Gene therapy for diseases caused by unbalanced nucleotide pools including mitochondrial dna depletion syndromes

Patent metadata

Field	Value
Publication number	US-2021100917-A1
Application number	US-201917048236-A
Country	US
Kind code	A1
Filing date	Apr 18, 2019
Priority date	Apr 18, 2018
Publication date	Apr 8, 2021
Grant date	—

Abstract

The invention relates generally to a method of treatment for a human genetic disease, such as diseases characterized by unbalanced nucleotide pools, e.g., mitochondrial DNA depletion syndromes, and more specifically, thymidine kinase 2 (TK2) deficiency, using gene therapy. The gene therapy may involve administration of one or more constructs, such as a viral vector, containing a nucleic acid encoding a functional protein. The functional protein may correspond to a nuclear gene. For treatment of TK2 deficiency, the gene therapy may involve administration of one or more constructs, such as a viral vector, containing a nucleic acid encoding a functional TK2 enzyme. The treatment may also involve the administration of pharmacological therapy in conjunction with the gene therapy. The treatment protocols of the disclosure, such as those involving gene therapy alone or in combination with pharmacological therapy, can be used to treat, prevent, and/or cure various other disorders of unbalanced nucleoside pools, especially those found in mitochondrial DNA depletion syndrome.

First claim

1 . A method of treating, preventing, and/or curing a disease or disorder characterized by unbalanced nucleotide pools in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a transgene encoding thymidine kinase 2 (TK2), deoxyguanosine kinase (dGK), thymidine phosphorylase (TP), p53 inducible small subunit of ribonucleotide reductase (p53R2), succinyl-CoA ligase ADP-forming subunit beta (SUCLA2), succinyl-CoA ligase GDP-forming subunit alpha (SUCLG1), mitochondrial inner membrane protein MPV17 (MPV17), and/or DNA polymerase subunit gamma (POLG).

2 . A method of restoring enzyme activity in a subject having a disease or disorder characterized by unbalanced nucleotide pools, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a transgene encoding TK2, dGK, TP, p53R2, SUCLA2, SUCLG1, MPV17, and/or POLG.

3 . A method of alleviating one or more symptoms associated with a disease or disorder characterized by unbalanced nucleotide pools in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a transgene encoding TK2, dGK, TP, p53R2, SUCLA2, SUCLG1, MPV17, and/or POLG.

4 . The method of any one of claims 1 - 3 , wherein the disease or disorder is a mitochondrial disease.

5 . The method of claim 4 , wherein the mitochondrial disease is a mitochondrial DNA depletion syndrome (MDS).

6 . The method of claim 5 , wherein the MDS is a myopathic MDS characterized by one or more mutations in an endogenous gene encoding TK2.

7 . The method of claim 5 , wherein the MDS is an encephalomyopathic form characterized by one or more mutations in an endogenous gene encoding SUCLA2.

8 . The method of claim 5 , wherein the MDS is a neurogastrointestinal encephalopathic form characterized by one or more mutations in an endogenous gene encoding TP.

9 . The method of claim 5 , wherein the MDS is a hepatopathic form characterized by one or more mutations in an endogenous gene encoding dGK, MPV17, and/or POLG.

10 . The method of any one of claims 1 - 9 , wherein the transgene encodes TK2.

11 . The method of claim 10 , wherein the TK2 has an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 1.

12 . The method of claim 11 , wherein the TK2 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 1.

13 . The method of claim 12 , wherein the TK2 has an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 1.

14 . The method of claim 13 , wherein the TK2 has the amino acid sequence of SEQ ID NO: 1.

15 . The method of any one of claims 10 - 14 , wherein the transgene has a nucleic acid sequence that is at least 70% identical to the nucleic acid sequence of SEQ ID NO: 2.

16 . The method of claim 15 , wherein the transgene has a nucleic acid sequence that is at least 85% identical to the nucleic acid sequence of SEQ ID NO: 2.

17 . The method of claim 16 , wherein the transgene has a nucleic acid sequence that is at least 95% identical to the nucleic acid sequence of SEQ ID NO: 2.

18 . The method of claim 17 , wherein the transgene has the nucleic acid sequence of SEQ ID NO: 2.

19 . The method of any one of claims 1 - 9 , wherein the transgene encodes dGK.

20 . The method of claim 19 , wherein the dGK has an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 3.

21 . The method of claim 20 , wherein the dGK has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 3.

22 . The method of claim 21 , wherein the dGK has an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 3.

23 . The method of claim 22 , wherein the dGK has the amino acid sequence of SEQ ID NO: 3.

24 . The method of any one of claims 19 - 23 , wherein the transgene has a nucleic acid sequence that is at least 70% identical to the nucleic acid sequence of SEQ ID NO: 4.

25 . The method of claim 24 , wherein the transgene has a nucleic acid sequence that is at least 85% identical to the nucleic acid sequence of SEQ ID NO: 4.

26 . The method of claim 25 , wherein the transgene has a nucleic acid sequence that is at least 95% identical to the nucleic acid sequence of SEQ ID NO: 4.

27 . The method of claim 26 , wherein the transgene has the nucleic acid sequence of SEQ ID NO: 4.

28 . The method of any one of claims 1 - 9 , wherein the transgene encodes TP.

29 . The method of claim 28 , wherein the TP has an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 5.

30 . The method of claim 29 , wherein the TP has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 5.

31 . The method of claim 30 , wherein the TP has an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 5.

32 . The method of claim 31 , wherein the TP has the amino acid sequence of SEQ ID NO: 5.

33 . The method of any one of claims 28 - 32 , wherein the transgene has a nucleic acid sequence that is at least 70% identical to the nucleic acid sequence of SEQ ID NO: 6.

34 . The method of claim 33 , wherein the transgene has a nucleic acid sequence that is at least 85% identical to the nucleic acid sequence of SEQ ID NO: 6.

35 . The method of claim 34 , wherein the transgene has a nucleic acid sequence that is at least 95% identical to the nucleic acid sequence of SEQ ID NO: 6.

36 . The method of claim 35 , wherein the transgene has the nucleic acid sequence of SEQ ID NO: 6.

37 . The method of any one of claims 1 - 9 , wherein the transgene encodes p53R2.

38 . The method of claim 37 , wherein the p53R2 has an amino acid sequence that is at least 85% identical to the amino acid sequence of SEQ ID NO: 7.

39 . The method of claim 38 , wherein the p53R2 has an amino acid sequence that is at least 90% identical to the amino acid sequence of SEQ ID NO: 7.

40 . The method of claim 39 , wherein the p53R2 has an amino acid sequence that is at least 95% identical to the amino acid sequence of SEQ ID NO: 7.

41 . The method of claim 40 , wherein the p53R2 has the amino acid sequence of SEQ ID NO: 7.

42 . The method of any one of claims 37 - 41 , wherein the transgene has a nucleic acid sequence that is at least 70% identical to the nucleic acid sequence of SEQ ID NO: 8.

43 . The method of claim 42 , wherein the transgene has a nucleic acid sequence that is at least 85% identical to the nucleic acid sequence of SEQ ID NO: 8.

44 . The method of claim 43 , wherein the transgene has a nucleic acid sequence that is at least 95% identical to the nucleic acid sequence of SEQ ID NO: 8.

45 . The method of claim 44 , wherein the transgene has the nucleic acid sequence of SEQ ID NO: 8.

46 .

Assignees

• Univ Columbia

Inventors

• Hirano Michio
• Akman Hasan O
• Lopez-Gomez Carlos

Classifications

• C12Y207/01113

  Deoxyguanosine kinase (2.7.1.113) · CPC title

• C12Y117/04001

  Ribonucleoside-diphosphate reductase (1.17.4.1) · CPC title

• C12N9/1211

  Thymidine kinase (2.7.1.21) · CPC title

• C12N2750/14143

  viral genome or elements thereof as genetic vector · CPC title

• A61K45/06

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