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Methods for the treatment of mitochondrial disease

A mitochondrial and disease technology, applied in metabolic diseases, sensory diseases, disease diagnosis, etc., can solve the problem of no cure for mitochondria-based diseases, etc.

Pending Publication Date: 2016-04-20
STEALTH BIOTHERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There is currently no cure for mitochondrial-based diseases

Method used

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  • Methods for the treatment of mitochondrial disease
  • Methods for the treatment of mitochondrial disease
  • Methods for the treatment of mitochondrial disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0227] Example 1: Confirmation of SURF1 Mutant Subjects

[0228] SURF1 mutations often produce profound complex IV defects. Monomeric complex IV is highly abnormal, showing reduced assembly and unusually high and low molecular weight complex IV structures ( figure 1 , Image 6 ). figure 1 Monomeric complex IV from pediatric and adult patients with Reye's disease is shown. Pediatric patients show reduced monomeric complex IV assembly with abnormal molecular weight forms of complex IV. These abnormal complex IV structures may represent abnormally assembled and dysfunctional complex IV. Image 6 Complex IV assembly is shown in two pediatric subjects with Reye's disease. Accordingly, subjects suffering from Reye's disease can be treated with the aromatic-cationic peptides disclosed herein.

Embodiment 2

[0229] Example 2: D-Arg-2',6'-Dmt-Lys-Phe-NH 2 (SS-31) Increased OXPHOS in SURF1 Mutations

[0230] SURF1 was mutated in two regions: 1) exon 4: 344-353del10, insAT (deleted sequence=TCTGCCAGCC) (heterozygous) and 2) exon 9: 875-876delCT (heterozygous). Fibroblasts were transformed with mutated SURF1.

[0231] Mutant SURF1-transformed cells were then grown in DMEM and divided into three groups. Group 1 (saline group) was treated with DMEM+saline. Group 2 (chronic treatment group) was treated with DMEM+10 nMSS-31 for 5 days. Group 3 (acute treatment group) was treated with DMEM+10 nMSS-31 for 1 day (16-24 hours). Untransformed fibroblasts were used as controls and divided into three treatment groups as listed above.

[0232] Transformed and control fibroblasts were also cultured under glycolysis inhibiting conditions. Under glycolysis-inhibited conditions, fibroblasts were cultured in glycolysis-inhibited medium supplemented with lactate and pyruvate. Conditions of...

Embodiment 3

[0240] Example 3: D-Arg-2',6'-Dmt-Lys-Phe-NH 2 Increased OXPHOS in POLG mutations

[0241] Fibroblasts transformed with the POLG mutant gene, a mutation at exon 7; c.13399G>A, p.Ala467Thr (homozygous). POLG encodes the catalytic subunit of DNA polymerase gamma, which is required for the replication and repair of mitochondrial DNA. Mutations in POLG are known to cause progressive external ophthalmoplegia (PEO), Alpers' disease, and sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO).

[0242] Mutant POLG fibroblasts were grown and divided into three groups. Group 1 (saline group) was treated with DMEM and saline. Group 2 (chronic treatment group) was treated with DMEM+10nMD-Arg-2',6'-Dmt-Lys-Phe-NH 2 Treat for 5 days. Group 3 (acute treatment group) was treated with DMEM+10nMD-Arg-2',6'-Dmt-Lys-Phe-NH 2 Treat for 1 day (16-24 hours). Untransformed fibroblasts were used as controls and divided into three treatment groups as listed above.

[0243]...

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Abstract

The disclosure provides methods of preventing, ameliorating or treating disruption of mitochondrial function and symptoms thereof. The methods provide administering aromatic-cationic peptides in effective amounts to prevent, treat or ameliorate the disruption of mitochondrial oxidative phosphorylation in a cell such as that found in a subject suffering from, or predisposed to a mitochondrial disease or disorder. In some embodiments, the methods comprise administering to a subject suffering from, or at risk for a mitochondrial disease or disorder, an effective amount of an aromatic-cationic peptide to subjects in need thereof.

Description

[0001] Cross references to related patent applications [0002] This application claims priority to U.S. Provisional Patent Application 61 / 771,534, filed March 1, 2013, and U.S. Provisional Patent Application 61 / 771,642, filed March 1, 2013, both of which are hereby incorporated by reference in their entirety . technical field [0003] The present technology generally relates to compositions and methods for preventing, alleviating or treating disruption of mitochondrial function and / or symptoms of disrupted mitochondrial function. In particular, embodiments of the present technology relate to the administration of an effective amount of an aromatic-cationic peptide to prevent, treat, or slow down, for example, a condition in which a protein at the surfeit site (SURF1) gene or DNA polymerase gamma (POLG) is affected or susceptible. Disruption of mitochondrial oxidative phosphorylation in cells or a symptom thereof seen in a subject of a mitochondrial disease or disorder associ...

Claims

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Application Information

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IPC IPC(8): A61K8/64A61K38/07C07K5/10C07K5/11
CPCA61K38/07C07K5/1016C07K5/1019A61P1/00A61P1/04A61P1/10A61P1/16A61P11/00A61P13/12A61P21/00A61P25/00A61P25/08A61P25/18A61P25/28A61P27/02A61P27/16A61P3/02A61P31/00A61P3/08A61P43/00A61P5/00A61P5/14A61P9/00A61P9/04A61P3/10A61K45/06A61K9/127C07K5/10A61L29/16C07K5/0817A61K9/0048G01N2800/207A61K9/5052A61K2300/00A61L2300/40A61K9/0051A61K38/06G01N2800/52A61Q19/08A61K38/08C07K14/705A61K38/03A61K9/5031C07K5/101C07K5/1024C07K5/0812C07K5/1008C07K5/06086A61K38/00
Inventor D·特拉维斯·威尔逊
Owner STEALTH BIOTHERAPEUTICS INC