# US 12,215,322 B2 · Treatment of liver disease with mitochondrial glycerol-3-phosphate acyltransferase (GPAM) inhibitors

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- Number: US 12,215,322 B2
- Document ID: US12215322B2
- Status: Granted
- Kind: B2
- Application number: 17/680,940
- Filed: 2022-02-25
- Published: 2022-09-29
- Granted: 2025-02-04
- Earliest claimed: 2021-02-27
- Assignees: Regeneron Pharmaceuticals, Inc.
- Applicants: Regeneron Pharmaceuticals, Inc.
- Inventors: Luca Andrea Lotta; Niek Verweij; Colm O'Dushlaine; Jonathan Marchini; Aris Baras
- Web page: https://patentgrep.com/patent/US12215322B2

## CPC

- A61K 38/45: Transferases (2)
- C12N 15/1137: {against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138)}
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 38/465: {acting on ester bonds (3.1), e.g. lipases, ribonucleases}
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- C12Q 1/6883: for diseases caused by alterations of genetic material
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/531: Stem-loop; Hairpin
- C12Q 1/6827: for detection of mutation or polymorphism
- C12Q 1/6874: involving nucleic acid arrays, e.g. sequencing by hybridisation
- C12Q 2600/156: Polymorphic or mutational markers
- C12Q 2600/158: Expression markers
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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

## Abstract

The present disclosure provides methods of treating subjects having liver disease, and methods of identifying subjects having an increased risk of developing liver disease.

## Claims

### Claim 1

A method of treating a subject having liver disease or at risk of having liver disease, having fatty liver disease or at risk of having fatty liver disease, having hepatocellular carcinoma or at risk of having hepatocellular carcinoma, having liver cirrhosis or at risk of having liver cirrhosis, having liver fibrosis or at risk of having liver fibrosis, and/or having simple steatosis, steatohepatitis, or non-alcoholic steatohepatitis (NASH) or at risk of having simple steatosis, steatohepatitis, or NASH, the method comprising administering a glycerol-3-phosphate acyltransferase (GPAM) inhibitor to the subject, wherein:
the GPAM inhibitor comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA) that hybridizes to a GPAM mRNA; and
the subject is heterozygous for a GPAM predicted loss-of-function variant mRNA molecule comprising SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, and/or SEQ ID NO: 14.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the fatty liver disease is alcoholic fatty liver disease (AFLD) or nonalcoholic fatty liver disease (NAFLD).

### Claim 3 (depends on 1)

The method according to claim 1, wherein the subject is heterozygous for a GPAM predicted loss-of-function variant mRNA molecule comprising SEQ ID NO: 10.