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

Patent metadata

Field	Value
Publication number	US-12419970-B2
Application number	US-201917048236-A
Country	US
Kind code	B2
Filing date	Apr 18, 2019
Priority date	Apr 18, 2018
Publication date	Sep 23, 2025
Grant date	Sep 23, 2025

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

The invention claimed is:

1. A method of increasing weight gain in a subject suffering from myopathic MDS characterized by one or more mutations in an endogenous gene encoding TK2, the method comprising administering to the subject a therapeutically effective amount of a composition comprising a vector of adeno-associated virus (AAV) and comprising a transgene encoding thymidine kinase 2 (TK2).

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

3. The method of claim 1 wherein the composition comprises an AAV and is an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAVrh74, AAVrh.8, or AAVrh.10.

4. The method of claim 1 wherein the AAV is AAV2/9 or AAV2/8.

5. The method of claim 1 , further comprising administering one or more of dT, dC, TMP and dCMP to the subject.

6. The method of claim 3 , wherein the AAV is AAV9.

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