-06-05 Gp Medical, Inc. Pharmaceutical composition of nanoparticles
JP5366406B2 (ja) * 2005-01-07 2013-12-11 レキシコン ファーマシューティカルズ インコーポレーテッド アンジオポエチン様タンパク質４（ａｎｇｐｔｌ４）に対するモノクローナル抗体
US8535702B2 (en) 2005-02-01 2013-09-17 Boston Scientific Scimed, Inc. Medical devices having porous polymeric regions for controlled drug delivery and regulated biocompatibility
US7404969B2 (en) 2005-02-14 2008-07-29 Sirna Therapeutics, Inc. Lipid nanoparticle based compositions and methods for the delivery of biologically active molecules
CA2597724A1 (en) 2005-02-14 2007-08-02 Sirna Therapeutics, Inc. Cationic lipids and formulated molecular compositions containing them
US20100221186A1 (en) 2005-03-11 2010-09-02 Hueseyin Firat Biomarkers for cardiovascular side-effects induced by cox-2 inhibitory compounds
WO2006110314A2 (en) * 2005-03-25 2006-10-19 Ambion, Inc. Methods and compositions for depleting abundant rna transcripts
US8415325B2 (en) 2005-03-31 2013-04-09 University Of Delaware Cell-mediated delivery and targeted erosion of noncovalently crosslinked hydrogels
US7638558B2 (en) 2005-04-01 2009-12-29 Intezyne Technologies, Inc. Polymeric micelles for drug delivery
AU2006235276A1 (en) 2005-04-07 2006-10-19 Novartis Vaccines And Diagnostics Inc. CACNA1E in cancer diagnosis, detection and treatment
EP1871911A2 (en) 2005-04-07 2008-01-02 Chiron Corporation Cancer-related genes (prlr)
EP1885403B1 (en) 2005-04-12 2013-05-08 Nektar Therapeutics Poly(ethyleneglycol) conjugates of Lysostaphin
EP1899467A2 (en) 2005-04-26 2008-03-19 Coley Pharmaceutical GmbH Modified oligoribonucleotide analogs with enhances immunostimulatory activity
KR101498834B1 (ko) 2005-05-09 2015-03-05 오노 야꾸힝 고교 가부시키가이샤 예정 사멸 인자 1(ｐｄ-1)에 대한 인간 모노클로날 항체, 및 항-ｐｄ-1 항체를 단독 사용하거나 기타 면역 요법제와 병용한 암 치료 방법
US8246995B2 (en) 2005-05-10 2012-08-21 The Board Of Trustees Of The Leland Stanford Junior University Hydrophobic nanotubes and nanoparticles as transporters for the delivery of drugs into cells
US20070072175A1 (en) * 2005-05-13 2007-03-29 Biogen Idec Ma Inc. Nucleotide array containing polynucleotide probes complementary to, or fragments of, cynomolgus monkey genes and the use thereof
US20060265771A1 (en) 2005-05-17 2006-11-23 Lewis David L Monitoring microrna expression and function
DE102005023170A1 (de) 2005-05-19 2006-11-23 Curevac Gmbh Optimierte Formulierung für mRNA
KR20130114758A (ko) * 2005-05-27 2013-10-17 오스페달레 산 라파엘 에스.알.엘. Ｍｉ-ｒｎａ를 포함하는 유전자 벡터
US20090208500A1 (en) 2005-06-03 2009-08-20 Genentech, Inc. Method of producing antibodies with improved function
US7550264B2 (en) 2005-06-10 2009-06-23 Datascope Investment Corporation Methods and kits for sense RNA synthesis
WO2006138572A2 (en) 2005-06-16 2006-12-28 Nektar Therapeutics Al, Corporation Conjugates having a degradable linkage and polymeric reagents useful in preparing such conjugates
US8202835B2 (en) 2005-06-17 2012-06-19 Yitzchak Hillman Disease treatment via antimicrobial peptides or their inhibitors
CN102016814B (zh) 2005-06-17 2013-10-23 北卡罗来纳大学查珀尔希尔分校 纳米粒子制备方法、系统及材料
WO2007005645A2 (en) 2005-06-30 2007-01-11 Archemix Corp. Materials and methods for the generation of fully 2'-modified nucleic acid transcripts
US8101385B2 (en) 2005-06-30 2012-01-24 Archemix Corp. Materials and methods for the generation of transcripts comprising modified nucleotides
US20080220471A1 (en) 2005-07-27 2008-09-11 Genentech, Inc. Vectors and Methods Using Same
SI1919503T1 (sl) 2005-08-10 2015-02-27 Macrogenics, Inc. Identifikacija in inĺ˝eniring protiteles z variantnimi fc regijami in postopki za njih uporabo
US9012219B2 (en) 2005-08-23 2015-04-21 The Trustees Of The University Of Pennsylvania RNA preparations comprising purified modified RNA for reprogramming cells
US20070048741A1 (en) 2005-08-24 2007-03-01 Getts Robert C Methods and kits for sense RNA synthesis
CA2621023C (en) 2005-09-01 2019-07-02 Novartis Vaccines And Diagnostics Gmbh & Co. Kg Multiple vaccination including serogroup c meningococcus
ATE499112T1 (de) 2005-09-01 2011-03-15 Celgene Corp Immunologische verwendungen von immunmodulatorischen verbindungen für einen impfstoff und therapie gegen infektionskrankheiten
US8420605B2 (en) 2005-09-07 2013-04-16 The University Of Strathclyde Hydrogel compositions
US20120021042A1 (en) 2005-09-15 2012-01-26 Steffen Panzner Efficient Method For Loading Amphoteric Liposomes With Nucleic Acid Active Substances
DE102005046490A1 (de) 2005-09-28 2007-03-29 Johannes-Gutenberg-Universität Mainz Modifikationen von RNA, die zu einer erhöhten Transkriptstabilität und Translationseffizienz führen
US20070087437A1 (en) 2005-10-14 2007-04-19 Jifan Hu Methods for rejuvenating cells in vitro and in vivo
WO2007052058A1 (en) 2005-11-04 2007-05-10 Novartis Vaccines And Diagnostics Srl Influenza vaccines including combinations of particulate adjuvants and immunopotentiators
US20070105124A1 (en) 2005-11-08 2007-05-10 Getts Robert C Methods and kits for nucleic acid amplification
JP2009515539A (ja) 2005-11-18 2009-04-16 バイオライン・リミテッド 酵素的ｄｎａポリメラーゼ反応を増強するための方法
JP5525729B2 (ja) 2005-11-28 2014-06-18 ゲンマブ エー／エス 組換え一価抗体およびその作製方法
TWI389709B (zh) 2005-12-01 2013-03-21 Novartis Ag 經皮治療系統
EP1954252B1 (en) 2005-12-02 2016-02-03 GlaxoSmithKline Biologicals SA Nanoparticles for use in immunogenic compositions
US8603457B2 (en) 2005-12-02 2013-12-10 University Of Rochester Nonsense suppression and genetic codon alteration by targeted modification
CA2632451C (en) 2005-12-06 2015-11-03 Centre National De La Recherche Scientifique Cell penetrating peptides for intracellular delivery of molecules
US7579318B2 (en) 2005-12-06 2009-08-25 Centre De La Recherche De La Scientifique Cell penetrating peptides for intracellular delivery of molecules
CA2630597A1 (en) 2005-12-08 2007-06-14 Novartis Ag Effects of inhibitors of fgfr3 on gene transcription
EP1795599A1 (en) 2005-12-09 2007-06-13 Schuler, Gerold, Prof. Dr. Methods for generating antigen-specific effector T cells
NZ569530A (en) 2005-12-13 2011-07-29 Univ Kyoto Nuclear reprogramming factor
JP2009519033A (ja) 2005-12-16 2009-05-14 ディアト 核酸を細胞に送達するための細胞貫通ペプチド結合体
WO2007082304A2 (en) 2006-01-12 2007-07-19 Massachusetts Institute Of Technology Biodegradable elastomers
AU2007208452B2 (en) 2006-01-13 2012-07-05 The Trustees Of The University Of Pennsylvania Vaccines and immunotherapeutics using codon optimized IL-15 and methods for using the same
US7399845B2 (en) 2006-01-27 2008-07-15 Isis Pharmaceuticals, Inc. 6-modified bicyclic nucleic acid analogs
CN103215293B (zh) 2006-01-27 2015-10-28 比奥根Ma公司 Nogo受体拮抗剂
US20070178103A1 (en) 2006-01-30 2007-08-02 Fey Georg H CD19-specific immunotoxin and treatment method
US8946155B2 (en) 2006-02-03 2015-02-03 Opko Biologics Ltd. Long-acting polypeptides and methods of producing and administering same
US9458444B2 (en) 2006-02-03 2016-10-04 Opko Biologics Ltd. Long-acting coagulation factors and methods of producing same
US8476234B2 (en) 2006-02-03 2013-07-02 Prolor Biotech Inc. Long-acting coagulation factors and methods of producing same
DE102006007433A1 (de) 2006-02-17 2007-08-23 Curevac Gmbh Adjuvanz in Form einer Lipid-modifizierten Nukleinsäure
US20100168034A1 (en) 2006-02-20 2010-07-01 Ewha University-Industry Collaboration Foundation Peptide having cell membrane penetrating activity
MX2008010841A (es) 2006-02-21 2008-10-27 Nektar Therapeutics Al Corp Polimeros degradables segmentados y conjugados hechos de los mismos.
US20080038278A1 (en) * 2006-02-24 2008-02-14 Jingsong Cao GPAT3 encodes a mammalian, microsomal acyl-coa:glycerol 3- phosphate acyltransferase
US8431160B2 (en) 2006-02-24 2013-04-30 Novartis Ag Microparticles containing biodegradable polymer and cationic polysaccharide for use in immunogenic compositions
US7910152B2 (en) 2006-02-28 2011-03-22 Advanced Cardiovascular Systems, Inc. Poly(ester amide)-based drug delivery systems with controlled release rate and morphology
EP4276469A3 (en) 2006-02-28 2024-01-17 Biogen MA Inc. Methods of treating inflammatory and autoimmune diseases with natalizumab
GB0605217D0 (en) 2006-03-15 2006-04-26 Novartis Ag Method and compositions for assessing acute rejection
EP2012751A4 (en) 2006-03-21 2010-11-24 Morehouse School Of Medicine NEW NANOPARTICLES FOR THE DELIVERY OF ACTIVE AGENTS
WO2008105773A2 (en) 2006-03-31 2008-09-04 Massachusetts Institute Of Technology System for targeted delivery of therapeutic agents
EP2007358A4 (en) 2006-04-04 2012-01-25 Stc Unm INFLATING PARTICLES FOR THE ADMINISTRATION OF A MEDICINAL PRODUCT
US20070281336A1 (en) 2006-04-14 2007-12-06 Epicentre Technologies Kits and methods for generating 5' capped RNA
WO2007118939A1 (fr) 2006-04-19 2007-10-25 Arcelor France Procede de fabrication d'une piece soudee a tres hautes caracteristiques mecaniques a partir d'une tole laminee et revetue
EP1852127A1 (en) 2006-05-02 2007-11-07 Charité - Universitätsmedizin Berlin Use of a B-cell-depleting antibody for treatment of polyoma virus infections
US8367113B2 (en) 2006-05-15 2013-02-05 Massachusetts Institute Of Technology Polymers for functional particles
HRP20120382T1 (hr) 2006-05-24 2012-06-30 Merck Serono Sa Kombinacija davanja interferona-beta i kladribina za liječenje multiple skleroze
EP2492684B1 (en) 2006-06-02 2016-12-28 President and Fellows of Harvard College Protein surface remodeling
WO2007149880A2 (en) * 2006-06-21 2007-12-27 Genentech, Inc. Crystal structure of ox40l and ox40l complexed with ox40 receptor
US20130004480A1 (en) 2006-07-04 2013-01-03 Paul Parren CD20 Binding Molecules for the Treatment of Copd
CA2706124A1 (en) 2006-07-07 2008-01-10 Aarhus Universitet Nanoparticles for nucleic acid delivery
US8404783B2 (en) 2006-07-12 2013-03-26 Novartis Ag Polymers
JP2009544287A (ja) 2006-07-20 2009-12-17 ノバルティス アーゲー 癌を処置、診断、または検出するためのａｍｉｇｏ−２インヒビター
US8728527B2 (en) 2006-07-24 2014-05-20 Luminus Biosciences, Inc. Solid nanoparticle formulation of water insoluble pharmaceutical substances with reduced ostwald ripening
CA2659301A1 (en) 2006-07-28 2008-02-07 Applera Corporation Dinucleotide mrna cap analogs
JP2010507361A (ja) 2006-07-31 2010-03-11 キュアバック ゲーエムベーハー 具体的には免疫刺激剤／アジュバントとしての、一般式（Ｉ）：ＧｌＸｍＧｎ、または一般式（ＩＩ）：ＣｌＸｍＣｎで表される核酸
DE102006035618A1 (de) 2006-07-31 2008-02-07 Curevac Gmbh Nukleinsäure der Formel (I): GlXmGn, insbesondere als immunstimulierendes Adjuvanz
RU2009108289A (ru) 2006-08-07 2010-09-20 Джензим Корпорейшн (Us) Комбинированная терапия
WO2008021290A2 (en) 2006-08-09 2008-02-21 Homestead Clinical Corporation Organ-specific proteins and methods of their use
US20080076701A1 (en) 2006-08-18 2008-03-27 Nastech Pharmaceutical Company Inc. Dicer substrate rna peptide conjugates and methods for rna therapeutics
US8658211B2 (en) 2006-08-18 2014-02-25 Arrowhead Madison Inc. Polyconjugates for in vivo delivery of polynucleotides
US7846895B2 (en) 2006-09-06 2010-12-07 The Regents Of The University Of California Selectively targeted antimicrobial peptides and the use thereof
US8192927B2 (en) 2006-09-07 2012-06-05 Crucell Holland B.V. Human bind molecules capable of neutralizing influenza virus h5n1 and uses thereof
AU2007292902B8 (en) 2006-09-08 2013-09-05 Johns Hopkins University Compositions and methods for enhancing transport through mucus
US8454948B2 (en) 2006-09-14 2013-06-04 Medgenics Medical Israel Ltd. Long lasting drug formulations
GB0619182D0 (en) 2006-09-29 2006-11-08 Leuven K U Res & Dev Oligonucleotide arrays
EP2068886B1 (en) 2006-10-03 2013-09-18 Tekmira Pharmaceuticals Corporation Lipid containing formulations
JP2010505877A (ja) 2006-10-05 2010-02-25 ザ・ジョンズ・ホプキンス・ユニバーシティー スマートな高分子ナノ粒子を用いた低水溶性薬物用の水分散性経口、非経口および局所的製剤
GB0619816D0 (en) * 2006-10-06 2006-11-15 Viragen Inc Novel interferon-alpha constructs for use in the treatment of cancer
DE102006051516A1 (de) * 2006-10-31 2008-05-08 Curevac Gmbh (Basen-)modifizierte RNA zur Expressionssteigerung eines Proteins
US8414927B2 (en) 2006-11-03 2013-04-09 Boston Scientific Scimed, Inc. Cross-linked polymer particles
EP2091552A4 (en) 2006-11-15 2010-01-06 Dana Farber Cancer Inst Inc STABILIZED MAML-PEPTIDES AND ITS USES
US7999087B2 (en) 2006-11-15 2011-08-16 Agilent Technologies, Inc. 2′-silyl containing thiocarbonate protecting groups for RNA synthesis
US8242258B2 (en) 2006-12-03 2012-08-14 Agilent Technologies, Inc. Protecting groups for RNA synthesis
US8399007B2 (en) 2006-12-05 2013-03-19 Landec Corporation Method for formulating a controlled-release pharmaceutical formulation
EP2121011B1 (en) 2006-12-06 2014-05-21 Novartis AG Vaccines including antigen from four strains of influenza virus
US9034348B2 (en) 2006-12-11 2015-05-19 Chi2Gel Ltd. Injectable chitosan mixtures forming hydrogels
MX2009006651A (es) 2006-12-18 2009-08-26 Acceleron Pharma Inc Antagonistas de activina-actrii y usos para incrementar los niveles de globulos rojo.
JP5452230B2 (ja) 2006-12-21 2014-03-26 ストライカー コーポレイション 生物学的因子の結晶、高分子ゲルおよび粒子懸濁液を含む持続放出処方物
DK2104739T3 (da) 2006-12-21 2013-10-07 Novozymes Inc Modificerede messenger-RNA-stabiliseringssekvenser til ekspression af gener i bakterieceller
WO2008078180A2 (en) 2006-12-22 2008-07-03 Archemix Corp. Materials and methods for the generation of transcripts comprising modified nucleotides
DE102006061015A1 (de) 2006-12-22 2008-06-26 Curevac Gmbh Verfahren zur Reinigung von RNA im präparativen Maßstab mittels HPLC
US8338166B2 (en) 2007-01-04 2012-12-25 Lawrence Livermore National Security, Llc Sorting, amplification, detection, and identification of nucleic acid subsequences in a complex mixture
DE102007001370A1 (de) 2007-01-09 2008-07-10 Curevac Gmbh RNA-kodierte Antikörper
WO2008091799A2 (en) 2007-01-22 2008-07-31 The Trustees Of Columbia University In The City Of New York Cell-based methods for identifying inhibitors of parkinson's disease-associated lrrk2 mutants
CN103755789B (zh) 2007-01-30 2016-12-07 埃皮瓦克斯公司 调节性t细胞表位、组合物及其用途
TW201940502A (zh) 2007-02-02 2019-10-16 美商艾瑟勒朗法瑪公司 衍生自ＡｃｔＲＩＩＢ的變體與其用途
US8859229B2 (en) 2007-02-02 2014-10-14 Yale University Transient transfection with RNA
WO2008096370A2 (en) 2007-02-05 2008-08-14 Natco Pharma Limited An efficient and novel purification method of recombinant hg-csf
US8333799B2 (en) 2007-02-12 2012-12-18 C. R. Bard, Inc. Highly flexible stent and method of manufacture
CA2689042A1 (en) 2007-02-16 2008-08-28 Merck & Co., Inc. Compositions and methods for potentiated activity of biologicaly active molecules
WO2008104294A1 (en) * 2007-02-27 2008-09-04 Bayer Schering Pharma Aktiengesellschaft Myh7 as a biomarker for ppara modulators
US8242087B2 (en) 2007-02-27 2012-08-14 K.U.Leuven Research & Development Phosphate modified nucleosides useful as substrates for polymerases and as antiviral agents
EP1964922A1 (en) 2007-03-02 2008-09-03 Boehringer Ingelheim Pharma GmbH & Co. KG Improvement of protein production
DK2126093T3 (da) 2007-03-02 2013-01-07 Boehringer Ingelheim Pharma Forbedring af proteinfremstilling
JP5249248B2 (ja) 2007-03-05 2013-07-31 ワシントン ユニバーシティー 膜組み込みペプチドのためのナノ粒子輸送システム
JP2010521966A (ja) 2007-03-20 2010-07-01 ミレニアム・ファーマシューティカルズ・インコーポレイテッド α４β７インテグリンに結合するヒト化免疫グロブリンをコードする核酸
DE602008005299D1 (de) 2007-04-27 2011-04-14 Echo Therapeutics Inc Hautpermeationsvorrichtung für Analytenmessung oder transdermale Arzneiabgabe
JP2010526087A (ja) 2007-04-30 2010-07-29 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー 抗ｉｌ−５抗体を投与するための方法
WO2008135855A2 (en) 2007-05-03 2008-11-13 Pfizer Products Inc. Nanoparticles comprising a cholesteryl ester transfer protein inhibitor and a nonionizable polymer
ES2531520T3 (es) 2007-05-04 2015-03-16 Marina Biotech, Inc. Lipoaminoácidos y usos de los mismos
US7682789B2 (en) 2007-05-04 2010-03-23 Ventana Medical Systems, Inc. Method for quantifying biomolecules conjugated to a nanoparticle
US8728491B2 (en) 2007-05-07 2014-05-20 Alba Therapeutics Corporation Transcutaneous delivery of therapeutic agents
JP5296328B2 (ja) 2007-05-09 2013-09-25 独立行政法人理化学研究所 １本鎖環状ｒｎａおよびその製造方法
HUE028389T2 (en) 2007-05-10 2016-12-28 Agilent Technologies Inc For the synthesis of thiocarbons protecting groups RNSS
MX2009012341A (es) 2007-05-14 2010-02-17 Medimmune Llc Metodos para reducir niveles de eosinofilos.
WO2008144365A2 (en) 2007-05-17 2008-11-27 Novartis Ag Method for making dry powder compositions containing ds-rna based on supercritical fluid technology
CN104480112B (zh) 2007-05-22 2018-06-12 阿克丘勒斯治疗公司 用于治疗的una寡聚体
JP2010529954A (ja) 2007-05-22 2010-09-02 ノバルティス アーゲー Ｆｇｆ２１関連障害を処置、診断および検出する方法
CN101802172A (zh) 2007-05-30 2010-08-11 通用医疗公司 由体细胞产生多能细胞的方法
DK2160464T3 (da) 2007-05-30 2014-08-04 Univ Northwestern Nukleinsyrefunktionaliserede nanopartikler til terapeutiske anvendelser
CN104072561B (zh) 2007-06-19 2017-12-22 路易斯安那州州立大学及农业机械学院管理委员会 信使rna帽的抗‑反向硫代磷酸类似物的合成和用途
EP2173872B1 (en) 2007-06-29 2014-04-02 CellScript, Inc. Copy dna and sense rna
US8367318B2 (en) 2007-07-23 2013-02-05 Dharmacon, Inc. Screening of micro-RNA cluster inhibitor pools
US20090042825A1 (en) 2007-08-06 2009-02-12 Majed Matar Composition, method of preparation & application of concentrated formulations of condensed nucleic acids with a cationic lipopolymer
US9144546B2 (en) 2007-08-06 2015-09-29 Clsn Laboratories, Inc. Nucleic acid-lipopolymer compositions
BRPI0815725A2 (pt) 2007-08-23 2015-02-10 Novartis Ag Métodos para detecção de oligonucleotídeos
WO2009030254A1 (en) 2007-09-04 2009-03-12 Curevac Gmbh Complexes of rna and cationic peptides for transfection and for immunostimulation
BRPI0816458A2 (pt) 2007-09-05 2013-03-12 Hoffmann La Roche terapia combinada com anticorpos anti-cd20 tipo i e tipo ii
US8506928B2 (en) 2007-09-07 2013-08-13 The Regents Of The University Of California Methods and compounds for targeting tissues
US20110086904A1 (en) 2007-09-17 2011-04-14 The Trustees Of The University Of Pennsylvania GENERATION OF HYPERSTABLE mRNAs
EP2205618B1 (en) 2007-09-26 2016-11-09 Intrexon Corporation Synthetic 5'utrs, expression vectors, and methods for increasing transgene expression
NZ584356A (en) 2007-09-26 2011-10-28 Univ Oregon Health & Science Cyclic undecapeptides and derivatives as multiple sclerosis therapies
EP2042193A1 (en) 2007-09-28 2009-04-01 Biomay AG RNA Vaccines
PL2644192T3 (pl) 2007-09-28 2017-09-29 Pfizer Inc. Ukierunkowanie na komórki nowotworowe z zastosowaniem nanocząstek
WO2009046388A1 (en) 2007-10-03 2009-04-09 United States Medical Research & Material Command Cr-2 binding peptide p28 as molecular adjuvant for dna vaccines
WO2009046738A1 (en) 2007-10-09 2009-04-16 Curevac Gmbh Composition for treating lung cancer, particularly of non-small lung cancers (nsclc)
WO2009046739A1 (en) 2007-10-09 2009-04-16 Curevac Gmbh Composition for treating prostate cancer (pca)
CA2702083C (en) 2007-10-12 2021-11-30 Massachusetts Institute Of Technology Vaccine nanotechnology
US20090098118A1 (en) 2007-10-15 2009-04-16 Thomas Friess Combination therapy of a type ii anti-cd20 antibody with an anti-bcl-2 active agent
KR101198354B1 (ko) * 2007-10-17 2013-03-14 주식회사 삼양바이오팜 핵산 전달용 저밀도 지단백질 유사(ＬＤＬ-ｌｉｋｅ) 양이온성 나노입자, 그의 제조방법 및 이를 이용한 핵산의 전달 방법
GB0720486D0 (en) * 2007-10-19 2007-11-28 Univ Edinburgh Cationic lipids
EP2205277B1 (en) 2007-10-22 2017-07-26 Genmab A/S Novel antibody therapies
WO2009058911A2 (en) 2007-10-31 2009-05-07 Applied Biosystems Inc. Preparation and isolation of 5' capped mrna
EP2209908B1 (en) 2007-11-01 2014-09-03 University Of Rochester Recombinant factor viii having increased stability
AU2008323815B2 (en) 2007-11-09 2013-09-19 Novartis Ag Uses of anti-CD40 antibodies
WO2009062348A1 (en) 2007-11-14 2009-05-22 Institute Of Microbiology, Chinese Academy Of Sciences Methods for inhibiting influenza virus infection and their drugs
EP2277124B1 (en) * 2007-11-21 2016-11-09 Medizinische Hochschule Hannover Means for treating myosin-related diseases
WO2009068649A2 (en) 2007-11-30 2009-06-04 Glaxo Group Limited Antigen-binding constructs
JP5530933B2 (ja) 2007-12-10 2014-06-25 アルナイラム ファーマシューティカルズ， インコーポレイテッド 第ｖｉｉ因子遺伝子発現阻害のための組成物及び方法
CN101939428B (zh) 2007-12-11 2014-05-07 斯克利普斯研究所 涉及mRNA翻译增强因子的组合物和方法
AU2008334948B2 (en) 2007-12-13 2014-11-20 Alnylam Pharmaceuticals, Inc. Methods and compositions for prevention or treatment of RSV infection
EP2072618A1 (en) 2007-12-14 2009-06-24 Johannes Gutenberg-Universität Mainz Use of RNA for reprogramming somatic cells
JP2011507897A (ja) 2007-12-21 2011-03-10 ジェネンテック， インコーポレイテッド リツキシマブ抵抗性関節リウマチ患者の治療
EP2224912B1 (en) * 2008-01-02 2016-05-11 TEKMIRA Pharmaceuticals Corporation Improved compositions and methods for the delivery of nucleic acids
JP5645044B2 (ja) 2008-01-22 2014-12-24 独立行政法人医薬基盤研究所 遺伝子発現制御機構を含む新規Ａｄベクター
EP2248906A4 (en) 2008-01-23 2012-07-11 Ajinomoto Kk PROCESS FOR THE PREPARATION OF L-AMINO ACID
JPWO2009093384A1 (ja) 2008-01-24 2011-05-26 独立行政法人産業技術総合研究所 ポリヌクレオチド及びポリヌクレオチド類似体並びにこれらを用いた遺伝子発現制御方法
JP5721441B2 (ja) 2008-01-31 2015-05-20 キュアバック ゲーエムベーハーＣｕｒｅｖａｃ Ｇｍｂｈ 免疫賦活剤／アジュバントとしての式（Ｉ）（ＮｕＧｌＸｍＧｎＮｖ）ａで表される核酸分子及びその誘導体
WO2009101407A2 (en) 2008-02-11 2009-08-20 Cambridge Enterprise Limited Improved reprogramming of mammalian cells, and the cells obtained
DK2240155T3 (da) 2008-02-13 2012-09-17 Intarcia Therapeutics Inc Indretninger, formuleringer og fremgangsmåder til levering af flere gavnlige midler
DE102008009920A1 (de) 2008-02-15 2009-08-20 Aj Innuscreen Gmbh Mobiles Gerät für die Nukleinsäureisolierung
US20120027813A1 (en) 2008-02-22 2012-02-02 Novartis Vaccines And Diagnostics Srl Adjuvanted influenza vaccines for pediatric use
US8506966B2 (en) 2008-02-22 2013-08-13 Novartis Ag Adjuvanted influenza vaccines for pediatric use
WO2009108891A2 (en) 2008-02-29 2009-09-03 Egen, Inc. Modified poloxamers for gene expression and associated methods
WO2009114854A1 (en) 2008-03-14 2009-09-17 Egen, Inc. Biodegradable cross-linked branched poly (alkylene imines)
ES2759075T3 (es) 2008-03-14 2020-05-07 Biocon Ltd Un anticuerpo monoclonal y un método del mismo
ES2441945T3 (es) 2008-03-28 2014-02-07 Glaxosmithkline Llc Métodos de tratamiento
JP5475753B2 (ja) * 2008-04-15 2014-04-16 プロチバ バイオセラピューティクス インコーポレイティッド 核酸送達用の脂質製剤
WO2009127230A1 (en) 2008-04-16 2009-10-22 Curevac Gmbh MODIFIED (m)RNA FOR SUPPRESSING OR AVOIDING AN IMMUNOSTIMULATORY RESPONSE AND IMMUNOSUPPRESSIVE COMPOSITION
KR20110042152A (ko) 2008-04-25 2011-04-25 노쓰웨스턴유니버시티 콜레스테롤을 격리시키기에 적합한 나노구조
WO2009134808A2 (en) 2008-04-28 2009-11-05 President And Fellows Of Harvard College Supercharged proteins for cell penetration
BRPI0913012B1 (pt) 2008-04-30 2021-12-14 The Government Of The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, Centers For Disease Control And Prevention Quimera de ácido nucleico, métodos para detectar um anticorpo do vírus da dengue em uma amostra de um paciente, e para produzir partículas virais que expressam proteínas prm e e do vírus da dengue, uso de vírus codificado pela quimera e flavivírus ou partícula viral quiméricos
US9394538B2 (en) 2008-05-07 2016-07-19 Shi-Lung Lin Development of universal cancer drugs and vaccines
WO2009137785A2 (en) 2008-05-08 2009-11-12 Replenish Pumps, Llc Drug-delivery pumps and methods of manufacture
US8697098B2 (en) 2011-02-25 2014-04-15 South Dakota State University Polymer conjugated protein micelles
CN103342789B (zh) 2008-05-13 2016-11-23 华盛顿大学 用于向细胞内递送的二嵌段共聚物和其多核苷酸复合物
US9738680B2 (en) 2008-05-21 2017-08-22 Rheinische Friedrich-Wilhelms-Universität Bonn 5′ triphosphate oligonucleotide with blunt end and uses thereof
AU2009253160B2 (en) 2008-05-26 2015-03-05 Universitat Zurich Protamine/RNA nanoparticles for immunostimulation
EP2297197B1 (en) 2008-05-29 2012-03-07 HanAll Biopharma Co., Ltd. Modified erythropoietin (epo)polypeptides that exhibit increased protease resistance and pharmaceutical compositions thereof
FR2931824B1 (fr) 2008-05-29 2014-11-28 Centre Nat Rech Scient Procede de synthese d'arn par voie chimique.
WO2009148528A2 (en) * 2008-05-30 2009-12-10 Millennium Pharmaceuticals, Inc. Assessment of chromosomal alterations to predict clinical outcome of bortezomib treatment
AU2009253780B2 (en) * 2008-06-05 2014-08-14 Immunovaccine Technologies Inc. Compositions comprising liposomes, an antigen, a polynucleotide and a carrier comprising a continuous phase of a hydrophobic substance
PL215513B1 (pl) 2008-06-06 2013-12-31 Univ Warszawski Nowe boranofosforanowe analogi dinukleotydów, ich zastosowanie, czasteczka RNA, sposób otrzymywania RNA oraz sposób otrzymywania peptydów lub bialka
TWI451876B (zh) 2008-06-13 2014-09-11 Lilly Co Eli 聚乙二醇化之離脯胰島素化合物
EP2309991B1 (en) 2008-06-16 2019-03-06 Pfizer Inc Therapeutic polymeric nanoparticles comprising vinca alkaloids and methods of making and using same
US8613951B2 (en) 2008-06-16 2013-12-24 Bind Therapeutics, Inc. Therapeutic polymeric nanoparticles with mTor inhibitors and methods of making and using same
KR20160116062A (ko) 2008-06-16 2016-10-06 바인드 쎄라퓨틱스, 인크. 약물 부하된 중합체성 나노입자, 및 이의 제조 및 사용 방법
ES2654533T3 (es) 2008-06-16 2018-02-14 Pfizer Inc. Procedimientos para la preparación de copolímeros dibloque funcionalizados con un agente de direccionamiento para su uso en la fabricación de nanopartículas terapéuticas
CA2729554C (en) * 2008-06-27 2018-03-06 Centre National De La Recherche Scientifique Molecular signature of liver tumor grade and use to evaluate prognosis and therapeutic regimen
AU2009270020B2 (en) * 2008-07-10 2014-09-25 Regenesance B.V. Complement antagonists and uses thereof
US20100009424A1 (en) 2008-07-14 2010-01-14 Natasha Forde Sonoporation systems and methods
EP2313085A2 (en) 2008-07-15 2011-04-27 Novartis AG Immunogenic amphipathic peptide compositions
WO2010009065A2 (en) 2008-07-15 2010-01-21 Novartis Ag Amphipathic peptide compositions
EP2321414B1 (en) * 2008-07-25 2018-01-10 Alnylam Pharmaceuticals, Inc. Enhancement of sirna silencing activity using universal bases or mismatches in the sense strand
EP2326331A4 (en) 2008-08-18 2013-05-15 Merck Sharp & Dohme NEW LIPID NANOPARTICLES AND NEW COMPONENTS FOR THE RELEASE OF NUCLEIC ACIDS
CA2734340C (en) 2008-08-28 2019-03-05 Novartis Ag Cell surface display of polypeptide isoforms by stop codon readthrough
US20110172126A1 (en) 2008-09-03 2011-07-14 Xenome Ltd Libraries of peptide conjugates and methods for making them
EP2326656B1 (en) 2008-09-06 2017-01-25 Chemgenes Corporation Rna synthesis - phosphoramidites for synthetic rna in the reverse direction, and application in convenient introduction of ligands, chromophores and modifications of synthetic rna at the 3' - end
WO2010027903A2 (en) 2008-09-08 2010-03-11 Fred Hutchinson Cancer Research Center Lung cancer diagnosis
US20100087337A1 (en) 2008-09-10 2010-04-08 Bind Biosciences, Inc. High Throughput Fabrication of Nanoparticles
TW201438738A (zh) 2008-09-16 2014-10-16 建南德克公司 治療進展型多發性硬化症之方法
US20120021519A1 (en) 2008-09-19 2012-01-26 Presidents And Fellows Of Harvard College Efficient induction of pluripotent stem cells using small molecule compounds
JP2012513953A (ja) * 2008-09-23 2012-06-21 アルニラム ファーマスーティカルズ インコーポレイテッド 付加環化を用いたモノマーおよびオリゴヌクレオチドの化学修飾
WO2010037408A1 (en) 2008-09-30 2010-04-08 Curevac Gmbh Composition comprising a complexed (m)rna and a naked mrna for providing or enhancing an immunostimulatory response in a mammal and uses thereof
WO2010042490A1 (en) 2008-10-06 2010-04-15 Boston Medical Center Corporation A single lentiviral vector system for induced pluripotent (ips) stem cells derivation
CA2740000C (en) 2008-10-09 2017-12-12 Tekmira Pharmaceuticals Corporation Improved amino lipids and methods for the delivery of nucleic acids
US8535655B2 (en) 2008-10-10 2013-09-17 Polyactiva Pty Ltd. Biodegradable polymer—bioactive moiety conjugates
US8343498B2 (en) 2008-10-12 2013-01-01 Massachusetts Institute Of Technology Adjuvant incorporation in immunonanotherapeutics
WO2010047765A2 (en) 2008-10-20 2010-04-29 Massachussetts Institute Of Technology Nanostructures for drug delivery
US20120015899A1 (en) 2008-10-25 2012-01-19 Plant Bioscience, Limited Modified plant virus particles and uses therefor
MX353900B (es) 2008-11-07 2018-02-01 Massachusetts Inst Technology Lipidoides de aminoalcohol y usos de los mismos.
CA2743139C (en) * 2008-11-10 2019-04-02 Alnylam Pharmaceuticals, Inc. Novel lipids and compositions for the delivery of therapeutics
US8734853B2 (en) 2008-11-17 2014-05-27 University Of North Texas Health Science Center At Fort Worth HDL particles for delivery of nucleic acids
KR101073875B1 (ko) * 2008-11-28 2011-10-14 한국생명공학연구원 대장암 진단 마커 및 이를 이용한 대장암 진단방법
EP2191840A1 (en) 2008-11-28 2010-06-02 Sanofi-Aventis Antitumor combinations containing antibodies recognizing specifically CD38 and melphalan
EP2196476A1 (en) 2008-12-10 2010-06-16 Novartis Ag Antibody formulation
NZ593618A (en) 2008-12-10 2013-02-22 Alnylam Pharmaceuticals Inc Gnaq targeted dsrna compositions and methods for inhibiting expression
WO2010068866A2 (en) 2008-12-12 2010-06-17 Bind Biosciences Therapeutic particles suitable for parenteral administration and methods of making and using same
WO2010068918A2 (en) 2008-12-12 2010-06-17 The Regents Of The University Of California Novel targets for treatment of hypercholesterolemia
JP2012512175A (ja) 2008-12-15 2012-05-31 バインド バイオサイエンシズ インコーポレイテッド 治療薬を徐放するための長時間循環性ナノ粒子
WO2010080724A1 (en) 2009-01-12 2010-07-15 Merck Sharp & Dohme Corp. Novel lipid nanoparticles and novel components for delivery of nucleic acids
JP2012515217A (ja) 2009-01-16 2012-07-05 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー ベンダムスチンおよび抗−ｃｄ２０抗体の組合せを用いた癌治療
WO2010084371A1 (en) 2009-01-26 2010-07-29 Mitoprod Novel circular interfering rna molecules
EP3243504A1 (en) 2009-01-29 2017-11-15 Arbutus Biopharma Corporation Improved lipid formulation
US8669085B2 (en) 2009-02-05 2014-03-11 Ut-Battelle, Llc Transformation of gram positive bacteria by sonoporation
WO2010088927A1 (en) 2009-02-09 2010-08-12 Curevac Gmbh Use of pei for the improvement of endosomal release and expression of transfected nucleic acids, complexed with cationic or polycationic compounds
US20140141089A1 (en) 2009-02-11 2014-05-22 Colorado School Of Mines Nanoparticles, Compositions Thereof, and Methods of Use, and Methods of Making the Same
EP2401365B1 (en) 2009-02-24 2016-04-27 The Scripps Research Institute Reengineering mrna primary structure for enhanced protein production
US8685458B2 (en) 2009-03-05 2014-04-01 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives
WO2010141135A2 (en) 2009-03-05 2010-12-09 Trustees Of Boston University Bacteriophages expressing antimicrobial peptides and uses thereof
BRPI1009551B1 (pt) 2009-03-12 2021-02-02 Illinois Tool Works Inc inibidor para um conjunto de entrada de reabastecimento de sistema de combustível de veículo e conjunto de gargalo de entrada de sistema de combustível de veículo
JP2012520085A (ja) 2009-03-13 2012-09-06 エーゲン、インコーポレイテッド 生物活性ｒｎａの送達のための組成物及び方法
CN102438978B (zh) 2009-03-20 2017-02-22 Clsn实验室股份有限公司 聚胺衍生物
US20120095077A1 (en) 2009-03-23 2012-04-19 University Of Utah Research Foundation Methods and compositions related to modified guanine bases for controlling off-target effects in rna interference
WO2010109289A1 (en) 2009-03-24 2010-09-30 Council Of Scientific & Industrial Research Process for the preparation of agarose polymer from seaweed extractive
US9415392B2 (en) 2009-03-24 2016-08-16 The University Of Chicago Slip chip device and methods
JP5622254B2 (ja) 2009-03-31 2014-11-12 国立大学法人東京大学 二本鎖リボ核酸ポリイオンコンプレックス
SMT202000246T1 (it) 2009-04-03 2020-07-08 Univ Chicago Composizioni e metodi relativi a varianti della proteina a (spa)
US9724404B2 (en) 2009-04-13 2017-08-08 INSERM (Institut National de la Santé et de la Recherche Médicale) HPV particles and uses thereof
AU2010236257A1 (en) 2009-04-17 2011-11-03 Biogen Idec Ma Inc. Compositions and methods to treat acute myelogenous leukemia
EA201101530A1 (ru) 2009-04-21 2012-03-30 Селекта Байосайенсиз, Инк. ИММУНОНАНОТЕРАПИЯ, ОБЕСПЕЧИВАЮЩАЯ Th1-СМЕЩЕННЫЙ ОТВЕТ
WO2010123501A1 (en) * 2009-04-22 2010-10-28 Massachusetts Institute Of Technology Innate immune suppression enables repeated delivery of long rna molecules
EA027071B1 (ru) 2009-04-27 2017-06-30 Новартис Аг АНТИТЕЛО К ActRIIB И СОДЕРЖАЩАЯ ЕГО КОМПОЗИЦИЯ
US8287910B2 (en) 2009-04-30 2012-10-16 Intezyne Technologies, Inc. Polymeric micelles for polynucleotide encapsulation
US8715736B2 (en) 2009-04-30 2014-05-06 Florida Agricultural And Mechanical University Nanoparticle formulations for skin delivery
EP3028707A1 (en) 2009-05-01 2016-06-08 Ophthotech Corporation Methods for treating or preventing ophthalmological diseases
KR102229618B1 (ko) 2009-05-05 2021-03-18 알닐람 파마슈티칼스 인코포레이티드 지질 조성물
DE202009007116U1 (de) 2009-05-18 2010-10-14 Amoena Medizin-Orthopädie-Technik GmbH Antidekubituskissen
EA201500447A1 (ru) 2009-05-27 2017-03-31 Селекта Байосайенсиз, Инк. НАЦЕЛЕННЫЕ СИНТЕТИЧЕСКИЕ НАНОНОСИТЕЛИ С pH-ЧУВСТВИТЕЛЬНЫМ ВЫСВОБОЖДЕНИЕМ ИММУНОМОДУЛИРУЮЩИХ СРЕДСТВ
US8574835B2 (en) 2009-05-29 2013-11-05 Life Technologies Corporation Scaffolded nucleic acid polymer particles and methods of making and using
EP2440556A1 (en) 2009-06-10 2012-04-18 Vertex Pharmaceuticals Incorporated Inhibitors of phosphatidylinositol 3-kinase
US8765370B2 (en) 2009-06-11 2014-07-01 Scinopharm Taiwan, Ltd Inhibition-based high-throughput screen strategy for cell clones
NZ597504A (en) 2009-06-15 2013-10-25 Alnylam Pharmaceuticals Inc Lipid formulated dsrna targeting the pcsk9 gene
US20110097329A1 (en) 2009-06-26 2011-04-28 Massachusetts Institute Of Technology Compositions and methods for treating cancer and modulating stress granule formation
ES2613498T3 (es) 2009-07-01 2017-05-24 Protiva Biotherapeutics Inc. Nuevas formulaciones de lípidos para el suministro de agentes terapéuticos a tumores sólidos
US8569256B2 (en) 2009-07-01 2013-10-29 Protiva Biotherapeutics, Inc. Cationic lipids and methods for the delivery of therapeutic agents
WO2011005799A2 (en) 2009-07-06 2011-01-13 Novartis Ag Self replicating rna molecules and uses thereof
DE102009033507A1 (de) * 2009-07-15 2011-01-20 Niro-Plan Ag Vorrichtung und Verfahren zum Erzeugen von gekühltem Kaffee
US20120120311A1 (en) 2009-07-30 2012-05-17 Koninklijke Philips Electronics N.V. Distributed image retargeting
EA022786B1 (ru) * 2009-07-31 2016-03-31 Этрис Гмбх Рнк с комбинацией из немодифицированных и модифицированных нуклеотидов для экспрессии белков
EP2281579A1 (en) 2009-08-05 2011-02-09 BioNTech AG Vaccine composition comprising 5'-Cap modified RNA
US9181295B2 (en) 2009-08-20 2015-11-10 Sirna Therapeutics, Inc. Cationic lipids with various head groups for oligonucleotide delivery
US20110053829A1 (en) 2009-09-03 2011-03-03 Curevac Gmbh Disulfide-linked polyethyleneglycol/peptide conjugates for the transfection of nucleic acids
US20110070227A1 (en) 2009-09-18 2011-03-24 Anna-Marie Novotney-Barry Treatment of Autoimmune and Inflammatory Diseases
EP2485770A4 (en) 2009-10-08 2013-04-10 Merck Sharp & Dohme Novel cationic lipids with short lipid chains for oligonucleotide delivery
US8859284B2 (en) 2009-10-22 2014-10-14 The United States Of America, As Represented By The Secretary Of The Navy Delivery of nanoparticles to neurons
EP2496700B1 (en) 2009-11-04 2017-03-01 The University Of British Columbia Nucleic acid-containing lipid particles and related methods
US8449916B1 (en) 2009-11-06 2013-05-28 Iowa State University Research Foundation, Inc. Antimicrobial compositions and methods
WO2011060250A1 (en) 2009-11-13 2011-05-19 Bend Research, Inc. Cationic dextran polymer derivatives
WO2011062965A2 (en) 2009-11-18 2011-05-26 University Of Washington Through Its Center For Commercialization Targeting monomers and polymers having targeting blocks
US8530429B2 (en) 2009-11-24 2013-09-10 Arch Cancer Therapeutics, Inc. Brain tumor targeting peptides and methods
RS57314B1 (sr) 2009-12-01 2018-08-31 Translate Bio Inc Isporuka irnk za povećanje ekspresije proteina i enzima u humanim genetskim oboljenjima
DE102009056884B4 (de) 2009-12-03 2021-03-18 Novartis Ag Impfstoff-Adjuvantien und verbesserte Verfahren zur Herstellung derselben
US20110245756A1 (en) 2009-12-03 2011-10-06 Rishi Arora Devices for material delivery, electroporation, sonoporation, and/or monitoring electrophysiological activity
JP5903048B2 (ja) 2009-12-06 2016-04-13 バイオジェン ヘモフィリア インコーポレイテッド 第ＶＩＩＩ−Ｆｃ因子キメラおよびハイブリッドポリペプチドならびにその使用法
CN114317612B (zh) 2009-12-07 2024-10-29 宾夕法尼亚州大学信托人 用于重编程细胞的包含纯化的经修饰的rna的rna制剂
US20130189741A1 (en) 2009-12-07 2013-07-25 Cellscript, Inc. Compositions and methods for reprogramming mammalian cells
AU2010328336B2 (en) 2009-12-07 2017-03-02 Arbutus Biopharma Corporation Compositions for nucleic acid delivery
WO2011069529A1 (en) 2009-12-09 2011-06-16 Curevac Gmbh Mannose-containing solution for lyophilization, transfection and/or injection of nucleic acids
WO2011069528A1 (en) 2009-12-09 2011-06-16 Curevac Gmbh Lyophilization of nucleic acids in lactate-containing solutions
US8357401B2 (en) 2009-12-11 2013-01-22 Bind Biosciences, Inc. Stable formulations for lyophilizing therapeutic particles
EP2512487A4 (en) 2009-12-15 2013-08-07 THERAPEUTIC POLYMERNANOPARTICLES WITH CORTICOSTEROIDS AND METHOD FOR THE PRODUCTION AND USE THEREOF
US9295649B2 (en) 2009-12-15 2016-03-29 Bind Therapeutics, Inc. Therapeutic polymeric nanoparticle compositions with high glass transition temperature or high molecular weight copolymers
WO2011084521A2 (en) 2009-12-15 2011-07-14 Bind Biosciences, Inc. Therapeutic polymeric nanoparticles comprising epothilone and methods of making and using same
EP2512522A4 (en) 2009-12-16 2013-09-25 Brigham & Womens Hospital PARTICLES FOR ADMINISTRATION OF MULTIPLE AGENTS
DE102009058769A1 (de) 2009-12-16 2011-06-22 MagForce Nanotechnologies AG, 10589 Temperaturabhängige Aktivierung von katalytischen Nukleinsäuren zur kontrollierten Wirkstofffreisetzung
WO2011075656A1 (en) 2009-12-18 2011-06-23 The University Of British Columbia Methods and compositions for delivery of nucleic acids
EP2338520A1 (de) 2009-12-21 2011-06-29 Ludwig Maximilians Universität Konjugat mit Zielfindungsligand und dessen Verwendung
SG10201407996PA (en) 2009-12-23 2015-01-29 Novartis Ag Lipids, lipid compositions, and methods of using them
WO2011085231A2 (en) 2010-01-08 2011-07-14 Selecta Biosciences, Inc. Synthetic virus-like particles conjugated to human papillomavirus capsid peptides for use as vaccines
US8846631B2 (en) 2010-01-14 2014-09-30 Regulus Therapeutics Inc. MicroRNA compositions and methods
EP2526113B1 (en) 2010-01-22 2016-08-10 Sirna Therapeutics, Inc. Post-synthetic chemical modification of rna at the 2'-position of the ribose ring via "click" chemistry
JP5988435B2 (ja) 2010-01-24 2016-09-07 ノバルティス アーゲー 放射線照射された生分解性微粒子
EP2354247A1 (en) * 2010-02-11 2011-08-10 Academisch Medisch Centrum bij de Universiteit van Amsterdam Means and methods for typing a sample for rheumatoid arthritis or spondyloarthritis
NZ601737A (en) 2010-02-24 2013-06-28 Arrowhead Res Corp Compositions for targeted delivery of sirna
US8889193B2 (en) 2010-02-25 2014-11-18 The Johns Hopkins University Sustained delivery of therapeutic agents to an eye compartment
EP2539449B9 (en) 2010-02-26 2018-09-05 Qiagen GmbH Process for parallel isolation and/or purification of rna and dna
US20110218170A1 (en) 2010-03-02 2011-09-08 Southern Research Institute Use of 2'-deoxy-4'-thiocytidine and its analogues as dna hypomethylating anticancer agents
WO2011112608A1 (en) 2010-03-08 2011-09-15 University Of Rochester Synthesis of nanoparticles using reducing gases
AU2011227264A1 (en) 2010-03-16 2012-10-04 University Of Utah Research Foundation Cleavable modifications to reducible poly (amido ethylenimines)s to enhance nucleotide delivery
WO2011116072A1 (en) 2010-03-16 2011-09-22 Escape Therapeutics, Inc. Hybrid hydrogel scaffold compositions and methods of use
WO2011115862A1 (en) 2010-03-18 2011-09-22 Merck Sharp & Dohme Corp. Endosomolytic poly(amidoamine) disulfide polymers for the delivery of oligonucleotides
US20110230816A1 (en) 2010-03-18 2011-09-22 Tyco Healthcare Group Lp Gels for Transdermal Delivery
US9149432B2 (en) 2010-03-19 2015-10-06 Massachusetts Institute Of Technology Lipid vesicle compositions and methods of use
GB201005005D0 (en) 2010-03-25 2010-05-12 Angeletti P Ist Richerche Bio New vaccine
US8207290B2 (en) 2010-03-26 2012-06-26 Cerulean Pharma Inc. Methods and systems for generating nanoparticles
WO2011120053A1 (en) 2010-03-26 2011-09-29 Mersana Therapeutics, Inc. Modified polymers for delivery of polynucleotides, method of manufacture, and methods of use thereof
US20110247090A1 (en) 2010-04-02 2011-10-06 Intrexon Corporation Synthetic 5'UTRs, Expression Vectors, and Methods for Increasing Transgene Expression
EP2555794A4 (en) 2010-04-05 2014-01-15 Univ Chicago COMPOSITIONS AND METHODS RELATING TO PROTEIN A (SPA) ANTIBODIES AS IMMUNE REACTION AMPLIFIERS
US9744228B2 (en) 2010-04-07 2017-08-29 Norvartis Ag Method for generating a parvovirus B19 virus-like particle
WO2011127255A1 (en) 2010-04-08 2011-10-13 Merck Sharp & Dohme Corp. Preparation of lipid nanoparticles
US20130071430A1 (en) 2010-04-09 2013-03-21 The University Of Tokyo Microrna-controlled recombinant vaccinia virus and use thereof
US20110250264A1 (en) 2010-04-09 2011-10-13 Pacira Pharmaceuticals, Inc. Method for formulating large diameter synthetic membrane vesicles
US20110262491A1 (en) 2010-04-12 2011-10-27 Selecta Biosciences, Inc. Emulsions and methods of making nanocarriers
KR101196667B1 (ko) 2010-04-15 2012-11-02 포항공과대학교 산학협력단 피에이치 민감성 금속 나노 입자를 이용한 항암제 전달 시스템
EP2377938A1 (en) 2010-04-16 2011-10-19 Eukarys Capping-prone RNA polymerase enzymes and their applications
CA2796464C (en) 2010-04-16 2021-08-03 Immune Disease Institute, Inc. Sustained polypeptide expression from synthetic, modified rnas and uses thereof
CA2832672A1 (en) 2010-04-16 2011-10-20 Nuevolution A/S Bi-functional complexes and methods for making and using such complexes
US20130260460A1 (en) 2010-04-22 2013-10-03 Isis Pharmaceuticals Inc Conformationally restricted dinucleotide monomers and oligonucleotides
WO2011133890A1 (en) 2010-04-23 2011-10-27 University Of Massachusetts Cns targeting aav vectors and methods of use thereof
WO2012046149A1 (en) 2010-04-28 2012-04-12 Kimberly-Clark Worldwide, Inc. Method for increasing permeability of an epithelial barrier
US20130156845A1 (en) 2010-04-29 2013-06-20 Alnylam Pharmaceuticals, Inc. Lipid formulated single stranded rna
BR112012027816A2 (pt) 2010-04-30 2017-08-08 Novartis Ag marcadores preditivos úteis no tratamento da síndrome do x frágil (fxs).
US9254327B2 (en) 2010-05-10 2016-02-09 Alnylam Pharmaceuticals, Inc. Methods and compositions for delivery of active agents
EP2569276B1 (en) 2010-05-12 2021-02-24 Arbutus Biopharma Corporation Novel cationic lipids and methods of use thereof
US10077232B2 (en) 2010-05-12 2018-09-18 Arbutus Biopharma Corporation Cyclic cationic lipids and methods of use
EP2387999A1 (en) 2010-05-21 2011-11-23 CureVac GmbH Histidine-containing solution for transfection and/or injection of nucleic acids and uses thereof
JP2013531634A (ja) 2010-05-24 2013-08-08 メルク・シャープ・エンド・ドーム・コーポレイション オリゴヌクレオチド送達のための新規なアミノアルコールカチオン性脂質
WO2011150264A2 (en) 2010-05-26 2011-12-01 Selecta Biosciences, Inc. Synthetic nanocarrier combination vaccines
KR101967411B1 (ko) 2010-06-03 2019-04-10 알닐람 파마슈티칼스 인코포레이티드 활성제의 전달을 위한 생분해성 지질
US8748667B2 (en) 2010-06-04 2014-06-10 Sirna Therapeutics, Inc. Low molecular weight cationic lipids for oligonucleotide delivery
CA2800650C (en) 2010-06-14 2018-04-03 F. Hoffmann-La Roche Ag Cell-penetrating peptides and uses therof
WO2011163121A1 (en) 2010-06-21 2011-12-29 Alnylam Pharmaceuticals, Inc. Multifunctional copolymers for nucleic acid delivery
AU2011268507B2 (en) 2010-06-25 2014-08-14 Novartis Ag Combinations of meningococcal factor H binding proteins
US9066971B2 (en) 2010-07-01 2015-06-30 Postech Academy-Industry Foundation Method for treating and diagnosing cancer by using cell-derived microvesicles
ES2655701T3 (es) 2010-07-02 2018-02-21 The University Of Chicago Composiciones y métodos relacionados con variantes de la proteína A (SpA)
KR101130137B1 (ko) 2010-07-02 2012-03-28 연세대학교 산학협력단 발광다이오드 모듈
HUE026646T2 (en) 2010-07-06 2016-07-28 Glaxosmithkline Biologicals Sa Preferred liposomes containing lipids of PKA value for delivery of RNA
SI3243526T1 (sl) 2010-07-06 2020-02-28 Glaxosmithkline Biologicals S.A. Dostava RNA za sprožitev večih imunskih poti
US9192661B2 (en) 2010-07-06 2015-11-24 Novartis Ag Delivery of self-replicating RNA using biodegradable polymer particles
US9770463B2 (en) 2010-07-06 2017-09-26 Glaxosmithkline Biologicals Sa Delivery of RNA to different cell types
WO2012004276A2 (en) * 2010-07-06 2012-01-12 Fondazione Telethon Multiprotein biomarkers of amyotrophic lateral sclerosis in peripheral blood mononuclear cells, diagnostic methods and kits
PL2591114T3 (pl) 2010-07-06 2017-08-31 Glaxosmithkline Biologicals Sa Immunizacja dużych ssaków małymi dawkami rna
EP2590676B1 (en) 2010-07-06 2016-08-17 GlaxoSmithKline Biologicals SA Virion-like delivery particles for self-replicating rna molecules
EP3449910A1 (en) 2010-07-06 2019-03-06 GlaxoSmithKline Biologicals S.A. Cationic oil-in-water emulsions
CN103140237A (zh) 2010-07-09 2013-06-05 比奥根艾迪克依蒙菲利亚公司 因子ix多肽及其使用方法
WO2012006623A1 (en) 2010-07-09 2012-01-12 Biogen Idec Hemophilia Inc. Systems for factor viii processing and methods thereof
WO2012009406A2 (en) 2010-07-13 2012-01-19 University Of Utah Research Foundation Gold particles and methods of making and using the same in cancer treatment
GB201012410D0 (en) 2010-07-23 2010-09-08 Medical Res Council Intracellular immunity
DE102010032758B4 (de) 2010-07-29 2012-02-23 Fujitsu Technology Solutions Intellectual Property Gmbh Computersystem, Verfahren zum Programmieren einer Echtzeituhr und Computerprogrammprodukt
SG186706A1 (en) 2010-07-30 2013-02-28 Curevac Gmbh Complexation of nucleic acids with disulfide-crosslinked cationic components for transfection and immunostimulation
US20130190626A1 (en) 2010-08-02 2013-07-25 Curtin University Of Technology Determining location of, and imaging, a subsurface boundary
EP3578205A1 (en) 2010-08-06 2019-12-11 ModernaTX, Inc. A pharmaceutical formulation comprising engineered nucleic acids and medical use thereof
WO2012021516A2 (en) 2010-08-09 2012-02-16 The Trustees Of The University Of Pennsylvania Nanoparticle-oligonucletide hybrid structures and methods of use thereof
WO2012019630A1 (en) 2010-08-13 2012-02-16 Curevac Gmbh Nucleic acid comprising or coding for a histone stem-loop and a poly(a) sequence or a polyadenylation signal for increasing the expression of an encoded protein
US8829329B2 (en) 2010-08-18 2014-09-09 International Business Machines Corporation Solar cell and battery 3D integration
US20120225129A1 (en) 2010-08-20 2012-09-06 Cerulean Pharma Inc. Conjugates, particles, compositions, and related methods
WO2012024595A2 (en) 2010-08-20 2012-02-23 University Of Washington Circumferential aerosol device for delivering drugs to olfactory epithelium and brain
EP2605792B1 (en) 2010-08-20 2014-12-10 Novartis AG Soluble needle arrays for delivery of influenza vaccines
US20120058154A1 (en) 2010-08-20 2012-03-08 Selecta Biosciences, Inc. Synthetic nanocarrier vaccines comprising peptides obtained or derived from human influenza a virus m2e
EP3556396B1 (en) 2010-08-31 2022-04-20 Theraclone Sciences, Inc. Human immunodeficiency virus (hiv)-neutralizing antibodies
AU2011295938B2 (en) 2010-08-31 2016-01-14 Glaxosmithkline Biologicals S.A. Lipids suitable for liposomal delivery of protein-coding RNA
ES2908978T3 (es) 2010-08-31 2022-05-04 Sirna Therapeutics Inc Nuevas entidades químicas simples y métodos para la administración de oligonucleótidos
DK4008357T3 (da) 2010-08-31 2023-02-20 Glaxosmithkline Biologicals Sa Små liposomer til afgivelse af immunogen-kodende RNA
RS63329B1 (sr) 2010-08-31 2022-07-29 Glaxosmithkline Biologicals Sa Pegilovani lipozomi za isporuku rnk koja kodira imunogen
WO2012031205A2 (en) 2010-09-03 2012-03-08 The Brigham And Women's Hospital, Inc. Lipid-polymer hybrid particles
WO2012034077A2 (en) 2010-09-09 2012-03-15 The University Of Chicago Compositions and methods related to attenuated staphylococcal strains
WO2012034067A1 (en) 2010-09-09 2012-03-15 The University Of Chicago Methods and compositions involving protective staphylococcal antigens
WO2012039979A2 (en) 2010-09-10 2012-03-29 The Johns Hopkins University Rapid diffusion of large polymeric nanoparticles in the mammalian brain
US8466122B2 (en) 2010-09-17 2013-06-18 Protiva Biotherapeutics, Inc. Trialkyl cationic lipids and methods of use thereof
BR112013004585B1 (pt) 2010-09-20 2021-09-08 Merck Sharp & Dohme Corp Lipídeo catiônico, composição de lnp, e, uso de um lipídeo catiônico
WO2012038448A1 (en) 2010-09-21 2012-03-29 Riboxx Gmbh Method for synthesizing rna using dna template
BR112013008697A2 (pt) 2010-09-24 2016-06-21 Massachusetts Inst Technology géis nanoestruturados capazes de liberação controlada de agentes encapsulados
WO2012050975A2 (en) 2010-09-29 2012-04-19 The University Of North Carolina At Chapel Hill Novel circular mammalian rna molecules and uses thereof
WO2012044638A1 (en) 2010-09-30 2012-04-05 Merck Sharp & Dohme Corp. Low molecular weight cationic lipids for oligonucleotide delivery
HUE069586T2 (hu) 2010-10-01 2025-03-28 Modernatx Inc Módosított nukleozidok, nukleotidok és nukleinsavak, valamint ezek felhasználása
WO2013086505A1 (en) 2011-12-09 2013-06-13 Vanderbilt University Integrated organ-on-chip system and applications of the same
US8898864B1 (en) 2010-10-08 2014-12-02 David Porter Integrated rockably released leverage snap fastening system
WO2012051220A1 (en) 2010-10-11 2012-04-19 Wichita State University Composite magnetic nanoparticle drug delivery system
CN103269713B (zh) 2010-10-11 2016-01-20 诺华有限公司 抗原递送平台
KR20130124308A (ko) 2010-10-21 2013-11-13 머크 샤프 앤드 돔 코포레이션 올리고뉴클레오티드 전달을 위한 신규 저분자량 양이온성 지질
US20150056300A1 (en) 2010-10-22 2015-02-26 Bind Therapeutics, Inc. Therapeutic nanoparticles with high molecular weight copolymers
KR20130138789A (ko) 2010-10-29 2013-12-19 머크 샤프 앤드 돔 코포레이션 재조합 서브유닛 뎅기 바이러스 백신
US9067882B2 (en) 2010-11-05 2015-06-30 Sirna Therapeutics, Inc. Low molecular weight cyclic amine containing cationic lipids for oligonucleotide delivery
EP2635254B1 (en) 2010-11-05 2019-05-15 The John Hopkins University Compositions and methods relating to reduced mucoadhesion
JP2014500867A (ja) 2010-11-09 2014-01-16 ザ リージェンツ オブ ザ ユニバーシティ オブ カリフォルニア 皮膚浸透性および細胞侵入性（ｓｐａｃｅ）ペプチドとその使用法
EP3536703B1 (en) 2010-11-12 2021-05-26 The Trustees of the University of Pennsylvania Consensus prostate antigens, nucleic acid molecules encoding the same and uses thereof
EA030096B1 (ru) 2010-11-16 2018-06-29 Селекта Байосайенсиз, Инк. Способы, композиции и нуклеиновые кислоты для стимуляции гуморального иммунного ответа
SMT201800444T1 (it) 2010-11-17 2018-09-13 Aduro Biotech Inc Metodi e composizioni per indurre una risposta immunitaria contro egfrviii
US20140053294A1 (en) * 2010-11-19 2014-02-20 The University Of Queensland Pongamia Genetic Markers and Method of Use
WO2012068187A1 (en) 2010-11-19 2012-05-24 Merck Sharp & Dohme Corp. Poly(amide) polymers for the delivery of oligonucleotides
CN103415302A (zh) 2010-11-19 2013-11-27 艾德拉药物股份有限公司 调控基于toll-样受体的免疫应答的免疫调节寡核苷酸(iro)化合物
US8853377B2 (en) 2010-11-30 2014-10-07 Shire Human Genetic Therapies, Inc. mRNA for use in treatment of human genetic diseases
WO2012072096A1 (en) 2010-12-03 2012-06-07 Biontech Ag Method for cellular rna expression
WO2012103985A2 (en) 2010-12-16 2012-08-09 Steve Pascolo Pharmaceutical composition consisting of rna having alkali metal as counter ion and formulated with dications
US8901101B2 (en) 2010-12-17 2014-12-02 Sirna Therapeutics, Inc. Membrane lytic poly(amido amine) polymers for the delivery of oligonucleotides
US8501930B2 (en) 2010-12-17 2013-08-06 Arrowhead Madison Inc. Peptide-based in vivo siRNA delivery system
CA2825370A1 (en) 2010-12-22 2012-06-28 President And Fellows Of Harvard College Continuous directed evolution
WO2012089225A1 (en) 2010-12-29 2012-07-05 Curevac Gmbh Combination of vaccination and inhibition of mhc class i restricted antigen presentation
EP2658981B1 (en) 2010-12-29 2016-09-28 F.Hoffmann-La Roche Ag Small molecule conjugates for intracellular delivery of nucleic acids
WO2012092552A1 (en) 2010-12-30 2012-07-05 Selecta Biosciences, Inc. Synthetic nanocarriers with reactive groups that release biologically active agents
EP2661255B1 (en) 2011-01-04 2021-03-10 Brown University Nanotubes as carriers of nucleic acids into cells
WO2012094574A2 (en) 2011-01-06 2012-07-12 The Johns Hopkins University Stabilized polyribonucleotide nanoparticles
WO2012094653A2 (en) 2011-01-07 2012-07-12 Massachusetts Institute Of Technology Compositions and methods for macromolecular drug delivery
DK2663548T3 (en) 2011-01-11 2017-07-24 Alnylam Pharmaceuticals Inc PEGYLED LIPIDS AND THEIR USE FOR PHARMACEUTICAL SUPPLY
DE102011002640B4 (de) 2011-01-13 2021-10-07 Evonik Operations Gmbh Verfahren zur Aufreinigung von Biphephos
US20120189700A1 (en) 2011-01-19 2012-07-26 Zoraida Aguilar Nanoparticle Based Immunological Stimulation
US20140065172A1 (en) 2011-01-26 2014-03-06 Cenix Bioscience Gmbh Delivery system and conjugates for compound delivery via naturally occurring intracellular transport routes
US10363309B2 (en) 2011-02-04 2019-07-30 Case Western Reserve University Targeted nanoparticle conjugates
US20140066363A1 (en) 2011-02-07 2014-03-06 Arun K. Bhunia Carbohydrate nanoparticles for prolonged efficacy of antimicrobial peptide
WO2012116715A1 (en) 2011-03-02 2012-09-07 Curevac Gmbh Vaccination in newborns and infants
US20120207840A1 (en) 2011-02-10 2012-08-16 Aura Biosciences, Inc. Virion Derived Protein Nanoparticles For Delivering Diagnostic Or Therapeutic Agents For The Treatment Of Non-Melanoma Skin Cancer
CN103703013A (zh) 2011-02-14 2014-04-02 斯威夫特生物科学公司 多核苷酸引物和探针
CA2827118A1 (en) 2011-02-15 2012-08-23 Merrimack Pharmaceuticals, Inc. Compositions and methods for delivering nucleic acid to a cell
US20140081012A1 (en) 2011-02-15 2014-03-20 The University Of North Carolina At Chapel Hill Nanoparticle, liposomes, polymers, agents and proteins modified with reversible linkers
EP2489371A1 (en) 2011-02-18 2012-08-22 Instituto Nacional de Investigacion y Tecnologia Agraria y Alimentaria Carrier peptides for drug delivery
WO2012113413A1 (en) 2011-02-21 2012-08-30 Curevac Gmbh Vaccine composition comprising complexed immunostimulatory nucleic acids and antigens packaged with disulfide-linked polyethyleneglycol/peptide conjugates
BR112013021494B1 (pt) 2011-02-22 2021-09-08 California Institute Of Technology Vetor viral, polinucleotídeo isolado, uso de um vírus adeno-associado (aav) recombinante e método para produzir o mesmo
US8696637B2 (en) 2011-02-28 2014-04-15 Kimberly-Clark Worldwide Transdermal patch containing microneedles
US20140112950A1 (en) 2011-03-02 2014-04-24 Manmohan Singh Combination vaccines with lower doses of antigen and/or adjuvant
WO2012116714A1 (en) 2011-03-02 2012-09-07 Curevac Gmbh Vaccination in elderly patients
CA2832807A1 (en) 2011-03-07 2012-09-13 Massachusetts Institute Of Technology Methods for transfecting cells with nucleic acids
US20120237565A1 (en) 2011-03-14 2012-09-20 Intezyne Technologies, Incorporated Pegylated polyplexes containing two or more different polymers for polynucleotide delivery
WO2012125680A1 (en) 2011-03-16 2012-09-20 Novartis Ag Methods of treating vasculitis using an il-17 binding molecule
WO2012125987A2 (en) 2011-03-17 2012-09-20 Massachusetts Institute Of Technology Delivery system
PH12013501878A1 (en) 2011-03-17 2013-10-14 Novartis Ag Fgfr and ligands thereof as biomarkers for breast cancer in hr positive subjects
EP2688590B1 (en) 2011-03-24 2020-02-12 GlaxoSmithKline Biologicals SA Adjuvant nanoemulsions with phospholipids
WO2012129648A1 (en) 2011-03-25 2012-10-04 University Of Guelph Enhancing protein expression of adeno-associated virus vectors
EP2694040A4 (en) 2011-03-25 2014-09-03 Selecta Biosciences Inc SYNTHETIC NANOTRACKERS WITH OSMOTICALLY MEDIATED RELEASE
US9238716B2 (en) 2011-03-28 2016-01-19 Massachusetts Institute Of Technology Conjugated lipomers and uses thereof
US20140005070A1 (en) 2011-03-28 2014-01-02 Novartis Ag Markers associated with cyclin-dependent kinase inhibitors
WO2012130941A2 (de) 2011-03-31 2012-10-04 Schaefer Konstanze Perfluorierte verbindungen zum nicht-viralen transfer von nukleinsäuren
EP2691078A1 (en) 2011-03-31 2014-02-05 Ingell Technologies Holding B.V. Biodegradable compositions suitable for controlled release
US9901554B2 (en) 2011-03-31 2018-02-27 Ingell Technologies Holding B.V. Biodegradable compositions suitable for controlled release
JP2014511687A (ja) * 2011-03-31 2014-05-19 モデルナ セラピューティクス インコーポレイテッド 工学操作された核酸の送達および製剤
WO2012130471A1 (en) * 2011-04-01 2012-10-04 Universität Stuttgart Recombinant tnf ligand family member polypeptides with antibody binding domain and uses thereof
WO2012138453A1 (en) 2011-04-03 2012-10-11 The General Hospital Corporation Efficient protein expression in vivo using modified rna (mod-rna)
EP2694524B1 (en) 2011-04-04 2016-05-18 The U.S.A. As Represented By The Secretary, Department Of Health And Human Services 2'-o-aminooxymethyl nucleoside derivatives for use in the synthesis and modification of nucleosides, nucleotides and oligonucleotides
WO2012142132A1 (en) 2011-04-11 2012-10-18 Life Technologies Corporation Polymer particles and methods of making and using same
WO2012142240A1 (en) 2011-04-13 2012-10-18 The Trustees Of The University Of Pennsylvania Coated mesoporous nanoparticles
WO2013158127A1 (en) 2012-04-16 2013-10-24 Molecular Transfer, Inc. Agents for improved delivery of nucleic acids to eukaryotic cells
US20140178894A1 (en) 2011-04-20 2014-06-26 Novartis Forschungsstiftung, Zweigniederlassung Culture medium suitable for the culture of undifferentiated cells
CA2834349A1 (en) 2011-04-26 2012-11-01 Molecular Express, Inc. Liposomal formulations
WO2012148684A1 (en) 2011-04-27 2012-11-01 President And Fellows Of Harvard College Cell-friendly inverse opal hydrogels for cell encapsulation, drug and protein delivery, and functional nanoparticle encapsulation
CA2834365A1 (en) 2011-04-28 2012-11-01 Sandia Corporation Porous nanoparticle-supported lipid bilayers (protocells) for targeted delivery and methods of using same
EP2702075A4 (en) 2011-04-28 2015-04-22 Jackson H M Found Military Med NEUTRALIZING ANTIBODIES TO NIPAH AND HENDRA VIRUSES
AU2012249540B2 (en) 2011-04-29 2017-07-13 Selecta Biosciences, Inc. Tolerogenic synthetic nanocarriers to reduce immune responses to therapeutic proteins
JP2014515759A (ja) 2011-04-29 2014-07-03 ノバルティス アーゲー 扁平上皮がんを治療する方法関連出願
US20120283503A1 (en) 2011-04-29 2012-11-08 The Johns Hopkins University Nanoparticle loaded stem cells and their use in mri guided hyperthermia
UA116189C2 (uk) 2011-05-02 2018-02-26 Мілленніум Фармасьютікалз, Інк. КОМПОЗИЦІЯ АНТИ-α4β7 АНТИТІЛА
CN107012118A (zh) 2011-05-02 2017-08-04 韦恩州立大学 蛋白质诱导的多能细胞技术及其用途
EP2704565B1 (en) 2011-05-04 2018-08-22 The University Of Nottingham Novel polymers which resist bacterial attachment
US9327029B2 (en) 2011-05-05 2016-05-03 Celacare Technologies, Llc Antimicrobial silver hydrogel composition for the treatment of burns and wounds
US8945588B2 (en) 2011-05-06 2015-02-03 The University Of Chicago Methods and compositions involving protective staphylococcal antigens, such as EBH polypeptides
CN103547350A (zh) 2011-05-10 2014-01-29 巴斯夫欧洲公司 水包油乳液
CN103687624B (zh) 2011-05-11 2018-02-02 雷蒙特亚特特拉维夫大学有限公司 靶向的聚合缀合物和其用途
EP2706983A1 (en) 2011-05-12 2014-03-19 Helmut Vockner Novel pharmaceutical formulation
ES2762224T3 (es) 2011-05-12 2020-05-22 Yissum Res Dev Co Of Hebrew Univ Jerusalem Ltd Liposomas que comprenden lípidos conjugados con polímero y usos relacionados
WO2012158613A1 (en) 2011-05-13 2012-11-22 Novartis Ag Pre-fusion rsv f antigens
US8691750B2 (en) 2011-05-17 2014-04-08 Axolabs Gmbh Lipids and compositions for intracellular delivery of biologically active compounds
CA2835428A1 (en) 2011-05-17 2012-11-22 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof for non-human vertebrates
EP2710196A1 (en) 2011-05-20 2014-03-26 Kohler Co. Toilet installation system and method
HRP20230443T1 (hr) 2011-05-24 2023-09-15 BioNTech SE Individualizirana cjepiva protiv raka
MX340453B (es) 2011-05-25 2016-07-08 Novartis Ag Biomarcadores para cancer de pulmon.
US20120302940A1 (en) 2011-05-26 2012-11-29 Jackson State University Popcorn Shape Gold Nanoparticle For Targeted Diagnosis, Photothermal Treatment and In-Situ Monitoring Therapy Response for Cancer and Multiple Drug Resistance Bacteria
WO2012166923A2 (en) 2011-05-31 2012-12-06 Bind Biosciences Drug loaded polymeric nanoparticles and methods of making and using same
CN103857387B (zh) 2011-06-02 2017-03-15 加利福尼亚大学董事会 膜包封的纳米颗粒及使用方法
WO2012166241A1 (en) 2011-06-02 2012-12-06 Novartis Ag Biomarkers for hedgehog inhibitor therapy
EP2717911A1 (en) 2011-06-06 2014-04-16 Novartis Forschungsstiftung, Zweigniederlassung Protein tyrosine phosphatase, non-receptor type 11 (ptpn11) and triple-negative breast cancer
CN103748078B (zh) * 2011-06-08 2016-11-09 夏尔人类遗传性治疗公司 可裂解脂质
LT2717893T (lt) * 2011-06-08 2019-08-12 Translate Bio, Inc. Lipidų nanodalelių kompozicijos ir mrnr pristatymo būdai
MX345704B (es) 2011-06-10 2017-02-10 Novartis Tiergesundheit Ag Vacuna bovinas y métodos.
WO2012170607A2 (en) 2011-06-10 2012-12-13 Novartis Ag Use of pcsk9 antagonists
US8636696B2 (en) 2011-06-10 2014-01-28 Kimberly-Clark Worldwide, Inc. Transdermal device containing microneedles
WO2012168491A1 (en) 2011-06-10 2012-12-13 Novartis Ag Pharmaceutical formulations of pcsk9 antagonists
US8916696B2 (en) 2011-06-12 2014-12-23 City Of Hope Aptamer-mRNA conjugates for targeted protein or peptide expression and methods for their use
WO2012172495A1 (en) 2011-06-14 2012-12-20 Novartis Ag Compositions and methods for antibodies targeting tem8
CN103717249B (zh) 2011-06-15 2017-03-22 克洛恩泰克制药股份公司 注射针和装置
CN103635490A (zh) 2011-06-16 2014-03-12 诺瓦提斯公司 用作治疗剂的可溶性蛋白
JP6113155B2 (ja) 2011-06-20 2017-04-12 ユニバーシティ オブ ピッツバーグ − オブ ザ コモンウェルス システム オブ ハイヤー エデュケイション 計算で最適化した広い反応性を示すｈ１ｎ１インフルエンザの抗原
US9862926B2 (en) 2011-06-27 2018-01-09 Cellscript, Llc. Inhibition of innate immune response
EP3473296B1 (en) 2011-06-28 2020-08-05 Inovio Pharmaceuticals, Inc. A minimally invasive dermal electroporation device
ES2692519T3 (es) 2011-07-01 2018-12-04 Novartis Ag Método para tratar trastornos metabólicos
JP2014520506A (ja) 2011-07-04 2014-08-25 コモンウェルス サイエンティフィック アンド インダストリアル リサーチ オーガニゼイション 核酸複合体
EP3508219A1 (en) 2011-07-06 2019-07-10 GlaxoSmithKline Biologicals S.A. Self-replicating rna prime - protein boost vaccines
TR201802662T4 (tr) 2011-07-06 2018-03-21 Glaxosmithkline Biologicals Sa Nükleik asitler içeren su içinde yağ emülsiyonları.
EP3456316A1 (en) 2011-07-06 2019-03-20 GlaxoSmithKline Biologicals S.A. Cationic oil-in-water emulsions
EP3332802A1 (en) 2011-07-06 2018-06-13 GlaxoSmithKline Biologicals SA Immunogenic combination compositions and uses thereof
JP2014520806A (ja) 2011-07-06 2014-08-25 ノバルティス アーゲー Ｒｎａ分子の送達のための有用なｎ：ｐ比を有するリポソーム
US8975302B2 (en) 2011-07-07 2015-03-10 Life Technologies Corporation Polymer particles, nucleic acid polymer particles and methods of making and using the same
WO2013009717A1 (en) 2011-07-10 2013-01-17 Elisabet De Los Pinos Virion derived protein nanoparticles for delivering diagnostic or therapeutic agents for the treatment of skin-related diseases
US20130012566A1 (en) 2011-07-10 2013-01-10 Aura Biosciences, Inc. Virion Derived Protein Nanoparticles For Delivering Diagnostic Or Therapeutic Agents For The Treatment of Alopecia
EP2758458A4 (en) 2011-07-10 2015-10-21 Harvard College COMPOSITIONS AND METHODS FOR SELF-ASSEMBLING POLYMERS WITH COMPLEMENTARY MACROSCOPIC AND MICROSCOPIC SCALE UNITS
US20140148503A1 (en) 2011-07-20 2014-05-29 University Of Iowa Research Foundation Nucleic acid aptamers
GB2492999A (en) 2011-07-20 2013-01-23 Univ Central Lancashire Neutron detector
ES2670944T3 (es) 2011-07-21 2018-06-04 Croda International Plc Copolímeros de bloques de poliéter-poliamida ramificados y métodos de preparación y uso de los mismos
ES2687129T3 (es) 2011-07-25 2018-10-23 Glaxosmithkline Biologicals Sa Composiciones y métodos para evaluar la inmunogenicidad funcional de vacunas contra parvovirus
US9493549B2 (en) 2011-07-25 2016-11-15 The Rockefeller University Antibodies directed toward the HIV-1 GP120 CD4 binding site with increased potency and breadth
CA2843274A1 (en) 2011-07-29 2013-02-07 Selecta Biosciences, Inc. Synthetic nanocarriers that generate humoral and cytotoxic t lymphocyte (ctl) immune responses
AU2012296576B2 (en) 2011-08-15 2017-09-07 The University Of Chicago Compositions and methods related to antibodies to staphylococcal protein a
HK1199736A1 (en) 2011-08-26 2015-07-17 箭头研究公司 Poly(vinyl ester) polymers for in vivo nucleic acid delivery
US9126966B2 (en) 2011-08-31 2015-09-08 Protiva Biotherapeutics, Inc. Cationic lipids and methods of use thereof
US8889657B2 (en) 2011-08-31 2014-11-18 Mallinckrodt Llc Nanoparticle PEG modification with H-phosphonates
HUE041800T2 (hu) 2011-08-31 2019-05-28 Glaxosmithkline Biologicals Sa Pegilált liposzómák immunogént kódoló RNS bejuttatására
WO2013033620A1 (en) 2011-09-01 2013-03-07 Irm Llc Compounds and compositions as pdgfr kinase inhibitors
EA201490553A1 (ru) 2011-09-02 2014-08-29 Новартис Аг Органические композиции для лечения связанных с hsf1 заболеваний
EP2755693A4 (en) * 2011-09-12 2015-05-20 Moderna Therapeutics Inc MANIPULATED NUCLEIC ACIDS AND METHOD OF APPLICATION THEREFOR
US9464124B2 (en) 2011-09-12 2016-10-11 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
WO2013039857A1 (en) * 2011-09-12 2013-03-21 modeRNA Therapeutics Engineered nucleic acids and methods of use thereof
US9358284B2 (en) 2011-09-14 2016-06-07 Glaxosmithkline Biologicals Sa Methods for making saccharide-protein glycoconjugates
CA2848410A1 (en) 2011-09-16 2013-03-21 The Trustees Of The University Of Pennsylvania Rna engineered t cells for the treatment of cancer
JP2014531456A (ja) 2011-09-22 2014-11-27 バインド セラピューティックス インコーポレイテッド 治療用ナノ粒子と癌を治療する方法
US9375388B2 (en) 2011-09-23 2016-06-28 Indian Institute Of Technology, Bombay Nanoparticle based cosmetic composition
TW201315742A (zh) 2011-09-26 2013-04-16 Novartis Ag 治療代謝病症之雙功能蛋白質
UY34346A (es) 2011-09-26 2013-04-30 Novartis Ag Proteínas de fusión para tratar trastornos metabólicos
US9951349B2 (en) 2011-09-27 2018-04-24 Yale University Compositions and methods for transient expression of recombinant RNA
AU2012315965A1 (en) 2011-09-27 2014-04-03 Alnylam Pharmaceuticals, Inc. Di-aliphatic substituted PEGylated lipids
WO2013045505A1 (en) 2011-09-28 2013-04-04 Novartis Ag Biomarkers for raas combination therapy
DK3682905T3 (da) 2011-10-03 2022-02-28 Modernatx Inc Modificerede nukleosider, nukleotider og nukleinsyrer og anvendelser deraf
GB201117279D0 (en) * 2011-10-06 2011-11-16 Nexeon Ltd Etched silicon structures, method of forming etched silicon structures and uses thereof
WO2013055971A1 (en) 2011-10-11 2013-04-18 Arizona Board Of Regents For And On Behalf Of Arizona State University Polymers for delivering a substance into a cell
CA2872033A1 (en) 2011-10-11 2013-04-18 Novartis Ag Recombinant self-replicating polycistronic rna molecules
WO2014066811A1 (en) 2012-10-25 2014-05-01 The Johns Hopkins University Bioreducible poly (b-amino ester)s for sirna delivery
WO2013055331A1 (en) 2011-10-12 2013-04-18 The Curators Of The University Of Missouri Pentablock polymers
US8673184B2 (en) * 2011-10-13 2014-03-18 Flexcon Company, Inc. Systems and methods for providing overcharge protection in capacitive coupled biomedical electrodes
AU2012323937A1 (en) 2011-10-14 2014-06-05 Stc.Unm Porous nanoparticle-supported lipid bilayers (protocells) for targeted delivery including transdermal delivery of cargo and methods thereof
CN109111523B (zh) 2011-10-14 2022-06-07 诺华股份有限公司 用于Wnt途径相关疾病的抗体和方法
EP3597644B1 (en) 2011-10-18 2021-09-29 Dicerna Pharmaceuticals, Inc. Amine cationic lipids and uses thereof
EP2768571B1 (en) 2011-10-18 2023-02-22 Micell Technologies, Inc. Drug delivery medical device
AU2012324398A1 (en) 2011-10-20 2014-05-01 Seqirus UK Limited Adjuvanted influenza B virus vaccines for pediatric priming
CN103930112B (zh) 2011-10-20 2018-11-09 诺华股份有限公司 预测对α7烟碱型乙酰胆碱受体激活剂疗法的响应的生物标志物
EP2770980A4 (en) 2011-10-25 2015-11-04 Univ British Columbia LOW SIZE LIPID NANOPARTICLES AND METHODS THEREOF
WO2013061290A1 (en) 2011-10-26 2013-05-02 Nanopass Technologies Ltd. Microneedle intradermal drug delivery device with auto-disable functionality
PE20181541A1 (es) 2011-10-27 2018-09-26 Massachusetts Inst Technology Derivados de aminoacidos funcionalizados en la terminal n capaces de formar microesferas encapsuladoras de farmaco
EP3574950B1 (en) 2011-10-27 2021-02-17 Sorrento Therapeutics, Inc. Transdermal delivery of high viscosity bioactive agents
AU2012328524B2 (en) 2011-10-28 2017-05-18 Excelse Bio, Inc. Protein formulations containing amino acids
EP2771043A4 (en) 2011-10-28 2015-04-29 Presage Biosciences Inc ACTIVE RELEASE PROCEDURE
WO2013062140A1 (en) 2011-10-28 2013-05-02 Kyoto University Method for efficiently inducing differentiation of pluripotent stem cells into hepatic lineage cells
CN104023793B (zh) 2011-10-31 2017-11-24 马林克罗特有限公司 用于治疗癌症的联合脂质体组合物
CN108704132A (zh) 2011-10-31 2018-10-26 弗·哈夫曼-拉罗切有限公司 抗体制剂
US10449257B2 (en) 2011-11-04 2019-10-22 Agency For Science, Technology And Research Self-assembled composite ultrasmall peptide-polymer hydrogels
US9872870B2 (en) 2011-11-04 2018-01-23 University Of Notre Dame Du Lac Multifunctional micellar nanoparticle-based drug and targeting agent system
WO2013064911A2 (en) 2011-11-04 2013-05-10 Nitto Denko Corporation Single use system for sterilely producing lipid-nucleic acid particles
CA2854457A1 (en) 2011-11-04 2013-05-10 David Jenkins Low density lipoprotein-related protein 6 (lrp6) - half life extender constructs
US20130115247A1 (en) 2011-11-05 2013-05-09 Aura Biosciences, Inc. Virion Derived Protein Nanoparticles For Delivering Radioisotopes For The Diagnosis And Treatment Of Malignant And Systemic Disease And The Monitoring Of Therapy
US20130116408A1 (en) 2011-11-05 2013-05-09 Aura Biosciences, Inc. Virion Derived Protein Nanoparticles For Delivering Radioisotopes For The Diagnosis And Treatment Of Malignant And Systemic Disease And The Monitoring Of Therapy
EP2776838A1 (en) 2011-11-08 2014-09-17 Novartis Forschungsstiftung, Zweigniederlassung Friedrich Miescher Institute For Biomedical Research Early diagnostic of neurodegenerative diseases
US9849087B2 (en) 2011-11-08 2017-12-26 The Board Of Trustees Of The University Of Arkansas Methods and compositions for X-ray induced release from pH sensitive liposomes
US20140314787A1 (en) 2011-11-08 2014-10-23 Novartis Forschungsstiftung, Zweigniederlassung, Friedrich Miescher Institute Treatment for neurodegenerative diseases
US20140287510A1 (en) 2011-11-08 2014-09-25 Novartis Forschungsstiftung, Zweigniederlassung Friedrich Miescher Institute Rod cell-specific promoter
WO2013070653A1 (en) 2011-11-09 2013-05-16 Board Of Trustees Michigan State University Metallic nanoparticle synthesis with carbohydrate capping agent
WO2013071047A1 (en) 2011-11-11 2013-05-16 Children's Medical Center Corporation Compositions and methods for in vitro transcription of rna
WO2013068847A2 (en) 2011-11-11 2013-05-16 Variation Biotechnologies, Inc. Compositions and methods for treatment of cytomegalovirus
BR112014011560A2 (pt) 2011-11-14 2017-05-09 Novartis Ag complexos imunogênicos de carbômeros polianiônicos e polipeptídeos env, e métodos de fabricação e uso dos mesmos
US20140343128A1 (en) 2011-11-15 2014-11-20 Novartis Ag Combination of a phosphoinositide 3-kinase inhibitor and a modulator of the Janus Kinase 2 - Signal Transducer and Activator of Transcription 5 pathway
ES2909777T3 (es) 2011-11-18 2022-05-10 Regeneron Pharma Formulación de liberación prolongada que comprende micropartículas para su uso en el humor vítreo del ojo para tratar trastornos oculares vasculares
BR112014012101A2 (pt) 2011-11-21 2019-09-24 Novartis Ag métodos de tratamento de artrite psoriática (psa) usando os antagonistas de il- 17 e alelos de resposta ou não resposta à psa
JP2015504563A (ja) * 2011-11-23 2015-02-12 プロテウス デジタル ヘルス， インコーポレイテッド マインドフルネス技法に基づいて行動変容を促進するデバイス、システム、および方法
WO2013078199A2 (en) 2011-11-23 2013-05-30 Children's Medical Center Corporation Methods for enhanced in vivo delivery of synthetic, modified rnas
US8930541B2 (en) * 2011-11-25 2015-01-06 International Business Machines Corporation System, method and program product for cost-aware selection of templates for provisioning shared resources
CA2856887C (en) * 2011-11-28 2021-06-15 Expanergy, Llc Energy search engine with autonomous control
CN103136247B (zh) * 2011-11-29 2015-12-02 阿里巴巴集团控股有限公司 属性数据区间划分方法及装置
WO2013082111A2 (en) 2011-11-29 2013-06-06 The University Of North Carolina At Chapel Hill Geometrically engineered particles and methods for modulating macrophage or immune responses
WO2013082427A1 (en) 2011-11-30 2013-06-06 3M Innovative Properties Company Microneedle device including a peptide therapeutic agent and an amino acid and methods of making and using the same
US9364549B2 (en) 2011-11-30 2016-06-14 Andreas Voigt Hydrophobic drug-delivery material, method for manufacturing thereof and methods for delivery of a drug-delivery composition
DE102011087509A1 (de) * 2011-12-01 2013-06-06 Robert Bosch Gmbh Sensorübertragungsvorrichtung und Verfahren zur Übertragung von Nutzdaten von einer Mehrzahl von Sensoren an eine Bussteuervorrichtung für ein Fahrzeug
EP2785333A4 (en) 2011-12-02 2015-04-01 Pegasus Lab Inc AMPHIPATIVE COMPOSITIONS WITH DELAYED RELIEF ON LIPID BASIS
WO2013082529A1 (en) 2011-12-02 2013-06-06 Yale University Enzymatic synthesis of poly(amine-co-esters) and methods of use thereof for gene delivery
WO2013082590A1 (en) 2011-12-02 2013-06-06 Invivo Therapeutics Corporation Peg based hydrogel for peripheral nerve injury applications and compositions and method of use of synthetic hydrogel sealants
MX382822B (es) 2011-12-05 2025-03-13 Factor Bioscience Inc Metodos y productos para transfeccion de celulas.
US9814867B2 (en) 2011-12-05 2017-11-14 Nano Precision Medical, Inc. Device having titania nanotube membrane for drug delivery
US8497124B2 (en) 2011-12-05 2013-07-30 Factor Bioscience Inc. Methods and products for reprogramming cells to a less differentiated state
CA3170051A1 (en) 2011-12-07 2013-06-13 Alnylam Pharmaceuticals, Inc. Branched alkyl and cycloalkyl terminated biodegradable lipids for the delivery of active agents
CA2856742A1 (en) 2011-12-07 2013-06-13 Alnylam Pharmaceuticals, Inc. Biodegradable lipids for the delivery of active agents
WO2013086373A1 (en) 2011-12-07 2013-06-13 Alnylam Pharmaceuticals, Inc. Lipids for the delivery of active agents
GB201121070D0 (en) 2011-12-07 2012-01-18 Isis Innovation composition for delivery of biotherapeutics
US9725687B2 (en) 2011-12-09 2017-08-08 President And Fellows Of Harvard College Integrated human organ-on-chip microphysiological systems
US10087422B2 (en) 2011-12-09 2018-10-02 President And Fellows Of Harvard College Organ chips and uses thereof
WO2013086526A1 (en) 2011-12-09 2013-06-13 The Regents Of The University Of California Liposomal drug encapsulation
US9839616B2 (en) 2011-12-12 2017-12-12 Kyowa Hakko Kirin Co., Ltd. Lipid nano particles comprising cationic lipid for drug delivery system
CN104159615B (zh) 2011-12-12 2017-08-18 协和发酵麒麟株式会社 含有阳离子性脂质的组合的脂质纳米粒子
US9750795B2 (en) 2011-12-12 2017-09-05 The Trustees Of The University Of Pennsylvania Proteins comprising MRSA PBP2a and fragments thereof, nucleic acids encoding the same, and compositions and their use to prevent and treat MRSA infections
EP2604253A1 (en) 2011-12-13 2013-06-19 Otto Glatter Water-in-oil emulsions and methods for their preparation
MX385832B (es) 2011-12-13 2025-03-18 Engeneic Molecular Delivery Pty Ltd Minicélulas bacterianamente derivadas, intactas para la formación de mágenes de tumores cerebrales.
US20150000936A1 (en) 2011-12-13 2015-01-01 Schlumberger Technology Corporation Energization of an element with a thermally expandable material
EP2791364A4 (en) 2011-12-14 2015-11-11 Moderna Therapeutics Inc PROCESS FOR RESPONSE TO A BIOLOGICAL THREAT
US20140343129A1 (en) 2011-12-14 2014-11-20 Moderna Therapeutics, Inc. Modified nucleic acids, and acute care uses thereof
WO2013090897A1 (en) 2011-12-15 2013-06-20 The Trustees Of The University Of Pennsylvania Using adaptive immunity to detect drug resistance
US9636414B2 (en) 2011-12-15 2017-05-02 Biontech Ag Particles comprising single stranded RNA and double stranded RNA for immunomodulation
BR112014014678A2 (pt) 2011-12-16 2017-06-13 Allergan Inc composições oftálmicas compreendendo copolímeros de enxertia de polivinil caprolactama-acetato de polivinila-polietileno glicol
HRP20220717T1 (hr) 2011-12-16 2022-07-22 Modernatx, Inc. Modificirani pripravci mrna
WO2013090601A2 (en) 2011-12-16 2013-06-20 Massachusetts Institute Of Technology Compact nanoparticles for biological applications
CA2859205A1 (en) 2011-12-16 2013-06-20 Massachusetts Institute Of Technology Alpha-aminoamidine polymers and uses thereof
KR20140103939A (ko) 2011-12-16 2014-08-27 노파르티스 아게 흡입 프로파일-비의존적 약물 전달을 위한 에어로졸화 장치
EP2791171A1 (en) 2011-12-16 2014-10-22 Synthon Biopharmaceuticals B.V. EXPRESSION OF SECRETORY IgA ANTIBODIES IN DUCKWEED
WO2013091001A1 (en) 2011-12-19 2013-06-27 The University Of Sydney A peptide-hydrogel composite
US9241829B2 (en) 2011-12-20 2016-01-26 Abbott Medical Optics Inc. Implantable intraocular drug delivery apparatus, system and method
RU2014129863A (ru) 2011-12-21 2016-02-10 Модерна Терапьютикс, Инк. Способы повышения жизнеспособности или увеличения продолжительности жизни органа или экспланта органа
US20130195851A1 (en) 2011-12-23 2013-08-01 Genentech, Inc. Articles of manufacture and methods for co-administration of antibodies
WO2013101908A1 (en) 2011-12-27 2013-07-04 Massachusetts Institute Of Technology Microneedle devices and uses thereof
US10596246B2 (en) 2011-12-29 2020-03-24 Glaxosmithkline Biological Sa Adjuvanted combinations of meningococcal factor H binding proteins
WO2013101690A1 (en) 2011-12-29 2013-07-04 modeRNA Therapeutics Modified mrnas encoding cell-penetrating polypeptides
EP3421601B1 (en) 2011-12-30 2019-12-04 Cellscript, Llc Making and using in vitro-synthesized ssrna for introducing into mammalian cells to induce a biological or biochemical effect
CN110025608A (zh) 2012-01-06 2019-07-19 燿石治疗公司 降低心血管疾病风险的方法
WO2013106496A1 (en) 2012-01-10 2013-07-18 modeRNA Therapeutics Methods and compositions for targeting agents into and across the blood-brain barrier
SG11201404361UA (en) 2012-01-26 2014-09-26 Life Technologies Corp Methods for increasing the infectivity of viruses
WO2013112778A1 (en) 2012-01-26 2013-08-01 Life Technologies Corporation Methods for increasing the infectivity of viruses
EP2623121A1 (en) 2012-01-31 2013-08-07 Bayer Innovation GmbH Pharmaceutical composition comprising a polymeric carrier cargo complex and an antigen
WO2013113326A1 (en) 2012-01-31 2013-08-08 Curevac Gmbh Pharmaceutical composition comprising a polymeric carrier cargo complex and at least one protein or peptide antigen
WO2013113325A1 (en) 2012-01-31 2013-08-08 Curevac Gmbh Negatively charged nucleic acid comprising complexes for immunostimulation
KR102081560B1 (ko) 2012-02-09 2020-02-25 라이프 테크놀로지스 코포레이션 친수성 중합체성 입자 및 그의 제조 방법
WO2013120497A1 (en) * 2012-02-15 2013-08-22 Curevac Gmbh Nucleic acid comprising or coding for a histone stem-loop and a poly(a) sequence or a polyadenylation signal for increasing the expression of an encoded therapeutic protein
HK1205751A1 (en) 2012-02-22 2015-12-24 Cerulean Pharma Inc. Conjugates, particles, compositions, and related methods
US20130243867A1 (en) 2012-02-23 2013-09-19 University Of South Florida (A Florida Non-Profit Corporation) Micelle compositions and methods for their use
WO2013130535A1 (en) 2012-02-27 2013-09-06 Newgen Biopharma Corporation Topical delivery of hormonal and non hormonal nano formulations, methods of making and using the same
MX353382B (es) 2012-03-01 2018-01-10 Amgen Res Munich Gmbh Moleculas de union polipeptido de larga duracion.
CN104271149B (zh) 2012-03-13 2016-03-16 夸祖鲁-纳塔尔大学 经皮递送装置
US10322089B2 (en) 2012-03-14 2019-06-18 The Board Of Trustees Of The Leland Stanford Junior University Nanoparticles, nanoparticle delivery methods, and systems of delivery
AU2013231638B2 (en) 2012-03-16 2017-10-12 Merck Patent Gmbh Targeting aminoacid lipids
EA032552B1 (ru) 2012-03-16 2019-06-28 Дзе Джонс Хопкинс Юниверсити Препараты с контролируемым высвобождением для доставки ингибиторов hif-1
AU2013232300B2 (en) 2012-03-16 2015-12-17 The Johns Hopkins University Non-linear multiblock copolymer-drug conjugates for the delivery of active agents
CN103325662B (zh) 2012-03-21 2016-03-30 清华大学 半导体性单壁碳纳米管的制备方法
WO2013142349A1 (en) 2012-03-23 2013-09-26 University Of Chicago Compositions and methods related to staphylococcal sbi
US9610346B2 (en) 2012-03-23 2017-04-04 International Aids Vaccine Initiative Recombinant viral vectors
WO2013148186A1 (en) 2012-03-26 2013-10-03 President And Fellows Of Harvard College Lipid-coated nucleic acid nanostructures of defined shape
WO2013143555A1 (en) 2012-03-26 2013-10-03 Biontech Ag Rna formulation for immunotherapy
KR102186497B1 (ko) 2012-03-27 2020-12-04 큐어백 아게 인공 핵산 분자
SG11201405545XA (en) 2012-03-27 2014-11-27 Curevac Gmbh Artificial nucleic acid molecules comprising a 5'top utr
MX2019002345A (es) 2012-03-27 2022-08-24 Curevac Ag Moleculas artificiales de acido nucleico para la expresion mejorada de proteina o peptido.
WO2013148541A1 (en) 2012-03-27 2013-10-03 Merck Sharp & Dohme Corp. DIETHER BASED BIODEGRADABLE CATIONIC LIPIDS FOR siRNA DELIVERY
CA2868030C (en) 2012-03-29 2021-05-25 Shire Human Genetic Therapies, Inc. Lipid-derived neutral nanoparticles
US10501513B2 (en) 2012-04-02 2019-12-10 Modernatx, Inc. Modified polynucleotides for the production of oncology-related proteins and peptides
JP6189415B2 (ja) 2012-04-02 2017-08-30 モデルナティエックス インコーポレイテッドＭｏｄｅｒｎａＴＸ，Ｉｎｃ． 細胞質および細胞骨格タンパク質の産生のための修飾ポリヌクレオチド
US10501512B2 (en) 2012-04-02 2019-12-10 Modernatx, Inc. Modified polynucleotides
US20140275229A1 (en) 2012-04-02 2014-09-18 Moderna Therapeutics, Inc. Modified polynucleotides encoding udp glucuronosyltransferase 1 family, polypeptide a1
US20150050354A1 (en) 2012-04-02 2015-02-19 Moderna Therapeutics, Inc. Modified polynucleotides for the treatment of otic diseases and conditions
CN108949772A (zh) * 2012-04-02 2018-12-07 现代泰克斯公司 用于产生与人类疾病相关的生物制剂和蛋白质的修饰多核苷酸
US9283287B2 (en) * 2012-04-02 2016-03-15 Moderna Therapeutics, Inc. Modified polynucleotides for the production of nuclear proteins
EP2833926A4 (en) 2012-04-05 2015-11-25 Univ Florida NEUROPHILIC NANOPARTICLES
EP2833918B1 (en) 2012-04-05 2019-05-08 Massachusetts Institute of Technology Immunostimulatory compositions and methods of use thereof
WO2013152351A2 (en) 2012-04-06 2013-10-10 The Trustees Of Columbia University In The City Of New York Fusion polypeptides and methods of use thereof
RU2635466C2 (ru) 2012-04-08 2017-11-13 Теракоат Лтд Препараты термообратимого гидрогеля для применения при лечении нарушений уротелия
NZ709953A (en) 2012-04-11 2016-09-30 Intezyne Technologies Inc Block copolymers for stable micelles
CA2869748C (en) 2012-04-12 2017-10-24 Yale University Vehicles for controlled delivery of different pharmaceutical agents
WO2013154766A1 (en) 2012-04-13 2013-10-17 New York University Microrna control of ldl receptor pathway
WO2013155513A1 (en) 2012-04-13 2013-10-17 President And Fellows Of Harvard College Devices and methods for in vitro aerosol delivery
JP2015515530A (ja) 2012-04-18 2015-05-28 アローヘッド リサーチ コーポレイション インビボ核酸送達のためのポリ（アクリラート）ポリマー
US9402816B2 (en) 2012-04-19 2016-08-02 Sima Therapeutics, Inc. Diester and triester based low molecular weight, biodegradeable cationic lipids for oligonucleotide delivery
EP2841056A4 (en) 2012-04-23 2015-09-16 Massachusetts Inst Technology STABLE LAYER COATED PARTICLES
AR090825A1 (es) 2012-04-25 2014-12-10 Regulus Therapeutics Inc COMPUESTO DE microARN Y METODOS DE MODULACION DE LA ACTIVIDAD DE miR-21
KR102310775B1 (ko) 2012-05-03 2021-10-07 칼라 파마슈티컬스, 인크. 개선된 점막 수송을 나타내는 제약 나노입자
JP6392209B2 (ja) 2012-05-04 2018-09-19 ザ・ジョンズ・ホプキンス・ユニバーシティー 粘液内層を通過する迅速な透過のための脂質ベース薬物キャリア
WO2013173657A1 (en) 2012-05-16 2013-11-21 Micell Technologies, Inc. Low burst sustained release lipophilic and biologic agent compositions
US9399672B2 (en) 2012-05-17 2016-07-26 The United States Of America, As Represented By The Secretary Department Of Health And Human Services Hepatitis C virus neutralizing antibody
WO2013173693A1 (en) 2012-05-18 2013-11-21 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Nanoparticles with enhanced entry into cancer cells
US9750819B2 (en) 2012-05-23 2017-09-05 Ohio State Innovation Foundation Lipid nanoparticle compositions and methods of making and methods of using the same
WO2013174409A1 (en) 2012-05-25 2013-11-28 Curevac Gmbh Reversible immobilization and/or controlled release of nucleic acid containing nanoparticles by (biodegradable) polymer coatings
CA2874453C (en) 2012-06-06 2021-05-18 Loma Vista Medical, Inc. Inflatable medical devices
EP2858677B1 (en) 2012-06-08 2020-08-05 ethris GmbH Pulmonary delivery of messenger rna
HK1208618A1 (en) 2012-06-08 2016-03-11 夏尔人类遗传性治疗公司 Pulmonary delivery of mrna to non-lung target cells
LT2858974T (lt) 2012-06-08 2018-12-10 Nitto Denko Corporation Lipidai, skirti terapinio agento pristatymo kompozicijoms
CN104507458B (zh) 2012-06-20 2018-05-22 滑铁卢大学 粘膜粘合剂纳米颗粒递送系统
WO2014014613A2 (en) 2012-06-20 2014-01-23 President And Fellows Of Harvard College Self-assembling peptides, peptide nanostructures and uses thereof
US9803010B2 (en) 2012-06-27 2017-10-31 Merck Sharp & Dohme Corp. Crystalline anti-human IL-23p19 antibodies
US9150841B2 (en) 2012-06-29 2015-10-06 Shire Human Genetic Therapies, Inc. Cells for producing recombinant iduronate-2-sulfatase
US9956291B2 (en) 2012-07-10 2018-05-01 Shaker A. Mousa Nanoformulation and methods of use of thyroid receptor beta1 agonists for liver targeting
EP2872120B1 (en) 2012-07-16 2017-05-03 Nanoderm Sciences, Inc. Therapeutic nanoparticles with a polymyxin b as targeting agent
EP2687251A1 (en) 2012-07-17 2014-01-22 Sanofi-Aventis Deutschland GmbH Drug delivery device
EP2687252A1 (en) 2012-07-17 2014-01-22 Sanofi-Aventis Deutschland GmbH Drug delivery device
CN112587658A (zh) 2012-07-18 2021-04-02 博笛生物科技有限公司 癌症的靶向免疫治疗
WO2014015334A1 (en) 2012-07-20 2014-01-23 Brown University System and methods for nanostructure protected delivery of treatment agent and selective release thereof
CN104781416B (zh) 2012-07-24 2017-07-04 哈佛学院院长及董事 核酸纳米结构的自装配
WO2014015422A1 (en) 2012-07-27 2014-01-30 Ontario Institute For Cancer Research Cellulose-based nanoparticles for drug delivery
GB201213624D0 (en) 2012-07-27 2012-09-12 Univ Ulster The Method and system for production of conjugated nanoparticles
WO2014024193A1 (en) 2012-08-07 2014-02-13 Prodel Pharma Ltd. Compositions and methods for rapid transmucosal delivery of pharmaceutical ingredients
WO2014025795A1 (en) 2012-08-07 2014-02-13 Northeastern University Compositions for the delivery of rna and drugs into cells
US9974886B2 (en) 2012-08-08 2018-05-22 Nanyang Technological University Methods of manufacturing hydrogel microparticles having living cells, and compositions for manufacturing a scaffold for tissue engineering
WO2014026044A2 (en) 2012-08-08 2014-02-13 Presage Biosciences, Inc. Extrusion methods and devices for drug delivery
CN104736181A (zh) 2012-08-10 2015-06-24 北德克萨斯大学健康科学中心 包含靶向聚氨基酸与脂肪酸之缀合物的药物递送载剂
WO2014027006A1 (en) 2012-08-13 2014-02-20 Edko Pazarlama Tanitim Ticaret Limited Sirketi Bioadhesive formulations for use in drug delivery
EP2882706A1 (en) 2012-08-13 2015-06-17 Massachusetts Institute of Technology Amine-containing lipidoids and uses thereof
WO2014026284A1 (en) 2012-08-14 2014-02-20 Froese Aaron Internal structured self assembling liposomes
WO2014028209A1 (en) 2012-08-14 2014-02-20 The Trustees Of The University Of Pennsylvania Stabilizing shear-thinning hydrogels
WO2014028429A2 (en) 2012-08-14 2014-02-20 Moderna Therapeutics, Inc. Enzymes and polymerases for the synthesis of rna
EP2885414B1 (en) 2012-08-15 2020-09-23 The University of Chicago Exosome-based therapeutics against neurodegenerative disorders
US10179134B2 (en) 2012-09-05 2019-01-15 Creighton University Polymeric nanoparticles in a thermosensitive gel for coital-independent vaginal prophylaxis of HIV
US8703197B2 (en) 2012-09-13 2014-04-22 International Business Machines Corporation Branched polyamines for delivery of biologically active materials
JP6356678B2 (ja) 2012-09-17 2018-07-11 ファイザー・インク 治療用ナノ粒子を製造する方法
CA2885022A1 (en) 2012-09-17 2014-03-20 Bind Therapeutics, Inc. Therapeutic nanoparticles comprising a therapeutic agent and methods of making and using same
WO2014047649A1 (en) 2012-09-24 2014-03-27 The Regents Of The University Of California Methods for arranging and packing nucleic acids for unusual resistance to nucleases and targeted delivery for gene therapy
WO2014052634A1 (en) 2012-09-27 2014-04-03 The University Of North Carolina At Chapel Hill Lipid coated nanoparticles containing agents having low aqueous and lipid solubilities and methods thereof
EP2716655A1 (en) 2012-10-04 2014-04-09 Institut Pasteur Neutralizing antibodies directed against Hepatitis C virus ectodomain glycoprotein E2
WO2014053879A1 (en) 2012-10-04 2014-04-10 Centre National De La Recherche Scientifique Cell penetrating peptides for intracellular delivery of molecules
CN104812372A (zh) 2012-10-04 2015-07-29 约翰内斯堡金山大学 脂质体药物递送系统
US20140100178A1 (en) 2012-10-04 2014-04-10 Aslam Ansari Composition and methods for site-specific drug delivery to treat malaria and other liver diseases
WO2014053882A1 (en) 2012-10-04 2014-04-10 Centre National De La Recherche Scientifique Cell penetrating peptides for intracellular delivery of molecules
WO2014053880A1 (en) 2012-10-04 2014-04-10 Centre National De La Recherche Scientifique Cell penetrating peptides for intracellular delivery of molecules
WO2014053881A1 (en) 2012-10-04 2014-04-10 Centre National De La Recherche Scientifique Cell penetrating peptides for intracellular delivery of molecules
EP2716689A1 (en) 2012-10-05 2014-04-09 National University of Ireland, Galway Polymer comprising a plurality of branches having at least one disulfide group and/or at least one vinyl group
WO2014064534A2 (en) 2012-10-05 2014-05-01 Chrontech Pharma Ab Injection needle, device, immunogenic compositions and method of use
US9931410B2 (en) 2012-10-09 2018-04-03 The Brigham And Women's Hospital, Inc. Nanoparticles for targeted delivery of multiple therapeutic agents and methods of use
US20140106260A1 (en) 2012-10-11 2014-04-17 The Trustees Of The University Of Pennsylvania Core-shell nanoparticulate compositions and methods
KR20150070318A (ko) 2012-10-16 2015-06-24 엔도사이트, 인코포레이티드 비천연 아미노산을 함유하는 약물 전달 컨쥬게이트 및 사용 방법
PL2908912T3 (pl) 2012-10-18 2021-05-17 The Rockefeller University Szeroko neutralizujące przeciwciała anty-hiv
CN104918639B (zh) 2012-10-22 2018-01-26 萨拜格Rfa公司 用于将治疗剂递送到活细胞和细胞核中的系统
US10172956B2 (en) 2012-10-26 2019-01-08 Vanderbilt University Polymeric nanoparticles
MX2015005328A (es) 2012-10-26 2015-09-25 Nlife Therapeutics S L Composiciones y metodos para la administracion selectiva de moleculas de oligonucleotidos a tipos de celulas.
WO2014066898A1 (en) 2012-10-26 2014-05-01 The Johns Hopkins University A layer-by-layer approach to co-deliver dna and sirna via aunps: a potential platform for modifying release kinetics
US20150376581A1 (en) 2012-10-29 2015-12-31 Technische Universitaet Dortmund T7 rna polymerase variants and methods of using the same
EP2752740A4 (en) * 2012-10-31 2015-03-11 Huawei Device Co Ltd DRAWING CONTROL METHOD, DEVICE THEREFOR AND MOBILE DEVICE
BR122019025678B1 (pt) 2012-11-01 2023-04-18 Factor Bioscience Inc Composições que compreendem ácido nucleico que codifica uma proteína de edição gênica
WO2014071072A2 (en) 2012-11-02 2014-05-08 Pungente Michael D Novel cationic carotenoid-based lipids for cellular nucleic acid uptake
US9444624B2 (en) 2012-11-02 2016-09-13 Facebook, Inc. Providing user authentication
US10017767B2 (en) 2012-11-05 2018-07-10 Fondazione Centro San Raffaele Targets in multiple myeloma and other disorders
MX367301B (es) 2012-11-06 2019-08-14 Rochal Ind Llc Liberacion de agentes biologicamente activos utilizando disolventes hidrofobicos volatiles.
US9975916B2 (en) 2012-11-06 2018-05-22 President And Fellows Of Harvard College Compositions and methods relating to complex nucleic acid nanostructures
US9669104B2 (en) 2012-11-07 2017-06-06 Council Of Scientific And Industrial Research Nanocomplex containing amphipathic peptide useful for efficient transfection of biomolecules
US9572893B2 (en) 2012-11-07 2017-02-21 Council Of Scientific And Industrial Research Nanocomplex containing cationic peptide for biomolecule delivery
RU2670943C9 (ru) 2012-11-08 2018-11-26 Илэвэн Байотерапьютикс, Инк. Антагонисты ил-6 и их применение
TW201428101A (zh) 2012-11-08 2014-07-16 Inviragen Inc 登革熱病毒血清型４型之建構物的組成物、方法及用途
AU2013343503B2 (en) 2012-11-08 2017-12-14 Albumedix Ltd. Albumin variants
ES3023054T3 (en) 2012-11-08 2025-05-29 Clearside Biomedical Inc Methods for the treatment of ocular disease in human subjects
WO2014072468A1 (en) 2012-11-09 2014-05-15 Velin-Pharma A/S Compositions for pulmonary delivery
US9200119B2 (en) 2012-11-09 2015-12-01 Momentive Performance Materials Inc. Silicon-containing zwitterionic linear copolymer composition
TR201809547T4 (tr) 2012-11-09 2018-07-23 Biontech Rna Pharmaceuticals Gmbh Hücresel RNA ifadesine yönelik yöntem.
WO2014071963A1 (en) 2012-11-09 2014-05-15 Biontech Ag Method for cellular rna expression
GB201220354D0 (en) 2012-11-12 2012-12-26 Medpharm Ltd Dermal compositions
AU2013341711A1 (en) 2012-11-12 2015-05-21 Redwood Bioscience, Inc. Compounds and methods for producing a conjugate
WO2014075047A2 (en) 2012-11-12 2014-05-15 Genvec, Inc. Malaria antigens and methods of use
WO2014078399A1 (en) 2012-11-13 2014-05-22 Baylor College Of Medicine Multi-arm biodegradable polymers for nucleic acid delivery
WO2014078636A1 (en) 2012-11-16 2014-05-22 President And Fellows Of Harvard College Nucleic acid hydrogel self-assembly
US9310374B2 (en) 2012-11-16 2016-04-12 Redwood Bioscience, Inc. Hydrazinyl-indole compounds and methods for producing a conjugate
EP2732825B1 (en) 2012-11-19 2015-07-01 Invivogen Conjugates of a TLR7 and/or TLR8 agonist and a TLR2 agonist
EP2919760A4 (en) 2012-11-19 2016-08-03 Technion Res & Dev Foundation LIPOSOMES FOR IN VIVO RELEASE
US20140141037A1 (en) 2012-11-20 2014-05-22 Novartis Ag Rsv f prefusion trimers
US20150290328A1 (en) 2012-11-20 2015-10-15 Phasebio Pharmaceuticals, Inc. Formulations of active agents for sustained release
WO2014081300A1 (en) 2012-11-22 2014-05-30 Tagworks Pharmaceuticals B.V. Channel protein activatable liposomes
EP2922574B1 (en) 2012-11-22 2023-05-17 Tagworks Pharmaceuticals B.V. Chemically cleavable group
WO2014081299A1 (en) 2012-11-22 2014-05-30 Tagworks Pharmaceuticals B.V. Activatable liposomes
EP2922554B1 (en) 2012-11-26 2022-02-23 ModernaTX, Inc. Terminally modified rna
WO2014093574A1 (en) 2012-12-13 2014-06-19 Moderna Therapeutics, Inc. Modified polynucleotides for altering cell phenotype
EP2931319B1 (en) 2012-12-13 2019-08-21 ModernaTX, Inc. Modified nucleic acid molecules and uses thereof
US20140193484A1 (en) 2013-01-10 2014-07-10 Sylvie Carine Bertholet Girardin Influenza virus immunogenic compositions and uses thereof
JP2016504050A (ja) 2013-01-17 2016-02-12 モデルナ セラピューティクス インコーポレイテッドＭｏｄｅｒｎａ Ｔｈｅｒａｐｅｕｔｉｃｓ，Ｉｎｃ． 細胞表現型の改変のためのシグナルセンサーポリヌクレオチド
EP2964234A4 (en) 2013-03-09 2016-12-07 Moderna Therapeutics Inc Heterologous untranslated regions for mrna
US20160022774A1 (en) 2013-03-12 2016-01-28 Moderna Therapeutics, Inc. Diagnosis and treatment of fibrosis
US20160024181A1 (en) 2013-03-13 2016-01-28 Moderna Therapeutics, Inc. Long-lived polynucleotide molecules
HK1219955A1 (zh) 2013-03-14 2017-04-21 Shire Human Genetic Therapies, Inc. 含4'-硫代修饰的核苷酸的核糖核酸及相关方法
EP2971010B1 (en) 2013-03-14 2020-06-10 ModernaTX, Inc. Formulation and delivery of modified nucleoside, nucleotide, and nucleic acid compositions
WO2014144767A1 (en) 2013-03-15 2014-09-18 Moderna Therapeutics, Inc. Ion exchange purification of mrna
US20160017313A1 (en) 2013-03-15 2016-01-21 Moderna Therapeutics, Inc. Analysis of mrna heterogeneity and stability
EP2971165A4 (en) 2013-03-15 2016-11-23 Moderna Therapeutics Inc DISSOLUTION OF DNA FRAGMENTS IN MRNA MANUFACTURING METHODS
US20160032273A1 (en) 2013-03-15 2016-02-04 Moderna Therapeutics, Inc. Characterization of mrna molecules
EP3578663A1 (en) 2013-03-15 2019-12-11 ModernaTX, Inc. Manufacturing methods for production of rna transcripts
US8980864B2 (en) 2013-03-15 2015-03-17 Moderna Therapeutics, Inc. Compositions and methods of altering cholesterol levels
EP3578652B1 (en) 2013-03-15 2023-07-12 ModernaTX, Inc. Ribonucleic acid purification
SI3019619T1 (sl) 2013-07-11 2021-12-31 Modernatx, Inc. Sestave, ki zajemajo sintetične polinukleotide, ki kodirajo proteine, pozvezane s crispr, in sintetične sgrna, ter metode uporabe
JP2016530294A (ja) 2013-09-03 2016-09-29 モデルナ セラピューティクス インコーポレイテッドＭｏｄｅｒｎａ Ｔｈｅｒａｐｅｕｔｉｃｓ，Ｉｎｃ． キメラポリヌクレオチド
EP3041938A1 (en) 2013-09-03 2016-07-13 Moderna Therapeutics, Inc. Circular polynucleotides
WO2015038892A1 (en) 2013-09-13 2015-03-19 Moderna Therapeutics, Inc. Polynucleotide compositions containing amino acids
EP3052106A4 (en) 2013-09-30 2017-07-19 ModernaTX, Inc. Polynucleotides encoding immune modulating polypeptides
EP3052511A4 (en) 2013-10-02 2017-05-31 Moderna Therapeutics, Inc. Polynucleotide molecules and uses thereof
EP3052479A4 (en) 2013-10-02 2017-10-25 Moderna Therapeutics, Inc. Polynucleotide molecules and uses thereof
KR20160067219A (ko) 2013-10-03 2016-06-13 모더나 세라퓨틱스, 인코포레이티드 저밀도 지단백질 수용체를 암호화하는 폴리뉴클레오타이드
US20160243221A1 (en) 2013-10-18 2016-08-25 Moderna Therapeutics, Inc. Compositions and methods for tolerizing cellular systems
US20170173128A1 (en) 2013-12-06 2017-06-22 Moderna TX, Inc. Targeted adaptive vaccines
US20150167017A1 (en) 2013-12-13 2015-06-18 Moderna Therapeutics, Inc. Alternative nucleic acid molecules and uses thereof
EP3092250A4 (en) 2014-01-08 2017-05-24 Moderna Therapeutics, Inc. Polynucleotides for the in vivo production of antibodies
HUE069802T2 (hu) 2014-04-23 2025-04-28 Modernatx Inc Nukleinsav vakcinák
EP2942143B1 (en) 2014-05-09 2017-03-15 Gestamp HardTech AB Methods for joining two blanks and blanks and products obtained
WO2015196128A2 (en) 2014-06-19 2015-12-23 Moderna Therapeutics, Inc. Alternative nucleic acid molecules and uses thereof
US20170175129A1 (en) 2014-06-19 2017-06-22 Moderna Therapeutics, Inc. Alternative nucleic acid molecules and uses thereof
US20170136132A1 (en) 2014-06-19 2017-05-18 Moderna Therapeutics, Inc. Alternative nucleic acid molecules and uses thereof
CA2955250A1 (en) 2014-07-16 2016-01-21 Moderna Therapeutics, Inc. Chimeric polynucleotides
CA2955238A1 (en) 2014-07-16 2016-01-21 Moderna Therapeutics, Inc. Circular polynucleotides
WO2016016676A1 (fr) 2014-07-30 2016-02-04 ArcelorMittal Investigación y Desarrollo, S.L. Procédé de fabrication de tôles d'acier, pour durcissement sous presse, et pièces obtenues par ce procédé
WO2016036902A1 (en) 2014-09-03 2016-03-10 Moderna Therapeutics, Inc. Tolerogenic compositions and methods
ES2749205T3 (es) 2014-11-19 2020-03-19 Nippon Steel Corp Junta soldada por láser, componente de vehículo, método de fabricación de junta soldada por láser y método de fabricación de componente de vehículo
US20180000953A1 (en) 2015-01-21 2018-01-04 Moderna Therapeutics, Inc. Lipid nanoparticle compositions
WO2016118725A1 (en) 2015-01-23 2016-07-28 Moderna Therapeutics, Inc. Lipid nanoparticle compositions
RU2727592C2 (ru) 2015-11-12 2020-07-22 Конинклейке Филипс Н.В. Конструкция накладки на грудь для молокоотсоса, молокоотсос и способ работы
US10870110B2 (en) 2015-12-11 2020-12-22 Babson Diagnostics, Inc. Specimen container and centrifugation method for separating serum or plasma from whole blood therewith
US10563897B2 (en) 2018-02-13 2020-02-18 Carrier Corporation Transport refrigeration unit with a renewable energy source and method of operation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090286852A1 (en) * 2005-08-23 2009-11-19 Katalin Kariko RNA containing modified nucleosides and methods of use thereof
WO2010144740A1 (en) * 2009-06-10 2010-12-16 Alnylam Pharmaceuticals, Inc. Improved lipid formulation
US20130115274A1 (en) * 2011-11-04 2013-05-09 Nitto Denko Corporation Method of producing lipid nanoparticles for drug delivery

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Semple et al.; Rational design of cationic lipids for siRNA delivery; Nature Biotechnology, Vol. 28, No. 2, pp. 172-176, published February 2010 *

Cited By (365)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11298426B2 (en) 2003-10-14 2022-04-12 BioNTech SE Recombinant vaccines and use thereof
US12385049B2 (en) 2005-09-28 2025-08-12 BioNTech SE Modification of RNA, producing an increased transcript stability and translation efficiency
US10106800B2 (en) 2005-09-28 2018-10-23 Biontech Ag Modification of RNA, producing an increased transcript stability and translation efficiency
US10576166B2 (en) 2009-12-01 2020-03-03 Translate Bio, Inc. Liver specific delivery of messenger RNA
US9447164B2 (en) 2010-08-06 2016-09-20 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
US9937233B2 (en) 2010-08-06 2018-04-10 Modernatx, Inc. Engineered nucleic acids and methods of use thereof
US9181319B2 (en) 2010-08-06 2015-11-10 Moderna Therapeutics, Inc. Engineered nucleic acids and methods of use thereof
US9701965B2 (en) 2010-10-01 2017-07-11 Modernatx, Inc. Engineered nucleic acids and methods of use thereof
US11135274B2 (en) 2010-11-30 2021-10-05 Translate Bio, Inc. MRNA for use in treatment of human genetic diseases
US9956271B2 (en) 2010-11-30 2018-05-01 Translate Bio, Inc. mRNA for use in treatment of human genetic diseases
US9061021B2 (en) 2010-11-30 2015-06-23 Shire Human Genetic Therapies, Inc. mRNA for use in treatment of human genetic diseases
US20140037560A1 (en) * 2011-02-01 2014-02-06 Isp Investments Inc. Novel peptides involved in the scf c-kit signaling pathway and compositions comprising same
US9364414B2 (en) 2011-02-01 2016-06-14 Isp Investments Inc. Method to protect skin from ultraviolet radiation using novel peptides involved in the improvement of microparasol organization in keratinocytes
US8962565B2 (en) * 2011-02-01 2015-02-24 Isp Investments Inc. Peptides involved in the SCF c-Kit signaling pathway and compositions comprising same
US12502431B2 (en) 2011-03-31 2025-12-23 Modernatx, Inc. Delivery and formulation of engineered nucleic acids
US12409226B2 (en) 2011-03-31 2025-09-09 Modernatx, Inc. Delivery and formulation of engineered nucleic acids
US12364763B2 (en) 2011-03-31 2025-07-22 Modernatx, Inc. Delivery and formulation of engineered nucleic acids
US9533047B2 (en) 2011-03-31 2017-01-03 Modernatx, Inc. Delivery and formulation of engineered nucleic acids
US11911474B2 (en) 2011-03-31 2024-02-27 Modernatx, Inc. Delivery and formulation of engineered nucleic acids
US12419957B2 (en) 2011-03-31 2025-09-23 Modernatx, Inc. Delivery and formulation of engineered nucleic acids
US9950068B2 (en) 2011-03-31 2018-04-24 Modernatx, Inc. Delivery and formulation of engineered nucleic acids
US10898574B2 (en) 2011-03-31 2021-01-26 Modernatx, Inc. Delivery and formulation of engineered nucleic acids
US11248264B2 (en) 2011-05-24 2022-02-15 Tron-Translationale Onkologie An Der Universitätsmedizin Der Johannes Gutenberg-Universität Mainz Ggmbh Individualized vaccines for cancer
US10738355B2 (en) 2011-05-24 2020-08-11 Tron-Translationale Onkologie An Der Universitätsmedizin Der Johannes Gutenberg-Universität Mainz Ggmbh Individualized vaccines for cancer
US11338044B2 (en) 2011-06-08 2022-05-24 Translate Bio, Inc. Lipid nanoparticle compositions and methods for mRNA delivery
US11185595B2 (en) 2011-06-08 2021-11-30 Translate Bio, Inc. Lipid nanoparticle compositions and methods for mRNA delivery
US10888626B2 (en) 2011-06-08 2021-01-12 Translate Bio, Inc. Lipid nanoparticle compositions and methods for mRNA delivery
US11052159B2 (en) 2011-06-08 2021-07-06 Translate Bio, Inc. Lipid nanoparticle compositions and methods for mRNA delivery
US11951180B2 (en) 2011-06-08 2024-04-09 Translate Bio, Inc. Lipid nanoparticle compositions and methods for MRNA delivery
US10507249B2 (en) 2011-06-08 2019-12-17 Translate Bio, Inc. Lipid nanoparticle compositions and methods for mRNA delivery
US10238754B2 (en) 2011-06-08 2019-03-26 Translate Bio, Inc. Lipid nanoparticle compositions and methods for MRNA delivery
US12121592B2 (en) 2011-06-08 2024-10-22 Translate Bio, Inc. Lipid nanoparticle compositions and methods for mRNA delivery
US10350303B1 (en) 2011-06-08 2019-07-16 Translate Bio, Inc. Lipid nanoparticle compositions and methods for mRNA delivery
US10413618B2 (en) 2011-06-08 2019-09-17 Translate Bio, Inc. Lipid nanoparticle compositions and methods for mRNA delivery
US11951181B2 (en) 2011-06-08 2024-04-09 Translate Bio, Inc. Lipid nanoparticle compositions and methods for mRNA delivery
US11730825B2 (en) 2011-06-08 2023-08-22 Translate Bio, Inc. Lipid nanoparticle compositions and methods for mRNA delivery
US11951179B2 (en) 2011-06-08 2024-04-09 Translate Bio, Inc. Lipid nanoparticle compositions and methods for MRNA delivery
US11547764B2 (en) 2011-06-08 2023-01-10 Translate Bio, Inc. Lipid nanoparticle compositions and methods for MRNA delivery
US11291734B2 (en) 2011-06-08 2022-04-05 Translate Bio, Inc. Lipid nanoparticle compositions and methods for mRNA delivery
US9186372B2 (en) 2011-12-16 2015-11-17 Moderna Therapeutics, Inc. Split dose administration
US9295689B2 (en) 2011-12-16 2016-03-29 Moderna Therapeutics, Inc. Formulation and delivery of PLGA microspheres
US10485884B2 (en) 2012-03-26 2019-11-26 Biontech Rna Pharmaceuticals Gmbh RNA formulation for immunotherapy
US11559587B2 (en) 2012-03-26 2023-01-24 Tron-Translationale Onkologie An Der Universitätsmedizin Der Johannes Gutenberg-Universität Mainz Ggmbh RNA formulation for immunotherapy
US9255129B2 (en) 2012-04-02 2016-02-09 Moderna Therapeutics, Inc. Modified polynucleotides encoding SIAH E3 ubiquitin protein ligase 1
US9301993B2 (en) 2012-04-02 2016-04-05 Moderna Therapeutics, Inc. Modified polynucleotides encoding apoptosis inducing factor 1
US9095552B2 (en) 2012-04-02 2015-08-04 Moderna Therapeutics, Inc. Modified polynucleotides encoding copper metabolism (MURR1) domain containing 1
US9587003B2 (en) 2012-04-02 2017-03-07 Modernatx, Inc. Modified polynucleotides for the production of oncology-related proteins and peptides
US9572897B2 (en) 2012-04-02 2017-02-21 Modernatx, Inc. Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
US10577403B2 (en) 2012-04-02 2020-03-03 Modernatx, Inc. Modified polynucleotides for the production of secreted proteins
US9107886B2 (en) 2012-04-02 2015-08-18 Moderna Therapeutics, Inc. Modified polynucleotides encoding basic helix-loop-helix family member E41
US9114113B2 (en) 2012-04-02 2015-08-25 Moderna Therapeutics, Inc. Modified polynucleotides encoding citeD4
US9782462B2 (en) 2012-04-02 2017-10-10 Modernatx, Inc. Modified polynucleotides for the production of proteins associated with human disease
US9814760B2 (en) 2012-04-02 2017-11-14 Modernatx, Inc. Modified polynucleotides for the production of biologics and proteins associated with human disease
US9828416B2 (en) 2012-04-02 2017-11-28 Modernatx, Inc. Modified polynucleotides for the production of secreted proteins
US9827332B2 (en) 2012-04-02 2017-11-28 Modernatx, Inc. Modified polynucleotides for the production of proteins
US10385106B2 (en) 2012-04-02 2019-08-20 Modernatx, Inc. Modified polynucleotides for the production of secreted proteins
US9303079B2 (en) 2012-04-02 2016-04-05 Moderna Therapeutics, Inc. Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins
US9878056B2 (en) 2012-04-02 2018-01-30 Modernatx, Inc. Modified polynucleotides for the production of cosmetic proteins and peptides
US9675668B2 (en) 2012-04-02 2017-06-13 Moderna Therapeutics, Inc. Modified polynucleotides encoding hepatitis A virus cellular receptor 2
US9283287B2 (en) 2012-04-02 2016-03-15 Moderna Therapeutics, Inc. Modified polynucleotides for the production of nuclear proteins
US10703789B2 (en) 2012-04-02 2020-07-07 Modernatx, Inc. Modified polynucleotides for the production of secreted proteins
US9149506B2 (en) 2012-04-02 2015-10-06 Moderna Therapeutics, Inc. Modified polynucleotides encoding septin-4
US9254311B2 (en) 2012-04-02 2016-02-09 Moderna Therapeutics, Inc. Modified polynucleotides for the production of proteins
US9233141B2 (en) 2012-04-02 2016-01-12 Moderna Therapeutics, Inc. Modified polynucleotides for the production of proteins associated with blood and lymphatic disorders
US9221891B2 (en) 2012-04-02 2015-12-29 Moderna Therapeutics, Inc. In vivo production of proteins
US9220755B2 (en) 2012-04-02 2015-12-29 Moderna Therapeutics, Inc. Modified polynucleotides for the production of proteins associated with blood and lymphatic disorders
US9220792B2 (en) 2012-04-02 2015-12-29 Moderna Therapeutics, Inc. Modified polynucleotides encoding aquaporin-5
US9216205B2 (en) 2012-04-02 2015-12-22 Moderna Therapeutics, Inc. Modified polynucleotides encoding granulysin
US9192651B2 (en) 2012-04-02 2015-11-24 Moderna Therapeutics, Inc. Modified polynucleotides for the production of secreted proteins
US10772975B2 (en) 2012-04-02 2020-09-15 Modernatx, Inc. Modified Polynucleotides for the production of biologics and proteins associated with human disease
US10245229B2 (en) 2012-06-08 2019-04-02 Translate Bio, Inc. Pulmonary delivery of mRNA to non-lung target cells
US11090264B2 (en) 2012-06-08 2021-08-17 Translate Bio, Inc. Pulmonary delivery of mRNA to non-lung target cells
US11254936B2 (en) 2012-06-08 2022-02-22 Translate Bio, Inc. Nuclease resistant polynucleotides and uses thereof
US9512456B2 (en) 2012-08-14 2016-12-06 Modernatx, Inc. Enzymes and polymerases for the synthesis of RNA
US9597380B2 (en) 2012-11-26 2017-03-21 Modernatx, Inc. Terminally modified RNA
US11504419B2 (en) 2012-11-28 2022-11-22 BioNTech SE Individualized vaccines for cancer
US10155031B2 (en) 2012-11-28 2018-12-18 Biontech Rna Pharmaceuticals Gmbh Individualized vaccines for cancer
US11787851B2 (en) 2013-02-15 2023-10-17 Bioverativ Therapeutics Inc. Optimized factor VIII gene
US10370431B2 (en) 2013-02-15 2019-08-06 Bioverativ Therapeutics Inc. Optimized factor VIII gene
US11603399B2 (en) 2013-03-13 2023-03-14 Modernatx, Inc. Long-lived polynucleotide molecules
US11510937B2 (en) 2013-03-14 2022-11-29 Translate Bio, Inc. CFTR MRNA compositions and related methods and uses
US9713626B2 (en) 2013-03-14 2017-07-25 Rana Therapeutics, Inc. CFTR mRNA compositions and related methods and uses
US11820977B2 (en) 2013-03-14 2023-11-21 Translate Bio, Inc. Methods for purification of messenger RNA
US11692189B2 (en) 2013-03-14 2023-07-04 Translate Bio, Inc. Methods for purification of messenger RNA
US12234446B2 (en) 2013-03-14 2025-02-25 Translate Bio, Inc. Methods for purification of messenger RNA
US9181321B2 (en) 2013-03-14 2015-11-10 Shire Human Genetic Therapies, Inc. CFTR mRNA compositions and related methods and uses
US10876104B2 (en) 2013-03-14 2020-12-29 Translate Bio, Inc. Methods for purification of messenger RNA
US10420791B2 (en) 2013-03-14 2019-09-24 Translate Bio, Inc. CFTR MRNA compositions and related methods and uses
US9957499B2 (en) 2013-03-14 2018-05-01 Translate Bio, Inc. Methods for purification of messenger RNA
US10087247B2 (en) 2013-03-14 2018-10-02 Translate Bio, Inc. Methods and compositions for delivering mRNA coded antibodies
US10584165B2 (en) 2013-03-14 2020-03-10 Translate Bio, Inc. Methods and compositions for delivering mRNA coded antibodies
US10258698B2 (en) 2013-03-14 2019-04-16 Modernatx, Inc. Formulation and delivery of modified nucleoside, nucleotide, and nucleic acid compositions
US10899830B2 (en) 2013-03-14 2021-01-26 Translate Bio, Inc. Methods and compositions for delivering MRNA coded antibodies
US10130649B2 (en) 2013-03-15 2018-11-20 Translate Bio, Inc. Synergistic enhancement of the delivery of nucleic acids via blended formulations
US10590161B2 (en) 2013-03-15 2020-03-17 Modernatx, Inc. Ion exchange purification of mRNA
US10077439B2 (en) 2013-03-15 2018-09-18 Modernatx, Inc. Removal of DNA fragments in mRNA production process
US10646504B2 (en) 2013-03-15 2020-05-12 Translate Bio, Inc. Synergistic enhancement of the delivery of nucleic acids via blended formulations
US11377470B2 (en) 2013-03-15 2022-07-05 Modernatx, Inc. Ribonucleic acid purification
US11845772B2 (en) 2013-03-15 2023-12-19 Modernatx, Inc. Ribonucleic acid purification
US10858647B2 (en) 2013-03-15 2020-12-08 Modernatx, Inc. Removal of DNA fragments in mRNA production process
US12453739B2 (en) 2013-03-15 2025-10-28 Translate Bio, Inc. Synergistic enhancement of the delivery of nucleic acids via blended formulations
US10138507B2 (en) 2013-03-15 2018-11-27 Modernatx, Inc. Manufacturing methods for production of RNA transcripts
US11222711B2 (en) 2013-05-10 2022-01-11 BioNTech SE Predicting immunogenicity of T cell epitopes
US20160120893A1 (en) * 2013-06-21 2016-05-05 President And Fellows Of Harvard College Methods and compositions relating to modulation of the permeability of the blood brain barrier
US11027025B2 (en) 2013-07-11 2021-06-08 Modernatx, Inc. Compositions comprising synthetic polynucleotides encoding CRISPR related proteins and synthetic sgRNAs and methods of use
US10023626B2 (en) 2013-09-30 2018-07-17 Modernatx, Inc. Polynucleotides encoding immune modulating polypeptides
US10815291B2 (en) 2013-09-30 2020-10-27 Modernatx, Inc. Polynucleotides encoding immune modulating polypeptides
US10385088B2 (en) 2013-10-02 2019-08-20 Modernatx, Inc. Polynucleotide molecules and uses thereof
US10052284B2 (en) 2013-10-22 2018-08-21 Translate Bio, Inc. Lipid formulations for delivery of messenger RNA
US9522176B2 (en) 2013-10-22 2016-12-20 Shire Human Genetic Therapies, Inc. MRNA therapy for phenylketonuria
US10780052B2 (en) 2013-10-22 2020-09-22 Translate Bio, Inc. CNS delivery of MRNA and uses thereof
US12016954B2 (en) 2013-10-22 2024-06-25 Translate Bio, Inc. CNS delivery of mRNA and uses thereof
US12509666B2 (en) 2013-10-22 2025-12-30 Translate Bio, Inc. MRNA therapy for phenylketonuria
US10208295B2 (en) 2013-10-22 2019-02-19 Translate Bio, Inc. MRNA therapy for phenylketonuria
US11224642B2 (en) 2013-10-22 2022-01-18 Translate Bio, Inc. MRNA therapy for argininosuccinate synthetase deficiency
US11377642B2 (en) 2013-10-22 2022-07-05 Translate Bio, Inc. mRNA therapy for phenylketonuria
US10959953B2 (en) 2013-10-22 2021-03-30 Translate Bio, Inc. Lipid formulations for delivery of messenger RNA
US11890377B2 (en) 2013-10-22 2024-02-06 Translate Bio, Inc. Lipid formulations for delivery of messenger RNA
US10493031B2 (en) 2013-10-22 2019-12-03 Translate Bio, Inc. Lipid formulations for delivery of messenger RNA
US9629804B2 (en) 2013-10-22 2017-04-25 Shire Human Genetic Therapies, Inc. Lipid formulations for delivery of messenger RNA
US12479928B2 (en) 2014-04-07 2025-11-25 Minerva Biotechnologies Corporation Anti-cancer peptide
US11702483B2 (en) * 2014-04-07 2023-07-18 Minerva Biotechnologies Corporation Method of treating an NME7 expressing cancer with a peptide
US9534225B2 (en) 2014-04-15 2017-01-03 Applied Genetic Technologies Corporation Codon optimized nucleic acid encoding a retinitis pigmentosa gtpase regulator (RPGR)
JP2017513484A (ja) * 2014-04-15 2017-06-01 アプライド ジェネティック テクノロジーズ コーポレイション 網膜色素変性症ｇｔｐアーゼレギュレーター（ｒｐｇｒ）をコードするコドン最適化核酸
WO2015160893A1 (en) * 2014-04-15 2015-10-22 Applied Genetic Technologies Corporation Codon optimized nucleic acid encoding a retinitis pigmentosa gtpase regulator (rpgr)
US9850269B2 (en) 2014-04-25 2017-12-26 Translate Bio, Inc. Methods for purification of messenger RNA
US10155785B2 (en) 2014-04-25 2018-12-18 Translate Bio, Inc. Methods for purification of messenger RNA
US12060381B2 (en) 2014-04-25 2024-08-13 Translate Bio, Inc. Methods for purification of messenger RNA
US11059841B2 (en) 2014-04-25 2021-07-13 Translate Bio, Inc. Methods for purification of messenger RNA
US11884692B2 (en) 2014-04-25 2024-01-30 Translate Bio, Inc. Methods for purification of messenger RNA
US10286083B2 (en) 2014-05-30 2019-05-14 Translate Bio, Inc. Biodegradable lipids for delivery of nucleic acids
US10912844B2 (en) 2014-05-30 2021-02-09 Translate Bio, Inc. Biodegradable lipids for delivery of nucleic acids
US10286082B2 (en) 2014-05-30 2019-05-14 Translate Bio, Inc. Biodegradable lipids for delivery of nucleic acids
US10022455B2 (en) 2014-05-30 2018-07-17 Translate Bio, Inc. Biodegradable lipids for delivery of nucleic acids
US11433144B2 (en) 2014-05-30 2022-09-06 Translate Bio, Inc. Biodegradable lipids for delivery of nucleic acids
US10293057B2 (en) 2014-05-30 2019-05-21 Translate Bio, Inc. Biodegradable lipids for delivery of nucleic acids
US10493166B2 (en) 2014-05-30 2019-12-03 Translate Bio, Inc. Biodegradable lipids for delivery of nucleic acids
WO2015196128A3 (en) * 2014-06-19 2016-05-19 Moderna Therapeutics, Inc. Alternative nucleic acid molecules and uses thereof
WO2015196130A3 (en) * 2014-06-19 2016-03-03 Moderna Therapeutics, Inc. Alternative nucleic acid molecules and uses thereof
US10286086B2 (en) 2014-06-19 2019-05-14 Modernatx, Inc. Alternative nucleic acid molecules and uses thereof
US10138213B2 (en) 2014-06-24 2018-11-27 Translate Bio, Inc. Stereochemically enriched compositions for delivery of nucleic acids
US11104652B2 (en) 2014-06-24 2021-08-31 Translate Bio, Inc. Stereochemically enriched compositions for delivery of nucleic acids
US12275970B2 (en) 2014-06-30 2025-04-15 Bioverativ Therapeutics Inc. Optimized factor IX gene
WO2016004113A1 (en) * 2014-06-30 2016-01-07 Biogen Ma Inc. Optimized factor ix gene
US11008561B2 (en) 2014-06-30 2021-05-18 Bioverativ Therapeutics Inc. Optimized factor IX gene
US9668980B2 (en) 2014-07-02 2017-06-06 Rana Therapeutics, Inc. Encapsulation of messenger RNA
US10407683B2 (en) 2014-07-16 2019-09-10 Modernatx, Inc. Circular polynucleotides
US10428156B2 (en) 2014-09-05 2019-10-01 Abbvie Stemcentrx Llc Anti-MFI2 antibodies and methods of use
US11173120B2 (en) 2014-09-25 2021-11-16 Biontech Rna Pharmaceuticals Gmbh Stable formulations of lipids and liposomes
US12220484B2 (en) 2014-09-25 2025-02-11 BioNTech SE Stable formulations of lipids and liposomes
WO2016049487A1 (en) * 2014-09-26 2016-03-31 Dow Agrosciences Llc Heterologous expression of glycine n-acyltransferase proteins
US10385380B2 (en) 2014-10-02 2019-08-20 The Regents Of The University Of California Personalized protease assay to measure protease activity in neoplasms
WO2016054554A1 (en) * 2014-10-03 2016-04-07 University Of Massachusetts Heterologous targeting peptide grafted aavs
US11014976B2 (en) 2014-10-03 2021-05-25 University Of Massachusetts Heterologous targeting peptide grafted AAVS
US10711270B2 (en) 2014-10-03 2020-07-14 University Of Massachusetts High efficiency library-identified AAV vectors
US12091659B2 (en) 2014-10-03 2024-09-17 University Of Massachusetts High efficiency library-identified AAV vectors
US10370432B2 (en) 2014-10-03 2019-08-06 University Of Massachusetts Heterologous targeting peptide grafted AAVS
US12291719B2 (en) 2014-10-03 2025-05-06 University Of Massachusetts Heterologous targeting peptide grafted AAVs
US11529417B2 (en) 2014-11-25 2022-12-20 Northwestern University Wound healing through sirt1 overexpression
US20180303941A1 (en) * 2014-11-25 2018-10-25 Northwestern University Wound healing through sirt1 overexpression
US10653782B2 (en) * 2014-11-25 2020-05-19 Nortwestern University Retroviral particles expressing Sirt1 embedded within PPCN
WO2016086088A3 (en) * 2014-11-25 2016-08-18 Northwestern University Wound healing through sirt1 overexpression
US9943595B2 (en) 2014-12-05 2018-04-17 Translate Bio, Inc. Messenger RNA therapy for treatment of articular disease
US10864267B2 (en) 2014-12-05 2020-12-15 Translate Bio, Inc. Messenger RNA therapy for treatment of articular disease
US11998601B2 (en) 2014-12-05 2024-06-04 Translate Bio, Inc. Messenger RNA therapy for treatment of articular disease
US11130811B2 (en) 2015-01-28 2021-09-28 Glaxosmithkline Intellectual Property Development Limited ICOS binding proteins
US10351627B2 (en) 2015-01-28 2019-07-16 Glaxosmithkline Intellectual Property Development Limited ICOS binding proteins
US9738718B2 (en) 2015-01-28 2017-08-22 Glaxosmithkline Intellectual Property Development Limited ICOS binding proteins
US9771424B2 (en) 2015-01-28 2017-09-26 Glaxosmithkline Intellectual Property Development Limited ICOS binding proteins
US11156617B2 (en) 2015-02-12 2021-10-26 BioNTech RNA Pharmaceuticals GbmH Predicting T cell epitopes useful for vaccination
US10584321B2 (en) 2015-02-13 2020-03-10 University Of Massachusetts Compositions and methods for transient delivery of nucleases
US11920168B2 (en) 2015-02-13 2024-03-05 University Of Massachusetts Compositions and methods for transient delivery of nucleases
US10172924B2 (en) 2015-03-19 2019-01-08 Translate Bio, Inc. MRNA therapy for pompe disease
US11712463B2 (en) 2015-03-19 2023-08-01 Translate Bio, Inc. MRNA therapy for pompe disease
US11090368B2 (en) 2015-03-19 2021-08-17 Translate Bio, Inc. MRNA therapy for Pompe disease
US12370268B2 (en) 2015-05-11 2025-07-29 Ucl Business Ltd Fabry disease gene therapy
US11103596B2 (en) 2015-05-11 2021-08-31 Ucl Business Plc Fabry disease gene therapy
US11084852B2 (en) 2015-06-15 2021-08-10 Oklahoma Medical Research Foundation Ubiquitin interacting motif peptides as therapeutics
WO2016205027A1 (en) * 2015-06-15 2016-12-22 Oklahoma Medical Research Foundation Ubiquitin interacting motif peptides as therapeutics
WO2017019756A1 (en) * 2015-07-28 2017-02-02 Lankaneu Institute For Medical Research Methods and compositions for the treatment of immunomodulatory diseases and disorders
US11951160B2 (en) 2015-08-28 2024-04-09 Immatics Biotechnologies Gmbh Peptides and T cells for use in immunotherapeutic treatment of various cancers
US11541107B2 (en) 2015-08-28 2023-01-03 Immatics Biotechnologies Gmbh Peptides and T cells for use in immunotherapeutic treatment of various cancers
US11975058B2 (en) 2015-08-28 2024-05-07 Immatics Biotechnologies Gmbh Peptides and T cells for use in immunotherapeutic treatment of various cancers
US11576954B2 (en) 2015-08-28 2023-02-14 Immatics Biotechnologies Gmbh Method for treating non-small lung cancer with a population of activated cells
US12156905B2 (en) 2015-08-28 2024-12-03 Immatics Biotechnologies Gmbh CCR8 peptide and T cells for use in immunotherapeutic treatment of various cancers
US11957742B2 (en) 2015-08-28 2024-04-16 Immatics Biotechnologies Gmbh Method for treating non-small lung cancer with a population of activated T cells
US12023372B2 (en) 2015-08-28 2024-07-02 Immatics Biotechnologies Gmbh Peptides and T cells for use in immunotherapeutic treatment of various cancers
US11744882B2 (en) 2015-08-28 2023-09-05 Immatics Biotechnologies Gmbh Peptides and T cells for use in immunotherapeutic treatment of various cancers
US12029785B2 (en) 2015-08-28 2024-07-09 Immatics Biotechnologies Gmbh GINS2 peptide and T cells for use in immunotherapeutic treatment of various cancers
US11559572B2 (en) 2015-08-28 2023-01-24 Immatics Biotechnologies Gmbh Peptides and T cells for use in immunotherapeutic treatment of various cancers
US11793866B2 (en) 2015-08-28 2023-10-24 Immatics Biotechnologies Gmbh Peptides and T cells for use in immunotherapeutic treatment of various cancers
US11065316B2 (en) 2015-08-28 2021-07-20 Immatics Biotechnologies Gmbh Peptides and T cells for use in immunother[[r]]apeutic treatment of various cancers
US11547750B2 (en) 2015-08-28 2023-01-10 Immatics Biotechnologies Gmbh Peptides and T cells for use in immunotherapeutic treatment hepatocellular carcinoma
US12071620B2 (en) 2015-09-17 2024-08-27 Modernatx, Inc. Polynucleotides containing a morpholino linker
US11434486B2 (en) 2015-09-17 2022-09-06 Modernatx, Inc. Polynucleotides containing a morpholino linker
US12109274B2 (en) 2015-09-17 2024-10-08 Modernatx, Inc. Polynucleotides containing a stabilizing tail region
US9713641B2 (en) 2015-10-01 2017-07-25 Potenza Therapeutics, Inc. Anti-TIGIT antigen-binding proteins and methods of use thereof
US11590224B2 (en) 2015-10-01 2023-02-28 Potenza Therapeutics, Inc. Anti-TIGIT antigen-binding proteins and methods of uses thereof
US10507244B2 (en) 2015-10-01 2019-12-17 Potenza Therapeutics, Inc. Anti-TIGIT antigen-binding proteins and methods of use thereof
US11590157B2 (en) 2015-10-05 2023-02-28 Modernatx, Inc. Methods for therapeutic administration of messenger ribonucleic acid drugs
US10849920B2 (en) 2015-10-05 2020-12-01 Modernatx, Inc. Methods for therapeutic administration of messenger ribonucleic acid drugs
US12246030B2 (en) 2015-10-05 2025-03-11 Modernatx, Inc. Methods for therapeutic administration of messenger ribonucleic acid drugs
US11492628B2 (en) 2015-10-07 2022-11-08 BioNTech SE 3′-UTR sequences for stabilization of RNA
US12516333B2 (en) 2015-10-07 2026-01-06 BioNTech SE 3′-UTR sequences for stabilization of RNA
US10144942B2 (en) 2015-10-14 2018-12-04 Translate Bio, Inc. Modification of RNA-related enzymes for enhanced production
US10995354B2 (en) 2015-10-14 2021-05-04 Translate Bio, Inc. Modification of RNA-related enzymes for enhanced production
US10519445B2 (en) * 2015-11-05 2019-12-31 The General Hospital Corporation Intrathecal delivery of nucleic acid sequences encoding ABCD1 for treatment of adrenomyeloneuropathy
US20180320176A1 (en) * 2015-11-05 2018-11-08 The General Hospital Corporation Intrathecal delivery of nucleic acid sequences encoding abcd1 for treatment of adrenomyeloneuropathy
US12472239B2 (en) 2015-11-16 2025-11-18 Research Institute At Nationwide Children's Hospital Guide RNA for repairing a mutant human titin gene using CRISPR technology
US12403204B2 (en) 2015-12-14 2025-09-02 The Trustees Of The University Of Pennsylvania Gene therapy for ocular disorders
US11090392B2 (en) 2015-12-14 2021-08-17 The Trustees Of The University Of Pennsylvania Gene therapy for ocular disorders
US10576168B2 (en) * 2015-12-16 2020-03-03 Ucl Business Ltd Treatment of lysosomal storage diseases
US11473083B2 (en) 2015-12-21 2022-10-18 Novartis Ag Compositions and methods for decreasing tau expression
US11753461B2 (en) 2016-02-01 2023-09-12 Bioverativ Therapeutics Inc. Optimized factor VIII genes
WO2017173256A1 (en) * 2016-04-01 2017-10-05 Kite Pharma, Inc. Chimeric antigen and t cell receptors and methods of use
US11505613B2 (en) 2016-04-01 2022-11-22 Kite Pharma, Inc. BCMA binding molecules and methods of use thereof
US10603380B2 (en) 2016-04-01 2020-03-31 Kite Pharma, Inc. Chimeric antigen and T cell receptors and methods of use
US10597456B2 (en) 2016-04-01 2020-03-24 Amgen Inc. Chimeric receptors and methods of use thereof
US10689450B2 (en) 2016-04-01 2020-06-23 Kite Pharma, Inc BCMA binding molecules and methods of use thereof
US10266843B2 (en) 2016-04-08 2019-04-23 Translate Bio, Inc. Multimeric coding nucleic acid and uses thereof
US11124804B2 (en) 2016-04-08 2021-09-21 Translate Bio, Inc. Multimeric coding nucleic acid and uses thereof
US10428349B2 (en) 2016-04-08 2019-10-01 Translate Bio, Inc. Multimeric coding nucleic acid and uses thereof
US11358993B2 (en) 2016-04-15 2022-06-14 Research Institute At Nationwide Children's Hospital Adeno-associated virus vector delivery of B-sarcoglycan and microrna-29 and the treatment of muscular dystrophy
US11286501B2 (en) 2016-04-20 2022-03-29 Centro De Investigaciones Energeticas, Medioambientales Y Tecnologicas O.A, M.P. Methods of treating or preventing pyruvate kinase deficiency
US12163151B2 (en) 2016-04-20 2024-12-10 Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas O.A, M.P. Methods of treating or preventing pyruvate kinase deficiency
US11078247B2 (en) 2016-05-04 2021-08-03 Curevac Ag RNA encoding a therapeutic protein
US12227549B2 (en) 2016-05-04 2025-02-18 CureVac SE RNA encoding a therapeutic protein
US12239742B2 (en) * 2016-05-18 2025-03-04 Modernatx, Inc. Polynucleotides encoding Citrin for the treatment of Citrullinemia type 2
US11649461B2 (en) 2016-05-18 2023-05-16 Modernatx, Inc. Polynucleotides encoding α-galactosidase A for the treatment of Fabry disease
US10494636B2 (en) 2016-05-18 2019-12-03 Modernatx, Inc. Polynucleotides encoding α-galactosidase A for the treatment of Fabry disease
US12377136B2 (en) * 2016-05-18 2025-08-05 Modernatx, Inc. Polynucleotides encoding porphobilinogen deaminase for the treatment of acute intermittent porphyria
US20230112986A1 (en) * 2016-05-18 2023-04-13 Modernatx, Inc. Polynucleotides encoding porphobilinogen deaminase for the treatment of acute intermittent porphyria
US20220071915A1 (en) * 2016-05-18 2022-03-10 Modernatx, Inc. Polynucleotides encoding citrin for the treatment of citrullinemia type 2
US10519455B2 (en) 2016-05-18 2019-12-31 Modernatx, Inc. Polynucleotides encoding alpha-galactosidase A for the treatment of Fabry disease
AU2024200877B2 (en) * 2016-05-27 2025-01-23 Transcriptx, Inc. Treatment of primary ciliary dyskinesia with synthetic messenger RNA
US11786610B2 (en) 2016-05-27 2023-10-17 Transcriptx, Inc. Treatment of primary ciliary dyskinesia with synthetic messenger RNA
US11642421B2 (en) 2016-05-27 2023-05-09 Transcriptx, Inc. Treatment of primary ciliary dyskinesia with synthetic messenger RNA
US20190117796A1 (en) * 2016-05-27 2019-04-25 Transcriptx, Inc. Treatment of primary ciliary dyskinesia with synthetic messenger rna
US12201677B2 (en) 2016-06-13 2025-01-21 Translate Bio, Inc. Messenger RNA therapy for the treatment of ornithine transcarbamylase deficiency
US10835583B2 (en) 2016-06-13 2020-11-17 Translate Bio, Inc. Messenger RNA therapy for the treatment of ornithine transcarbamylase deficiency
US12257321B2 (en) 2016-06-21 2025-03-25 The University Of North Carolina At Chapel Hill Optimized mini-dystrophin genes and expression cassettes and their use
US11547765B2 (en) 2016-06-21 2023-01-10 The University Of North Carolina At Chapel Hill Optimized mini-dystrophin genes and expression cassettes and their use
US12385034B2 (en) 2016-06-24 2025-08-12 Modernatx, Inc. Methods and apparatus for filtration
US11191849B2 (en) 2016-06-30 2021-12-07 Arbutus Biopharma Corporation Compositions and methods for delivering messenger RNA
US10927383B2 (en) * 2016-06-30 2021-02-23 Ethris Gmbh Cas9 mRNAs
US12419973B2 (en) 2016-07-08 2025-09-23 The Trustees Of The University Of Pennsylvania Methods and compositions for treatment of disorders and diseases involving RDH12
RU2764920C2 (ru) * 2016-07-08 2022-01-24 Зе Трастис Оф Зе Юниверсити Оф Пенсильвания Способы и композиции для лечения нарушений и заболеваний, связанных с rdh12
US11197936B2 (en) 2016-07-08 2021-12-14 The Trustees Of The University Of Pennsylvania Methods and compositions for treatment of disorders and diseases involving RDH12
WO2018009814A1 (en) * 2016-07-08 2018-01-11 The Trustees Of The University Of Pennsylvania Methods and compositions for treatment of disorders and diseases involving rdh12
TWI796299B (zh) * 2016-08-26 2023-03-21 德商英麥提克生物技術股份有限公司 用於頭頸鱗狀細胞癌和其他癌症免疫治療的新型肽和支架
US12221468B2 (en) 2016-08-26 2025-02-11 Immatics Biotechnologies Gmbh Peptides and scaffolds for use in immunotherapy against head and neck squamous cell carcinoma and other cancers
US11505574B2 (en) 2016-11-29 2022-11-22 The Regents Of The University Of California Modulation of P53 for the treatment of cancer
US10558661B2 (en) 2016-11-29 2020-02-11 Sap Se Query plan generation based on table adapter
WO2018102317A1 (en) * 2016-11-29 2018-06-07 The Regents Of The University Of California Modulation of p53 for the treatment of cancer
US11142570B2 (en) 2017-02-17 2021-10-12 Bristol-Myers Squibb Company Antibodies to alpha-synuclein and uses thereof
US11827695B2 (en) 2017-02-17 2023-11-28 Bristol-Myers Squibb Company Antibodies to alpha-synuclein and uses thereof
US11253605B2 (en) 2017-02-27 2022-02-22 Translate Bio, Inc. Codon-optimized CFTR MRNA
US11266677B2 (en) 2017-03-10 2022-03-08 Memorial Sloan Kettering Cancer Center Methods for treatment or prevention of leukemia
WO2018165482A1 (en) * 2017-03-10 2018-09-13 Memorial Sloan Kettering Cancer Center Methods for treatment or prevention of leukemia
US11453720B2 (en) 2017-03-30 2022-09-27 Potenza Therapeutics, Inc. Anti-TIGIT antigen-binding proteins and methods of use thereof
US10640766B2 (en) 2017-04-12 2020-05-05 Tempo Bioscience, Inc. Biosensors for chloride ions
WO2018191322A1 (en) * 2017-04-12 2018-10-18 Tempo Bioscience, Inc. Biosensors for cellular osmolarity
US10571480B2 (en) 2017-04-12 2020-02-25 Tempo Bioscience, Inc. Biosensors for cellular osmolarity
US11173190B2 (en) 2017-05-16 2021-11-16 Translate Bio, Inc. Treatment of cystic fibrosis by delivery of codon-optimized mRNA encoding CFTR
WO2018217982A1 (en) * 2017-05-26 2018-11-29 The Wistar Institute Of Anatomy And Biology Dtert vaccines and methods of treatment using the same
US11945851B2 (en) 2017-06-07 2024-04-02 The Wistar Institute Of Anatomy And Biology MAGE-A vaccines and methods of treatment using the same
WO2018226931A1 (en) * 2017-06-07 2018-12-13 David Weiner Mage-a vaccines and methods of treatment using the same
US12270813B2 (en) 2017-06-09 2025-04-08 BioNTech SE Methods for predicting the usefulness of disease specific amino acid modifications for immunotherapy
US11827898B2 (en) 2017-06-14 2023-11-28 The Trustees Of The University Of Pennsylvania Gene therapy for ocular disorders
WO2018232149A1 (en) * 2017-06-14 2018-12-20 The Trustees Of The University Of Pennsylvania Gene therapy for ocular disorders
WO2019009979A1 (en) * 2017-07-06 2019-01-10 The Medical College Of Wisconsin, Inc. NEW IN VITRO AND IN VIVO ENRICHMENT STRATEGY TARGETING CSH-DERIVED LYMPHOCYTES TRANSDUCED BY A VECTOR FOR DISEASE THERAPY
US11597917B2 (en) 2017-07-06 2023-03-07 The Medical College Of Wisconsin, Inc. In vitro and in vivo enrichment strategy targeting lymphocytes derived from vector transduced HSCs for therapy of disorders
US10329349B2 (en) 2017-07-27 2019-06-25 Iteos Therapeutics Sa Anti-TIGIT antibodies
US11439705B2 (en) 2017-07-27 2022-09-13 iTeos Belgium SA Anti-TIGIT antibodies
US20200255859A1 (en) * 2017-07-31 2020-08-13 Reflection Biotechnologies Limited Cellular models of and therapies for ocular diseases
WO2019028281A3 (en) * 2017-08-02 2019-04-11 The Regents Of The University Of California OPTIMIZED PEPTIDES FOR TARGETING HUMAN NERFS AND THEIR USE IN GUIDED SURGERY THROUGH THE IMAGING, DIAGNOSTICS AND ADMINISTRATION OF THERAPEUTIC AGENTS
US11299515B2 (en) 2017-08-02 2022-04-12 The Regents Of The University Of California Optimized peptides for targeting human nerves and their use in image guided surgery, diagnostics and therapeutic
US11021517B2 (en) 2017-08-02 2021-06-01 The Regents Of The University Of California Optimized peptides for targeting human nerves and their use in image guided surgery, diagnostics and therapeutic delivery
US11802138B2 (en) 2017-08-02 2023-10-31 The Regents Of The University Of California Optimized peptides for targeting human nerves and their use in image guided surgery, diagnostic and therapeutic delivery
US11788093B2 (en) 2017-09-07 2023-10-17 University Of Florida Research Foundation, Inc. Chimeric antigen receptor t-cells expressing interleukin-8 receptor
WO2019051047A1 (en) * 2017-09-07 2019-03-14 University Of Florida Research Foundation, Inc. CHIMERIC ANTIGEN RECEPTOR T-LYMPHOCYTES EXPRESSING THE INTERLEUKIN-8 RECEPTOR
WO2019079338A1 (en) * 2017-10-16 2019-04-25 Centro de Investigaciones Energeticas, Medioambientales Y Tecnologicas, O.A., M.P. LENTIVIRAL VECTORS FOR PKLR ADMINISTRATION TO TREAT PYRUVATE KINASE DEFICIENCY
US11642422B2 (en) 2017-10-16 2023-05-09 Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, O.A, M.P. Lentiviral vectors for delivery of PKLR to treat pyruvate kinase deficiency
US12496359B2 (en) 2017-10-16 2025-12-16 Centro de Investigaciones Energéticas, Medioambientales y Tecnológicas, O.A, M.P. Lentiviral vectors for delivery of PKLR to treat Pyruvate Kinase Deficiency
WO2019113123A1 (en) * 2017-12-04 2019-06-13 Precithera, Inc. TGF-ß RECEPTOR FUSION PROTEINS AND OTHER TGF-ß ANTAGONISTS FOR REDUCING TGF-ß SIGNALING
RU2830879C2 (ru) * 2017-12-13 2024-11-26 Иновио Фармасьютикалз, Инк. Мезотелин-нацеленные вакцины от рака и их применение
WO2019118760A1 (en) * 2017-12-13 2019-06-20 Inovio Pharmaceuticals, Inc. Cancer vaccines targeting mesothelin and uses thereof
RU2751252C1 (ru) * 2017-12-13 2021-07-12 Иновио Фармасьютикалз, Инк. Мезотелин-нацеленные вакцины от рака и их применение
US11154602B2 (en) 2017-12-13 2021-10-26 Inovio Pharmaceuticals, Inc. Cancer vaccines targeting mesothelin and uses thereof
US11986517B2 (en) 2017-12-13 2024-05-21 Inovio Pharmaceuticals, Inc. Cancer vaccines targeting mesothelin and uses thereof
US11167043B2 (en) 2017-12-20 2021-11-09 Translate Bio, Inc. Composition and methods for treatment of ornithine transcarbamylase deficiency
US12268754B2 (en) 2017-12-20 2025-04-08 Translate Bio, Inc. Composition and methods for treatment of ornithine transcarbamylase deficiency
US12263230B2 (en) 2018-01-31 2025-04-01 Research Institute At Nationwide Children's Hospital Gene therapy for limb-girdle muscular dystrophy type 2C
US12162994B2 (en) 2018-03-02 2024-12-10 Sigilon Therapeutics, Inc. Biocompatible hydrogel capsules and process for preparing same
US12161760B2 (en) 2018-04-04 2024-12-10 Sigilon Therapeutics, Inc. Implantable particles and related methods
WO2019210325A1 (en) * 2018-04-27 2019-10-31 Rocket Pharmaceuticals, Ltd. Gene therapy for cns degeneration
US12378576B2 (en) 2018-04-27 2025-08-05 Spacecraft Seven, Llc Gene therapy for CNS degeneration
US12239693B2 (en) 2018-04-27 2025-03-04 The Medical College Of Wisconsin, Inc. Use of lentivector-transduced T-Rapa cells for amelioration of lysosomal storage disorders
US11884716B2 (en) 2018-05-02 2024-01-30 The Trustees Of The University Of Pennsylvania Compositions and methods of phospholipase A2 receptor chimeric autoantibody receptor T cells
WO2019213434A1 (en) * 2018-05-02 2019-11-07 The Trustees Of The University Of Pennsylvania Compositions and methods of phospholipase a2 receptor chimeric autoantibody receptor t cells
US12391928B2 (en) 2018-06-29 2025-08-19 Research Institute At Nationwide Children's Hospital Recombinant adeno-associated virus products and methods for treating limb girdle muscular dystrophy 2A
US20200061211A1 (en) * 2018-08-22 2020-02-27 Blueallele, Llc Methods for delivering gene editing reagents to cells within organs
US11401339B2 (en) 2018-08-23 2022-08-02 Seagen Inc. Anti-TIGIT antibodies
US11174500B2 (en) 2018-08-24 2021-11-16 Translate Bio, Inc. Methods for purification of messenger RNA
US12084702B2 (en) 2018-08-24 2024-09-10 Translate Bio, Inc. Methods for purification of messenger RNA
CN109385487A (zh) * 2018-09-11 2019-02-26 浙江省食品药品检验研究院 贵细中草药西洋参的重组酶介导扩增恒温检测方法及试剂盒
US12453740B2 (en) 2018-09-25 2025-10-28 Emory University Nucleic acids for cell recognition and integration
US20220010281A1 (en) * 2018-10-29 2022-01-13 Ottawa Hospital Research Institute Genetically-engineered mesenchymal stem cells overexpressing aoah and uses thereof
US20210395751A1 (en) * 2018-10-31 2021-12-23 The University Of Sydney Compositions and methods for treating viral infections
US12195505B2 (en) 2018-11-21 2025-01-14 Translate Bio, Inc. Treatment of cystic fibrosis by delivery of nebulized mRNA encoding CFTR
US12365732B2 (en) 2018-12-20 2025-07-22 23Andme, Inc. Anti-CD96 antibodies and methods of use thereof
US11555073B2 (en) 2018-12-20 2023-01-17 23Andme, Inc. Anti-CD96 antibodies and methods of use thereof
US20220127318A1 (en) * 2019-01-15 2022-04-28 Cornell University Recombinant lubricins, and compositions and methods for using the same
US12304934B2 (en) * 2019-01-15 2025-05-20 Cornell University Recombinant lubricins, and compositions and methods for using the same
US12037413B2 (en) 2019-02-04 2024-07-16 Minerva Biotechnologies Corporation Anti-NME antibody and method of treating cancer or cancer metastasis
US12377170B2 (en) 2019-02-26 2025-08-05 Research Institute At Nationwide Children's Hospital Adeno-associated virus vector delivery of β-sarcoglycan and the treatment of muscular dystrophy
WO2020198685A1 (en) * 2019-03-27 2020-10-01 Sigilon Therapeutics, Inc. Compositions, devices and methods for treating fabry disease
WO2020219766A1 (en) * 2019-04-24 2020-10-29 The Trustees Of The University Of Pennsylvania Compositions useful in treatment of rett syndrome
US20210123077A1 (en) * 2019-04-27 2021-04-29 Ocugen, Inc. Adeno-associated virus vector mediated gene therapy for ophthalmic diseases
WO2020257731A1 (en) * 2019-06-20 2020-12-24 The Trustees Of The University Of Pennsylvania Compositions and methods for treatment of maple syrup urine disease
US12258573B2 (en) 2019-08-21 2025-03-25 Research Institute At Nationwide Children's Hospital Adeno-associated virus vector delivery of alpha-sarcoglycan and the treatment of muscular dystrophy
US12403164B2 (en) 2019-09-30 2025-09-02 Bioverativ Therapeutics Inc. Lentiviral vector formulations
WO2021067687A1 (en) * 2019-10-03 2021-04-08 Board Of Regents, The University Of Texas System Vcx/y peptides and use thereof
WO2021087282A1 (en) * 2019-10-30 2021-05-06 Amicus Therapeutics, Inc. Recombinant cdkl5 proteins, gene therapy and production methods
WO2021097088A1 (en) * 2019-11-12 2021-05-20 University Of Virginia Patent Foundation Optidicer construct for age-related macular degeneration
US20220401580A1 (en) * 2019-11-12 2022-12-22 University Of Virginia Patent Foundation Optidicer construct for age-related macular degeneration
WO2021163695A3 (en) * 2020-02-14 2021-09-23 H. Lee Moffitt Cancer Center And Research Institute, Inc. Novel t cell receptors (tcrs) that react to neoantigens
US20230265386A1 (en) * 2020-02-21 2023-08-24 Sky Perfect International Limited Methods and compositions for modulating arginine levels in immune cells
WO2021211614A1 (en) * 2020-04-14 2021-10-21 University Of Florida Research Foundation, Incorporated Aav-based gene therapies for treatment of autoimmune diseases
US12297444B2 (en) 2020-04-14 2025-05-13 University Of Florida Research Foundation, Incorporated AAV-based gene therapies for treatment of autoimmune diseases
WO2021222118A1 (en) * 2020-04-27 2021-11-04 The Trustees Of The University Of Pennsylvania Compositions useful in treatment of cdkl5 deficiency disorder (cdd)
US12049514B2 (en) 2020-06-08 2024-07-30 Minerva Biotechnologies Corporation Anti-NME antibody and method of treating cancer or cancer metastasis
US12173307B2 (en) 2020-06-24 2024-12-24 Bioverativ Therapeutics Inc. Methods for the purification of viral vectors
US12415868B1 (en) 2020-06-26 2025-09-16 Minerva Biotechnologies Corporation Anti-NME antibody and method of treating cancer or cancer metastasis
WO2022026516A1 (en) * 2020-07-29 2022-02-03 The Board Of Regents Of The University Of Texas System Transgene cassettes, aav vectors, and aav viral vectors for expression of human codon-optimized cstb
US11946065B2 (en) 2020-07-29 2024-04-02 The Board Of Regents Of The University Of Texas System Transgene cassettes, AAV vectors, and AAV viral vectors for expression of human codon-optimized CSTB
WO2022031708A1 (en) * 2020-08-03 2022-02-10 Prevail Therapeutics, Inc. Aav vectors encoding parkin and uses thereof
US12492422B2 (en) 2020-09-11 2025-12-09 Sunbird Bio, Inc. Ex vivo protease activity detection for disease detection/diagnostic, staging, monitoring and treatment
US12305217B2 (en) * 2020-09-11 2025-05-20 Sunbird Bio, Inc. Ex vivo protease activity detection for disease detection/diagnostic, staging, monitoring and treatment
US20230341397A1 (en) * 2020-09-11 2023-10-26 Montana Molecular Llc Protease biosensors and methods of virus detection
US20230175037A1 (en) * 2020-09-11 2023-06-08 Glympse Bio, Inc. Ex vivo protease activity detection for disease detection/diagnostic, staging, monitoring and treatment
WO2022072325A1 (en) * 2020-09-29 2022-04-07 NeuExcell Therapeutics Inc. Neurod1 combination vector
US20230405109A1 (en) * 2020-11-11 2023-12-21 City Of Hope Nucleic acids, proteins, and vaccines of sars-cov-2
WO2022147249A1 (en) * 2020-12-30 2022-07-07 Mayo Foundation For Medical Education And Research Suppression-replacement gene therapy
US12161729B2 (en) 2021-01-14 2024-12-10 Alume Biosciences, Inc. Methods and compositions for visualizing a ureter in a surgical procedure
US12104181B2 (en) * 2021-03-31 2024-10-01 The Board Of Regents Of The University Of Texas System Compositions and methods for treating viral infections targeting TRIM7
US20220325255A1 (en) * 2021-03-31 2022-10-13 The Board Of Regents Of The University Of Texas System Compositions and methods for treating viral infections targeting trim7
US12173061B2 (en) * 2021-04-09 2024-12-24 Board Of Regents, The University Of Texas System Compositions and methods for treatment of chronic lung diseases
WO2022217037A1 (en) * 2021-04-09 2022-10-13 Board Of Regents, The University Of Texas System Compositions and methods for treatment of chronic lung diseases
US20240067713A1 (en) * 2021-04-09 2024-02-29 Board Of Regents, The University Of Texas System Compositions and methods for treatment of chronic lung diseases
WO2022221320A1 (en) * 2021-04-12 2022-10-20 The Regents Of The University Of California Gene therapy for arrhythmogenic right ventricular cardiomyopathy
WO2023019193A1 (en) * 2021-08-11 2023-02-16 The Trustees Of Indiana University Epigenetic modulators for tissue reprogramming
WO2023049846A1 (en) * 2021-09-24 2023-03-30 The Trustees Of The University Of Pennsylvania Compositions useful for treatment of charcot-marie-tooth disease
US12285497B2 (en) 2021-10-15 2025-04-29 Research Institute At Nationwide Children's Hospital Self-complementary adeno-associated virus vector and its use in treatment of muscular dystrophy
WO2023196539A3 (en) * 2022-04-07 2023-11-23 Aleta Biotherapeutics Inc. Compositions and methods for treatment of cancer
WO2023230003A1 (en) * 2022-05-23 2023-11-30 Yale University Compositions and methods for treating liver disease
WO2024026336A3 (en) * 2022-07-26 2024-04-11 The Board Of Trustees Of The Leland Stanford Junior University Methods and reagents for detection, quantitation, and genotyping of epstein-barr virus
WO2024042236A1 (en) 2022-08-26 2024-02-29 Ethris Gmbh Stable lipid or lipidoid nanoparticle suspensions
EP4327829A1 (en) 2022-08-26 2024-02-28 Ethris GmbH Stabilization of lipid or lipidoid nanoparticle suspensions
WO2024097737A1 (en) * 2022-11-01 2024-05-10 Ohio State Innovation Foundation Gene therapy for bves-related disorders
WO2024097772A1 (en) * 2022-11-01 2024-05-10 Lacerta Therapeutics, Inc. Compositions and methods for treatment of friedreich's ataxia
WO2024226729A3 (en) * 2023-04-26 2025-03-20 Astellas Gene Therapies, Inc. Compositions and methods for opa1 gene therapy
WO2025045767A1 (en) 2023-08-25 2025-03-06 Ethris Gmbh Stabilized lipid and lipidoid nanoparticle formulations with specific surfactant properties for enhanced pharmaceutical applications
WO2025122940A1 (en) * 2023-12-06 2025-06-12 Oyster Point Pharma, Inc. Aav vector encoding diamine oxidase and uses thereof
CN117756911A (zh) * 2023-12-26 2024-03-26 无锡佰翱得生物科学股份有限公司 一种溶质载体蛋白urat1及其制备方法和应用

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