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

A nucleotide and mitochondrial technology, applied in the direction of single-stranded DNA virus, gene therapy, recombinant DNA technology, etc., can solve problems such as mtDNA depletion and mtDNA loss

Pending Publication Date: 2021-02-02
THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In addition, mutations in these nuclear genes can also lead to multiple deletions of mtDNA, with or without mtDNA depletion (Béhin et al. 2012; Garone et al. 2012; Longley et al. 2006; Nishino et al. 1999; Paradas et al. 2001; Tyynismaa et al 2012; Tyynismaa et al 2009; Van Goethem et al 2001)

Method used

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

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0452] Example 1 - Materials and methods

[0453] Mouse Model of TK2 Deficiency

[0454] A homozygous Tk2 H126N knock-in mutation (Tk2 - / - ) mice (Akman et al. 2008). Between postnatal days 10 and 13, Tk2 - / - Mice rapidly develop fatal encephalomyopathies characterized by reduced walking ability, unsteady gait, gross tremors, growth retardation and rapid progression to early death by 14 to 16 days of age. Molecular and biochemical analyzes of mouse models demonstrated that the pathogenesis of the disease is due to loss of enzyme activity and subsequent imbalance of the dNTP pool with reduced dTTP levels in the brain and both dTTP and dCTP levels in the liver. This in turn leads to mtDNA depletion and defects in respiratory chain enzymes containing mtDNA-encoded subunits, most notably in the brain and spinal cord.

[0455] All experiments were performed according to protocols approved by the Institutional Animal Care and Use Committee of Columbia University Medical Cent...

Embodiment 2

[0478] Example 2 - Administration of AAV9-hTK2 results in increased lifespan

[0479] Mutant mice described in Example 1 were administered the AAV9-hTK2 construct (containing approximately 4.2 x 10 11 or 4.2x10 10 genome or vector copy).

[0480] Treatment with AAV9-hTK2 produced a dose-dependent response in which 4.2x10 10 vc prolongs lifespan by 3 times (average 39 days), which is similar to 520mg / kg / day dC+dT therapy. Apply 4.2x10 11 vc prolongs the lifespan by 6 times (89 days on average), and the maximum value is 129 days. see figure 2

Embodiment 3

[0481] Example 3 - Administration of AAV9-hTK2 results in increased growth, strength and motor function in mutant mice

[0482] The mice described in Example 1 were treated with the AAV9-hTK2 construct also described in Example 1 as described in Example 1.

[0483] With a lower dose of AAV9-hTK2 (4.2x10 10 vc) Tk2 treated - / - Mice were treated with 520 mg / kg / day of dC+dT in those Tk2 - / - Mice grow at the same rate. They are still working with Tk2 + Mice grew at the same rate until postnatal day 20 when they reached a plateau.

[0484] With a higher dose of AAV9-hTK2 (4.2x10 11 vc) Tk2 treated - / - mice with Tk2 + Mice were grown at the same rate until P30.

[0485] In untreated Tk2 + compared with higher doses of AAV9-hTK2 (4.2x10 11 vc) Tk2 treated + No difference was seen between. see image 3 .

[0486] Compared with untreated or AAV9-hTK2-treated wild-type mice, at P1 with 4.2x10 11 vc-treated Tk2 - / - The mice showed no difference in strength. Strengt...

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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 treatmentprotocols 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 unbalancednucleoside pools, especially those found in mitochondrial DNA depletion syndrome.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to U.S. Provisional Patent Application Serial No. 62 / 659,281, filed April 18, 2018, which is hereby incorporated by reference in its entirety. [0003] Statement of Government Funding [0004] This invention was made with government support under HD080642 awarded by NIH. The government has certain rights in this invention. technical field [0005] The present invention relates to the field of gene therapy for the treatment of genetic diseases, including human diseases, characterized by an unbalanced nucleotide repertoire. Examples of such diseases are mitochondrial DNA depletion syndromes, such as thymidine kinase 2 (TK2) deficiency. [0006] Background of the invention [0007] Mitochondrial diseases are clinically heterogeneous diseases attributed to defects in the mitochondrial respiratory chain (RC) and oxidative phosphorylation, the biochemical pathways that convert energy from e...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00A61P43/00C12N15/86C12N15/864
CPCA61K48/005C12Q1/6883C12Q2600/156C12N2750/14143C07K14/705C12Y207/01021C12Y207/01076C12Y207/01113C12Y204/02004C12Y117/04001C12Y207/07007C12Y602/01004C12Y602/01005C12N9/1211A61K31/7068A61K31/7072A61K45/06A61P43/00C12N15/86C12N9/1077C12N9/0093C12N9/93C12N9/12
Inventor M·希拉诺H·O·阿克曼C·洛佩兹-戈麦斯
Owner THE TRUSTEES OF COLUMBIA UNIV IN THE CITY OF NEW YORK
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