# US 2021/0330744 A1 · Methods and Compositions for Treating Neurodegeneration and Fibrosis

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- Number: US 2021/0330744 A1
- Document ID: US20210330744A1
- Status: Published application
- Kind: A1
- Application number: 16/484,953
- Filed: 2018-02-12
- Published: 2021-10-28
- Earliest claimed: 2017-02-10
- Applicants: Temple University-Of The Commonwealth System of Higher Education
- Inventors: John W. Elrod; Pooja Jadiya; Alyssa A. Lombardi; Timothy S. Luongo
- Web page: https://patentgrep.com/patent/US20210330744A1

## CPC

- A61K 38/1738: {Calcium binding proteins, e.g. calmodulin}
- A01K 67/0276: Knock-out vertebrates
- A61K 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
- A61K 35/761: Adenovirus
- A61K 38/16: Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof {(enzyme inhibitors A61K38/005)}
- A61K 38/45: Transferases (2)
- A61K 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered}
- 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
- C07K 14/705: Receptors; Cell surface antigens; Cell surface determinants {(tumour specific antigens C07K14/4748)}
- C07K 16/24: against cytokines, lymphokines or interferons
- C12N 15/79: Vectors or expression systems specially adapted for eukaryotic hosts
- C12Y 207/01011: 6-Phosphofructokinase (2.7.1.11)
- A01K 2217/075: inducing loss of function, i.e. knock out
- A01K 2217/15: Animals comprising multiple alterations of the genome, by transgenesis or homologous recombination, e.g. obtained by cross-breeding
- A01K 2227/105: Murine
- A01K 2267/0312: Animal model for Alzheimer's disease
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C12N 15/86: Viral vectors
- C12N 2710/10343: viral genome or elements thereof as genetic vector
- 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)
- A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- 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

This invention is generally related to novel compositions and methods for treating or preventing fibrosis, diseases or disorders associated with fibrosis, neurodegeneration, diseases or disorders associated with neurodegeneration and cardiovascular disease or disorders.

## Claims

### Claim 1

A method for treating or preventing neurodegeneration or a neurodegeneration-related disease or disorder the method comprising administering a composition comprising an activator of mitochondrial Na+/Ca2+ exchanger (mNCX) to a subject in need thereof.

### Claim 2 (depends on 1)

The method of claim 1, wherein the activator is selected from the group consisting of a chemical compound, a protein, a peptide, a peptidomemetic, an antibody, a ribozyme, a small molecule chemical compound, a nucleic acid, a vector, and an antisense nucleic acid molecule.

### Claim 3 (depends on 1)

The method of claim 1, wherein the neurodegeneration-related disease or disorder is selected from the group consisting of Alzheimer's Disease, amyotrophic lateral sclerosis, Parkinson's, Alzheimer's, Huntington's, Batten disease, prion disease, motor neuron diseases, traumatic brain injury, blast injury, dementia, Tay-Sachs, Niemann-Pick, PDH deficiency, aggregation disorders, encephalopathies, ataxia disorders, and neurodegeneration associated with aging

### Claim 4 (depends on 1)

The method of claim 1, wherein the activator increases one or more of transcription, translation, and activity of mNCX.

### Claim 5

A method for treating or preventing fibrosis or a fibrosis-related disease or disorder the method comprising administering a composition comprising an modulator of a target to a subject in need thereof, wherein the target is selected from the group consisting of mitochondrial Na+/Ca2+ exchanger (mNCX), a PDH kinase, a PDH phosphatase, an alpha-ketoglutarate dependent demethylase, phosphofructokinase-2 (PFK-2), calcium sensitive alpha-ketoglutarate dehydrogenase, and the ratio of alpha-ketoglutarate to succinate.

### Claim 6 (depends on 5)

The method of claim 5, wherein the alpha-ketoglutarate dependent demethylase is selected from the group consisting of a Ten-eleven translocation (TET) enzyme and a Jmj C-domain containing histone demethylase (JHDM).

### Claim 7 (depends on 5)

The method of claim 5, wherein the modulator is an activator.

### Claim 8 (depends on 5)

The method of claim 5, wherein the modulator is an inhibitor.

### Claim 9 (depends on 8)

The method of claim 8, wherein the inhibitor prevents one or more of transcription, translation, and activity of mNCX.

### Claim 10 (depends on 6)

The method of claim 6, wherein the modulator is selected from the group consisting of a chemical compound, a protein, a peptide, a peptidomemetic, an antibody, a ribozyme, a small molecule chemical compound, a nucleic acid, a vector, and an antisense nucleic acid molecule.

### Claim 11 (depends on 6)

The method of claim 6, wherein the fibrosis-related disease or disorder is selected from the group consisting of cardiac fibrosis, interstitial lung diseases, liver cirrhosis, wound healing, systemic scleroderma, and Sjogren syndrome.

### Claim 12

A method for treating or preventing neurodegeneration or a cardiovascular disease or disorder the method comprising administering a composition comprising a modulator of mitochondrial Na+/Ca2+ exchanger (mNCX) to a subject in need thereof

### Claim 13 (depends on 12)

The method of claim 12, wherein the modulator decreases one or more of transcription, translation, and activity of mNCX.

### Claim 14 (depends on 12)

The method of claim 12, wherein the modulator increases one or more of transcription, translation, and activity of mNCX.

### Claim 15 (depends on 12)

The method of claim 12, wherein the wherein the modulator is selected from the group consisting of a small interfering RNA (siRNA), a microRNA, an antisense nucleic acid, a ribozyme, an expression vector encoding a transdominant negative mutant, an antibody, a peptide, a nucleic acid, a protein, a peptide, a peptidomemetic, a chemical compound and a small molecule.

### Claim 16 (depends on 12)

The method of claim 12, wherein the cardiovascular disease or disorder is selected from the group consisting of carotid artery disease, arteritis, myocarditis, cardiovascular inflammation, myocardial infarction, and ischemia.