# US 12,215,382 B2 · Liver protective MARC variants and uses thereof > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,215,382 B2 - Document ID: US12215382B2 - Status: Granted - Kind: B2 - Application number: 16/807,125 - Filed: 2020-03-02 - Published: 2021-08-26 - Granted: 2025-02-04 - Earliest claimed: 2019-03-01 - Assignees: The General Hospital Corporation - Applicants: The General Hospital Corporation - Inventors: Sekar Kathiresan; Connor Emdin - Web page: https://patentgrep.com/patent/US12215382B2 ## CPC - C12Q 1/6858: Allele-specific amplification - C12Q 1/6883: for diseases caused by alterations of genetic material - A61K 31/7088: Compounds having three or more nucleosides or nucleotides - A61K 31/713: Double-stranded nucleic acids or oligonucleotides - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - C12Q 2600/156: Polymorphic or mutational markers - C12Q 2600/158: Expression markers - 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 - 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) ## Abstract Described herein are MARC variants that associate with a risk of liver diseases or a symptom(s) thereof, such as cirrhosis, or protection against such liver diseases or symptom(s) thereof. Also described herein are compositions and formulations that can be capable of modulating MARC in a subject and/or treatment of a liver disease or a symptom thereof. ## Claims ### Claim 1 A method of making a protective modification of a MARC1 gene in a subject comprising: detecting a MARC1 protein variant or a MARC1 protein variant-encoding polynucleotide in the subject, wherein the MARC1 protein variant comprises alanine at a position in the MARC1 protein of the subject corresponding to position 165 of SEQ ID NO: 1; and administering, to the subject thereof having the MARC1 protein variant or the MARC1 protein variant-encoding polynucleotide, a programmable nuclease-based system comprising a nuclease or a guide polynucleotide each configured to bind a target polynucleotide, wherein the target polynucleotide is the MARC1 protein variant-encoding polynucleotide, and wherein the programmable nuclease-based system is configured to modify the MARC1 protein variant-encoding polynucleotide from the alanine at the position in the MARC1 protein of the subject corresponding to position 165 of SEQ ID NO: 1 to a threonine, thereby making a protective modification of the MARC1 gene in the subject. ### Claim 2 (depends on 1) The method of claim 1, wherein the subject has a liver disease or symptom thereof. ### Claim 3 (depends on 2) The method of claim 2, wherein the liver disease or symptom thereof comprises alcoholic cirrhosis, non-alcoholic cirrhosis, a hepatitis-related cirrhosis, hepatic steatosis, alcohol-related fatty liver disease (ALD), or nonalcoholic fatty liver disease (NAFLD). ### Claim 4 (depends on 1) The method of claim 1, wherein the subject has an elevated amount, activity of, or both of or one or more of aminotransferase (ALT), alkaline phosphatase (ALP), total cholesterol, low-density lipoprotein (LDL) cholesterol, or a combination thereof as compared to a subject having threonine at position 165 of MARC1 prior to administration. ### Claim 5 (depends on 1) The method of claim 1, wherein the protective modification of the MARC1 gene produces in the subject a decrease in: (a) an amount of, activity of, or both of aminotransferase (ALT), alkaline phosphatase (ALP), or any combination thereof in the subject; (b) an amount of total cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, or any combination thereof in the subject; or (c) both (a) and (b). ### Claim 6 (depends on 1) The method of claim 1, wherein the subject is a) heterozygous for a MARC1 variant allele comprising alanine at a position in the MARC1 protein of the subject corresponding to position 165 of SEQ ID NO: 1; or b) homozygous for the MARC1 variant allele comprising alanine at a position in the MARC1 protein of the subject corresponding to position 165 of SEQ ID NO: 1. ### Claim 7 A method of reducing total cholesterol, low-density lipoprotein, or a combination thereof in a subject thereof, comprising: detecting a MARC1 protein variant or a MARC1 protein variant-encoding polynucleotide in the subject, wherein the MARC1 protein variant comprises alanine at a position in the MARC1 protein of the subject corresponding to position 165 of SEQ ID NO: 1; and administering to the subject having the MARC1 protein variant or the MARC1 protein variant-encoding polynucleotide a programmable nuclease-based system comprising a nuclease or a guide polynucleotide each configured to bind a target polynucleotide, wherein the target polynucleotide is the MARC1 protein variant-encoding polynucleotide, wherein the programmable nuclease-based system is configured to modify the MARC1 protein variant-encoding polynucleotide, wherein the modification comprises modifying the alanine at the position in the MARC1 protein of the subject corresponding to position 165 of SEQ ID NO: 1 to a threonine, thereby reducing total cholesterol, low-density lipoprotein, or a combination thereof in the subject. ### Claim 8 (depends on 7) The method of claim 7, wherein the subject is a) heterozygous for a MARC1 variant allele comprising alanine at a position in the MARC1 protein of the subject corresponding to position 165 of SEQ ID NO: 1; or b) homozygous for the MARC1 variant allele comprising alanine at a position in the MARC1 protein of the subject corresponding to position 165 of SEQ ID NO: 1. ### Claim 9 (depends on 8) The method of claim 8, wherein the MARC1 protein variant is SEQ ID NO: 22. ### Claim 10 (depends on 7) The method of claim 7, wherein the subject has an elevated amount, activity of, or both of or one or more of aminotransferase (ALT), alkaline phosphatase (ALP), or a combination thereof prior to administration. ### Claim 11 (depends on 7) The method of claim 7, wherein the subject has a liver disease or a symptom thereof, wherein the liver disease is selected from the group consisting of: alcoholic cirrhosis, non-alcoholic cirrhosis, a hepatitis-related cirrhosis, hepatic steatosis, alcohol-related fatty liver disease (ALD), and nonalcoholic fatty liver disease (NAFLD). ### Claim 12 (depends on 1) The method of claim 1, wherein the MARC1 protein variant is SEQ ID NO: 22.