# US 12,180,478 B2 · Antisense oligonucleotides targeting alpha-synuclein 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 12,180,478 B2 - Document ID: US12180478B2 - Status: Granted - Kind: B2 - Application number: 17/815,493 - Filed: 2022-07-27 - Published: 2023-06-22 - Granted: 2024-12-31 - Earliest claimed: 2018-01-12 - Assignees: Bristol-Myers Squibb Company; Roche Innovation Center Copenhagen A/S - Applicants: Bristol-Myers Squibb Company; Roche Innovation Center Copenhagen A/S - Inventors: Richard E. Olson; Angela M. Cacace; Jere E. Meredith, Jr.; Nino Devidze; James K. Loy; Carl J. Baldick; Annapurna Pendri; Ivar M. McDonald; Peter Hagedorn; Marianne Lerbech Jensen - Web page: https://patentgrep.com/patent/US12180478B2 ## CPC - 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)} - A61K 31/712: Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose - C12N 2310/11: Antisense - C12N 2310/315: Phosphorothioates - C12N 2310/3231: having an additional ring, e.g. LNA, ENA - C12N 2310/341: Gapmers, i.e. of the type ===---=== - C12N 2310/344: Position-specific modifications, e.g. on every purine, at the 3'-end - C12N 2310/351: Conjugate - 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) ## Abstract The present disclosure relates to antisense oligonucleotides, which target SNCA mRNA (e.g., at an intron exon junction) in a cell, leading to reduced expression of SNCA protein. Reduction of SNCA protein expression is beneficial for the treatment of certain medical disorders, e.g., a neurological disorder. ## Claims ### Claim 1 A method of preparing an antisense oligonucleotide (ASO) that is capable of specifically binding to a target region of a SNCA transcript, the method comprising synthesizing the contiguous nucleotide sequence of AtTcctttacaccACAC (SEQ ID NO: 4), wherein the upper letter is beta-D-oxy-LNA and the lower letter is DNA. ### Claim 2 (depends on 1) The method of claim 1, wherein the contiguous nucleotide sequence is synthesized to comprises an internucleotide linkage selected from the group consisting of a phosphodiester linkage, a phosphotriester linkage, a methylphosphonate linkage, a phosphoramidate linkage, a phosphorothioate linkage, and combinations thereof. ### Claim 3 (depends on 2) The method of claim 2, wherein the internucleotide linkage is a phosphorothioate linkage. ### Claim 4 (depends on 1) The method of claim 1, wherein the contiguous nucleotide sequence is synthesized to have the chemical structure: OxyAs DNAts OxyTs DNAcs DNAcs DNAts DNAts DNAts DNAas DNAcs DNAas DNAcs DNAcs OxyAs OxyMCs OxyAs OxyMC, wherein the OxyA, OxyT, and OxyMC are adenine beta D-oxy-LNA, thymine beta D-oxy-LNA, and methyl cytosine beta D-oxy-LNA, respectively, wherein DNAt, DNAc, and DNAa are thymine DNA, cytosine DNA, and adenine DNA, respectively, and wherein sis a phosphorothioate linkage between two nucleotides. ### Claim 5 (depends on 1) The method of claim 1, wherein the ASO comprises the structure: wherein M+ is a counterion. ### Claim 6 (depends on 5) The method of claim 5, wherein the counterion is selected from the group consisting of H+, Na+, NH4+, and any combination thereof. ### Claim 7 (depends on 6) The method of claim 6, wherein the counterion is Na+. ### Claim 8 (depends on 1) A conjugate comprising the ASO prepared by the method of claim 1, wherein the ASO is covalently attached to at least one non-nucleotide or non-polynucleotide moiety. ### Claim 9 (depends on 8) The conjugate of claim 8, wherein the non-nucleotide or non-polynucleotide moiety comprises a protein, a fatty acid chain, a sugar residue, a glycoprotein, a polymer, or any combinations thereof. ### Claim 10 (depends on 1) A pharmaceutical composition comprising the ASO prepared by the method of claim 1 and a pharmaceutically acceptable carrier. ### Claim 11 (depends on 10) The composition of claim 10, which further comprises a therapeutic agent. ### Claim 12 (depends on 11) The composition of claim 11, wherein the therapeutic agent is an alpha-synuclein antagonist. ### Claim 13 (depends on 1) A kit comprising the ASO prepared by the method of claim 1 and instructions for use. ### Claim 14 (depends on 1) A method of inhibiting or reducing expression of SNCA RNA and/or SNCA protein in a cell, the method comprising administering the ASO prepared by the method of claim 1 to the cell expressing SNCA protein, wherein the SNCA protein expression in the cell is inhibited or reduced after the administration. ### Claim 15 (depends on 1) A method for treating a synucleinopathy in a subject in need thereof, comprising administering an effective amount of the ASO prepared by the method of claim 1 to the subject. ### Claim 16 (depends on 15) The method of claim 15, wherein the synucleinopathy is selected from the group consisting of Parkinson's disease, Parkinson's Disease Dementia (PDD), multiple system atrophy, dementia with Lewy bodies, and any combinations thereof. ### Claim 17 (depends on 3) A pharmaceutical composition comprising the ASO prepared by the method of claim 3 and a pharmaceutically acceptable carrier. ### Claim 18 (depends on 4) A pharmaceutical composition comprising the ASO prepared by the method of claim 4 and a pharmaceutically acceptable carrier. ### Claim 19 (depends on 5) A pharmaceutical composition comprising the ASO prepared by the method of claim 5 and a pharmaceutically acceptable carrier. ### Claim 20 (depends on 7) A pharmaceutical composition comprising the ASO prepared by the method of claim 7 and a pharmaceutically acceptable carrier.