NZ791007B2 - Delivery of mRNA for the augmentation of proteins and enzymes in human genetic diseases - Google Patents
Delivery of mRNA for the augmentation of proteins and enzymes in human genetic diseases Download PDFInfo
- Publication number
- NZ791007B2 NZ791007B2 NZ791007A NZ79100710A NZ791007B2 NZ 791007 B2 NZ791007 B2 NZ 791007B2 NZ 791007 A NZ791007 A NZ 791007A NZ 79100710 A NZ79100710 A NZ 79100710A NZ 791007 B2 NZ791007 B2 NZ 791007B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- composition
- lipids
- mrna
- peg
- modified
- Prior art date
Links
- 108020004999 messenger RNA Proteins 0.000 title claims abstract 14
- 102000004169 proteins and genes Human genes 0.000 title claims abstract 7
- 108090000623 proteins and genes Proteins 0.000 title claims abstract 7
- 102000004190 Enzymes Human genes 0.000 title 1
- 108090000790 Enzymes Proteins 0.000 title 1
- 208000026350 Inborn Genetic disease Diseases 0.000 title 1
- 230000003416 augmentation Effects 0.000 title 1
- 208000016361 genetic disease Diseases 0.000 title 1
- 150000002632 lipids Chemical class 0.000 claims abstract 12
- 125000002091 cationic group Chemical group 0.000 claims abstract 7
- 239000002502 liposome Substances 0.000 claims abstract 6
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract 6
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims abstract 4
- NRJAVPSFFCBXDT-HUESYALOSA-N 1,2-distearoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCCCCCCCCCCC NRJAVPSFFCBXDT-HUESYALOSA-N 0.000 claims abstract 3
- 235000012000 cholesterol Nutrition 0.000 claims abstract 2
- 210000004185 liver Anatomy 0.000 claims abstract 2
- 101710191958 Amino-acid acetyltransferase Proteins 0.000 claims 2
- 102000004452 Arginase Human genes 0.000 claims 2
- 108700024123 Arginases Proteins 0.000 claims 2
- 102000009042 Argininosuccinate Lyase Human genes 0.000 claims 2
- 102000007981 Ornithine carbamoyltransferase Human genes 0.000 claims 2
- 101710198224 Ornithine carbamoyltransferase, mitochondrial Proteins 0.000 claims 2
- -1 cationic lipid Chemical class 0.000 claims 2
- 102100020999 Argininosuccinate synthase Human genes 0.000 claims 1
- 102000053640 Argininosuccinate synthases Human genes 0.000 claims 1
- 108700024106 Argininosuccinate synthases Proteins 0.000 claims 1
- 108091026898 Leader sequence (mRNA) Proteins 0.000 claims 1
- 102000003960 Ligases Human genes 0.000 claims 1
- 108090000364 Ligases Proteins 0.000 claims 1
- 239000002202 Polyethylene glycol Substances 0.000 claims 1
- 229930185560 Pseudouridine Natural products 0.000 claims 1
- PTJWIQPHWPFNBW-UHFFFAOYSA-N Pseudouridine C Natural products OC1C(O)C(CO)OC1C1=CNC(=O)NC1=O PTJWIQPHWPFNBW-UHFFFAOYSA-N 0.000 claims 1
- 108091036066 Three prime untranslated region Proteins 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 230000004075 alteration Effects 0.000 claims 1
- WGDUUQDYDIIBKT-UHFFFAOYSA-N beta-Pseudouridine Natural products OC1OC(CN2C=CC(=O)NC2=O)C(O)C1O WGDUUQDYDIIBKT-UHFFFAOYSA-N 0.000 claims 1
- 125000003827 glycol group Chemical group 0.000 claims 1
- NFQBIAXADRDUGK-KWXKLSQISA-N n,n-dimethyl-2,3-bis[(9z,12z)-octadeca-9,12-dienoxy]propan-1-amine Chemical compound CCCCC\C=C/C\C=C/CCCCCCCCOCC(CN(C)C)OCCCCCCCC\C=C/C\C=C/CCCCC NFQBIAXADRDUGK-KWXKLSQISA-N 0.000 claims 1
- 125000003729 nucleotide group Chemical group 0.000 claims 1
- 229920001223 polyethylene glycol Polymers 0.000 claims 1
- 102000004196 processed proteins & peptides Human genes 0.000 claims 1
- PTJWIQPHWPFNBW-GBNDHIKLSA-N pseudouridine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1C1=CNC(=O)NC1=O PTJWIQPHWPFNBW-GBNDHIKLSA-N 0.000 claims 1
- 230000014509 gene expression Effects 0.000 abstract 1
- 230000002035 prolonged effect Effects 0.000 abstract 1
- 230000010473 stable expression Effects 0.000 abstract 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
- A61K48/0025—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid
- A61K48/0033—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition wherein the non-active part clearly interacts with the delivered nucleic acid the non-active part being non-polymeric
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
- A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
- A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/5123—Organic compounds, e.g. fats, sugars
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J43/00—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton
- C07J43/003—Normal steroids having a nitrogen-containing hetero ring spiro-condensed or not condensed with the cyclopenta(a)hydrophenanthrene skeleton not condensed
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
- C12N15/67—General methods for enhancing the expression
Abstract
Disclosed is a composition for modulating the expression of a protein or peptide in a target cell, wherein said composition comprises at least one messenger RNA (mRNA) molecule encapsulated in a liposome; said liposome comprises one or more cationic lipids which constitute about 20-70% of total lipids present, one or more non-cationic lipids comprising DOPE or DSPC, one or more cholesterol-based lipids, and one or more PEG-modified lipids and has a size of less than 125 nm. Said composition is capable of providing prolonged stable expression of the protein or peptide encoded by the mRNA in a liver of the subject.
Claims (15)
1. A composition comprising a messenger RNA (mRNA) encoding an protein or peptide, wherein the mRNA is encapsulated in a liposome, wherein the liposome comprises one or more cationic lipids, one or more non-cationic lipids, one or more cholesterol-based lipids and one or more PEG-modified lipids and has a size of less than 125 nm, and wherein the one or more cationic lipids constitute about 20 to 70% of the total lipids present in the liposome, n the one or more non-cationic lipids comprise DOPE or DSPC, and wherein said composition is capable of providing ged stable sion of the protein or peptide encoded by the mRNA in a liver of the subject.
2. The composition of claim 1, wherein the one or more cationic lipids comprise DLinDMA, A or DLin-K-XTC2-DMA.
3. The composition of claim 1 or claim 2, wherein the one or more PEG-modified lipids comprise DMG-PEG-2000 or C8-PEG-2000.
4. The composition of any one of claims 1 to 3, wherein the non-cationic lipid comprises DOPE.
5. The composition of any one of claims 1 to 3, wherein the non-cationic lipid comprises DSPC.
6. The composition of any one of claims 1 to 5, wherein the mRNA is of at least 30 kDa.
7. The composition of any one of claims 1 to 6, wherein the mRNA is modified to enhance stability.
8. The composition of claim 6, wherein the mRNA is ed to include a modified nucleotide, an alteration to the 5’ or 3’ untranslated region, a cap structure or a poly A tail.
9. The composition of claim 7 or 8, wherein the mRNA is modified to include a pseudouridine.
10. The composition of any one of claims 1 to 6, wherein the mRNA is unmodified.
11. The composition of any one of claims 1 to 10, wherein the one or more ic lipids are formulated to carry a net ve charge at a physiological pH.
12. The composition of any one of claims 1 to 11, wherein the one or more PEG-modified lipids se a polyethylene glycol chain of up to 5 kDa in mass covalently ed to a lipid with alkyl chain(s) of C6-C20 length.
13. The composition of any one of claims 1 to 12, wherein the one or more PEG-modifi ed lipids constitute up to about 20% by molar ratio of the total lipids present in the liposome.
14. The composition of any one of claims 1 to 13, wherein the protein or peptide is selected from ornithine transcarbamylase (OTC), carbamyl phosphate synthetase (CPS), argininosuccinate synthetase 1 (ASS1), argininosuccinate lyase (ASL) or arginase (ARG).
15. The composition of any one of claims 1 to 14, wherein the ition comprises two or more mRNAs encoding two or more distinct proteins or peptides.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US26565309P | 2009-12-01 | 2009-12-01 | |
| NZ750556A NZ750556A (en) | 2009-12-01 | 2010-11-30 | Delivery of mrna for the augmentation of proteins and enzymes in human genetic diseases |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| NZ791007A NZ791007A (en) | 2024-02-23 |
| NZ791007B2 true NZ791007B2 (en) | 2024-05-24 |
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