Engineered nucleic acids and methods of use thereof

Patent metadata

Field	Value
Publication number	US-2018318446-A1
Application number	US-201815905576-A
Country	US
Kind code	A1
Filing date	Feb 26, 2018
Priority date	Sep 12, 2011
Publication date	Nov 8, 2018
Grant date	—

Abstract

Provided are compositions and methods for delivering biological moieties such as modified nucleic acids into cells to kill or reduce the growth of viruses. Such compositions and methods include the use of modified messenger RNAs, and are useful to treat or prevent viral infection, or to improve a subject's heath or wellbeing.

First claim

1 . A pharmaceutical composition comprising:
i) an effective amount of a synthetic messenger ribonucleic acid (mRNA) encoding an anti-viral polypeptide (AVP); and ii) a pharmaceutically acceptable carrier,
wherein the synthetic mRNA comprises at least one nucleoside modification, and
wherein the anti-viral polypeptide is about 6 to about 100 amino acids in length.

2 . The pharmaceutical composition of claim 1 , wherein the anti-viral polypeptide is about 6 to about 75 amino acids, about 6 to 50 amino acids, or about 15 to 45 amino acids in length.

3 .- 4 . (canceled)

5 . The pharmaceutical composition of claim 1 , wherein the anti-viral polypeptide is substantially cationic and amphipathic.

6 . The pharmaceutical composition of claim 1 , wherein the anti-viral polypeptide is cytostatic or cytotoxic to a virus.

7 . The pharmaceutical composition of claim 1 , wherein the at least one nucleoside modification is selected from the group consisting of pyridin-4-one ribonucleoside, 5-aza-uridine, 2-thio-5-aza-uridine, 2-thiouridine, 4-thio-pseudouridine, 2-thio-pseudouridine, 5-hydroxyuridine, 3-methyluridine, 5-carboxymethyl-uridine, 1-carboxymethyl-pseudouridine, 5-propynyl-uridine, 1-propynyl-pseudouridine, 5-taurinomethyluridine, 1-taurinomethyl-pseudouridine, 5-taurinomethyl-2-thio-uridine, 1-taurinomethyl-4-thio-uridine, 5-methyl-uridine, 1-methyl-pseudouridine, 4-thio-1-methyl-pseudouridine, 2-thio-1-methyl-pseudouridine, 1-methyl-1-deaza-pseudouridine, 2-thio-1-methyl-1-deaza-pseudouridine, dihydrouridine, dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2-methoxyuridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4-methoxy-2-thio-pseudouridine, 5-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine, N4-acetylcytidine, 5-formylcytidine, N4-methylcytidine, 5-hydroxymethylcytidine, 1-methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo-pseudoisocytidine, 2-thio-cytidine, 2-thio-5-methyl-cytidine, 4-thio-pseudoisocytidine, 4-thio-1-methyl-pseudoisocytidine, 4-thio-1-methyl-1-deaza-pseudoisocytidine, 1-methyl-1-deaza-pseudoisocytidine, zebularine, 5-aza-zebularine, 5-methyl-zebularine, 5-aza-2-thio-zebularine, 2-thio-zebularine, 2-methoxy-cytidine, 2-methoxy-5-methyl-cytidine, 4-methoxy-pseudoisocytidine, 4-methoxy-1-methyl-pseudoisocytidine, 2-aminopurine, 2, 6-diaminopurine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza-2-aminopurine, 7-deaza-8-aza-2-aminopurine, 7-deaza-2,6-diaminopurine, 7-deaza-8-aza-2,6-diaminopurine, 1-methyladenosine, N6-methyladenosine, N6-isopentenyladenosine, N6-(cis-hydroxyisopentenyl)adenosine, 2-methylthio-N6-(cis-hydroxyisopentenyl) adenosine, N6-glycinylcarbamoyladenosine, N6-threonylcarbamoyladenosine, 2-methylthio-N6-threonyl carbamoyladenosine, N6,N6-dimethyladenosine, 7-methyladenine, 2-methylthio-adenine, 2-methoxy-adenine, inosine, 1-methyl-inosine, wyosine, wybuto sine, 7-deaza-guanosine, 7-deaza-8-aza-guanosine, 6-thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8-aza-guanosine, 7-methyl-guanosine, 6-thio-7-methyl-guanosine, 7-methylinosine, 6-methoxy-guanosine, 1-methylguanosine, N2-methylguanosine, N2,N2-dimethylguanosine, 8-oxo-guanosine, 7-methyl-8-oxo-guanosine, 1-methyl-6-thio-guanosine, N2-methyl-6-thio-guanosine, and N2,N2-dimethyl-6-thio-guanosine.

8 . The pharmaceutical composition of claim 1 , wherein the composition is suitable for administration selected from the group consisting of, systemic, local, intravenous, topical, oral, administration via a dressing, administration via a bandage, rectal, vaginal, intramuscular, transarterial, intraperitoneal, intranasally, subcutaneously, endoscopically, transdermally and intrathecally.

9 . The pharmaceutical composition of claim 8 , wherein the administration is intravenous.

10 . The pharmaceutical composition of claim 8 , wherein the administration is repeated at least once.

11 . The pharmaceutical composition of claim 1 , wherein the anti-viral polypeptide is a secreted polypeptide.

12 . The pharmaceutical composition of claim 1 , wherein the anti-viral polypeptide is useful in a treatment of an infection by a viral pathogen selected from the group consisting of human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2), human T-cell leukemia viruses 1 and 2 (HTLV-1 and HTLV-2), respiratory syncytial virus (RSV), human papilloma virus (HPV), adenovirus, hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), human herpes virus 8 (HHV-8), Yellow Fever virus, Dengue virus, Japanese Encephalitis and West Nile viruses.

13 . The pharmaceutical composition of claim 1 , wherein the anti-viral polypeptide is selected from the group consisting of SEQ ID NOs: 1-1762.

14 . The pharmaceutical composition of claim 1 , further comprising a lipid-based transfection reagent.

15 . A method to treat a viral infection, comprising administering to a subject the pharmaceutical composition of claim 1 .

16 . The method of claim 15 wherein the viral infection is caused by a viral pathogen selected from the group consisting of human immunodeficiency viruses 1 and 2 (HIV-1 and HIV-2), human T-cell leukemia viruses 1 and 2 (HTLV-1 and HTLV-2), respiratory syncytial virus (RSV), human papilloma virus (HPV), adenovirus, hepatitis B virus (HBV), hepatitis C virus (HCV), Epstein-Barr virus (EBV), varicella zoster virus (VZV), cytomegalovirus (CMV), herpes simplex viruses 1 and 2 (HSV-1 and HSV-2), human herpes virus 8 (HHV-8), Yellow Fever virus, Dengue virus, Japanese Encephalitis and West Nile viruses.

17 . The method of claim 15 , wherein the subject is human.

18 . (canceled)

19 . The method of claim 15 , wherein the pharmaceutical composition is administered by a route selected from the group consisting of systemic, local, intravenous, topical, oral, administration via a dressing, administration via a bandage, rectal, vaginal, intramuscular, transarterial, intraperitoneal, intranasally, subcutaneously, endoscopically, transdermally and intrathecally.

20 . The method of claim 19 , wherein the route is intravenous.

21 . The method of claim 19 , wherein the administration is repeated at least once.

22 . The method of claim 15 , further comprising administering an effective amount of a small molecule anti-viral compound to the subject at the same time or at a different time from the administration of the pharmaceutical composition.

23 . A kit, comprising the pharmaceutical composition of claim 1 , and packaging and instructions for use thereof.

Assignees

• Modernatx Inc

Inventors

• Bancel Stephane
• Schrum Jason P
• Aristarkhov Alexander

Classifications

• C12N2320/32

  Special delivery means, e.g. tissue-specific · CPC title

• C07K14/4723

  Cationic antimicrobial peptides, e.g. defensins · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K48/005 Primary

  characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered · CPC title

• A61K48/0066 Primary

  Manipulation of the nucleic acid to modify its expression pattern, e.g. enhance its duration of expression, achieved by the presence of particular introns in the delivered nucleic acid · CPC title