# US 2021/0275543 A1 · Methods for the treatment of mitochondrial genetic diseases

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- Number: US 2021/0275543 A1
- Document ID: US20210275543A1
- Status: Published application
- Kind: A1
- Application number: 16/497,704
- Filed: 2018-03-29
- Published: 2021-09-09
- Earliest claimed: 2017-03-30
- Assignees: Nserm (Institut National De La Santé Et De La Recherche MéDicale); Centre National de la Recherche Scientifique (CNRS); Universite Paris Descartes; Assistance Publique-HôPitaux De Paris (Aphp)
- Applicants: Nserm (Institut National De La Santé Et De La Recherche MéDicale); Centre National De La Recherche Scientifique (Cnrs); Université Paris Descartes; Assistance Publique-HôPitaux De Paris (Aphp)
- Inventors: Guillaume CANAUD
- Web page: https://patentgrep.com/patent/US20210275543A1

## CPC

- A61K 31/553: having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12Q 1/485: {involving kinase}
- G01N 2333/91215: with a definite EC number (2.7.1.-)
- G01N 2500/04: Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

The invention relates to a method for treating mitochondrial genetic diseases. The inventors have worked with primary fibroblasts from patients and control individuals and collected protein lysates for western blotting. Importantly, they observed that the genetic mitochondrial disorders, show a significant increase in phosphorylation of ribosomal protein S6 (pS6) compared to control fibroblasts, indicative of hyperactivated mTOR signaling. Patients with mitochondrial disorders and controls cells were treated for 48 hours with DMSO or BYL719. All lines from patients with mitochondrial diseases show reduced membrane potential, determined by TMRE staining intensity, and abnormal morphology, fragmentation and the presence of depolarized (low TMRE staining) mitochondria. Treatment with BYL719 attenuated these phenotypes in all MELAS fibroblasts while having no overt impact on the control cells. Similar experiments using flow cytometry confirmed membrane potential (TMRE) rescue by BYL719 treatment in MELAS fibroblasts.

## Claims

### Claim 1

A method for treating mitochondrial genetic diseases in a subject in need thereof comprising administrating to the subject a therapeutically effective amount of a PI3K inhibitor.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the PI3K inhibitor is a small molecule.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the PI3K inhibitor is BYL719 (Alpelisib).

### Claim 4 (depends on 1)

The method according to claim 1, wherein the PI3K inhibitor is GDC-0032 (Taselisib).

### Claim 5 (depends on 1)

The method according to claim 1, wherein the mitochondrial genetic disease is Leigh Syndrome.

### Claim 6 (depends on 1)

The method according to claim 1, wherein the mitochondrial genetic disease is ataxia.

### Claim 7 (depends on 1)

The method according to claim 1, wherein the mitochondrial genetic disease is cerebellar hypoplasia.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the mitochondrial genetic disease is kearns-sayre syndrome.

### Claim 9

A method of screening a drug suitable for the treatment of mitochondrial genetic diseases comprising i) providing a test compound ii) determining the ability of said test compound to inhibit the activity of PI3K, and, based on results from the determining step, iii) identifying the test compound as a suitable drug.