# US 11,298,409 B2 · Mutant huntingtin-mediated protein dysfunction

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- Number: US 11,298,409 B2
- Document ID: US11298409B2
- Status: Granted
- Kind: B2
- Application number: 16/689,523
- Filed: 2019-11-20
- Published: 2020-03-19
- Granted: 2022-04-12
- Earliest claimed: 2014-04-17
- Assignees: University of Pittsburgh—Of the Commonwealth System of Higher Education; Washington University
- Applicants: University of Pittsburgh—of the Commonwealth System of Higher Education; Washington University
- Inventors: Robert Friedlander; Hiroko Yano
- Web page: https://patentgrep.com/patent/US11298409B2

## CPC

- A61K 38/45: Transferases (2)
- A61K 38/1709: {from mammals}
- 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
- C12N 9/1205: {Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases}
- C12N 15/62: DNA sequences coding for fusion proteins
- C12Y 207/11001: Non-specific serine/threonine protein kinase (2.7.11.1), i.e. casein kinase or checkpoint kinase
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES

## Abstract

The present invention relates to methods of inhibiting neurodegeneration in a subject suffering from or genetically at risk and/or destined to develop Huntington's Disease comprising increasing, in neurons of the subject, the activity of the TIM23 mitochondrial protein import complex.

## Claims

### Claim 1

A method for attenuating a mitochondrial protein import defect in a subject, comprising administering to the subject an effective amount of an agent that comprises:
(a) an exogenous TIM23 complex protein consisting essentially of the translocase of inner mitochondrial membrane 23 (Tim23) subunit, translocase of inner mitochondrial membrane 50 (Tim50) subunit, and translocase of inner mitochondrial membrane 17a (Tim17a) subunit; or
(b) a nucleic acid molecule encoding the subunits Tim23, Tim50, and Tim17a.

### Claim 2 (depends on 1)

The method of claim 1, wherein the nucleic acid molecule is operably linked to a promoter that is constitutively active or inducible in the subject, and wherein the promoter is a PGK promoter.

### Claim 3 (depends on 1)

The method of claim 1, wherein the nucleic acid molecule is administered to the subject via a vector.

### Claim 4 (depends on 1)

The method of claim 1, wherein the subject is a human subject.

### Claim 5 (depends on 1)

The method of claim 1, wherein the subject has Huntington's Disease.

### Claim 6

A method for attenuating a mitochondrial protein import defect in a neuron, comprising:
(a) contacting the neuron with an effective amount of an exogenous TIM23 complex protein that consists essentially of the translocase of inner mitochondrial membrane 23 (Tim23) subunit, translocase of inner mitochondrial membrane 50 (Tim50) subunit, and translocase of inner mitochondrial membrane 17a (Tim17a) subunit; or
(b) introducing into the neuron a nucleic acid molecule encoding the subunits Tim23, Tim50, and Tim17a.

### Claim 7 (depends on 6)

The method of claim 6, wherein the nucleic acid molecule is operably linked to a promoter that is constitutively active or inducible in the neuron, and wherein the promoter is a PGK promoter.

### Claim 8 (depends on 6)

The method of claim 6, wherein the nucleic acid molecule is introduced into the neuron via a vector.

### Claim 9 (depends on 6)

The method of claim 6, wherein the neuron is a human neuron.

### Claim 10 (depends on 6)

The method of claim 6, wherein the neuron locates in vivo in a human subject.

### Claim 11 (depends on 10)

The method of claim 10, wherein the human subject has Huntington's Disease.

### Claim 12 (depends on 10)

The method of claim 10, the human subject is genetically susceptible to Huntington's Disease.

### Claim 13 (depends on 10)

The method of claim 10, the human subject has a family member who has Huntington's Disease.