# US 10,246,712 B2 · Genetic or pharmacological reduction of PERK enhances cortical- and hippocampus-dependent cognitive function

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- Number: US 10,246,712 B2
- Document ID: US10246712B2
- Status: Granted
- Kind: B2
- Application number: 15/335,466
- Filed: 2016-10-27
- Published: 2018-09-20
- Granted: 2019-04-02
- Earliest claimed: 2015-10-28
- Assignees: Carmel-Haifa University Economic Corp. Ltd.
- Applicants: Carmel-Haifa University Economic Corp. Ltd
- Inventors: Kobi Rosenblum; Vijendra Sharma; Hadile Ounallah Saad
- Web page: https://patentgrep.com/patent/US10246712B2

## CPC

- C12N 15/1137: {against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138)}
- A61K 9/0085: {Brain, e.g. brain implants; Spinal cord}
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- 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
- C12N 2330/51: Specially adapted vectors
- C12Y 207/11001: Non-specific serine/threonine protein kinase (2.7.11.1), i.e. casein kinase or checkpoint kinase
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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
- C12Y: ENZYMES

## Abstract

A method for improving a cognitive function in a subject comprising administering to said subject an active agent reducing PKR-like endoplasmic reticulum kinase (PERK) activity is provided.

## Claims

### Claim 1

A method for improving a cognitive function in a subject having age-related cognitive dysfunction, said method comprising administering to said subject an active agent reducing PKR-like endoplasmic reticulum kinase (PERK) activity.

### Claim 2 (depends on 1)

The method of claim 1, wherein said active agent is administered locally to the cerebral cortex or hippocampus of said subject.

### Claim 3 (depends on 1)

The method of claim 1, wherein said active agent is a small molecule inhibitor of the formula (I):
wherein
X is H or F; and
R is selected from 3-trifluoromethylphenyl, 2-pyridinyl, 3-pyridinyl, 4-pyridynyl, 2-methylpyridin-6-yl, 2-trifluoromethylpyridin-6-yl, 3-methylpyrazol-1-yl, 5-methylpyrazol-1-yl, or 3,5-dimethylpyrazol-1yl.

### Claim 4 (depends on 3)

The method of claim 3, wherein X is H and R is 3-trifluoromethylphenyl (compound 1) or X is F and R is 2-methylpyridin-6-yl (compound 6), 2-trifluoromethylpyridin-6-yl (compound 8), or 3,5-dimethylpyrazol-1yl (compound 12).

### Claim 5 (depends on 1)

The method of claim 1, wherein said active agent is a nucleic acid molecule that reduces the gene expression level of PERK.

### Claim 6 (depends on 5)

The method of claim 5, wherein said nucleic acid molecule is an shRNA or artificial siRNA molecule comprising a nucleic acid sequence being complementary to a sequence within a nucleic acid sequence encoding said PERK, or a nucleic acid molecule encoding said shRNA or artificial siRNA molecule.

### Claim 7 (depends on 6)

The method of claim 6, wherein said PERK is a human PERK.

### Claim 8 (depends on 7)

The method of claim 7, wherein said PERK is encoded by a nucleic acid sequence herein identified as SEQ ID NO: 2.

### Claim 9 (depends on 7)

The method of claim 7, wherein said siRNA or shRNA molecule comprises a nucleic acid sequence being perfectly complementary to a sequence within the nucleic acid sequence encoding said PERK.

### Claim 10 (depends on 5)

The method of claim 5, wherein said nucleic acid molecule is comprised within a vector.

### Claim 11 (depends on 10)

The method of claim 10, wherein said vector is a modified virus derived from a virus selected from the group consisting of a retrovirus, adenovirus, adeno-associated virus, pox virus, alphavirus, herpes virus and lentivirus.

### Claim 12 (depends on 11)

The method of claim 11, wherein said vector is a modified adeno-associated virus.

### Claim 13 (depends on 1)

The method of claim 1, wherein said cognitive function is selected from the group consisting of learning, behavioral plasticity and long term memory or a combination thereof.

### Claim 14 (depends on 1)

The method of claim 1, wherein said cognitive function is a cortical or hippocampus dependent cognitive function.

### Claim 15 (depends on 1)

The method of claim 1, wherein said age-related cognitive dysfunction is mild cognitive impairment.

### Claim 16 (depends on 1)

The method of claim 1 comprising administering to said subject a modified adeno-associated virus vector comprising a nucleic acid molecule encoding an shRNA molecule comprising a nucleic acid sequence being perfectly complementary to a sequence within SEQ ID NO: 2.

### Claim 17 (depends on 16)

The method of claim 16, wherein said age-related cognitive dysfunction is mild cognitive impairment.