# US 9,434,943 B2 · RNA interference for the treatment of gain-of-function disorders > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 9,434,943 B2 - Document ID: US9434943B2 - Status: Granted - Kind: B2 - Application number: 14/161,266 - Filed: 2014-01-22 - Published: 2014-12-18 - Granted: 2016-09-06 - Earliest claimed: 2003-09-12 - Assignees: University of Massachusetts - Applicants: University of Massachusetts - Inventors: Neil Aronin; Phillip D. Zamore - Web page: https://patentgrep.com/patent/US9434943B2 ## 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 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 - C07H 21/02: with ribosyl as saccharide radical - C12N 5/06: {Animal cells or tissues; Human cells or tissues (preservation of excised living parts A01N1/10)} - C12N 15/111: {General methods applicable to biologically active non-coding nucleic acids} - C12N 2310/14: interfering nucleic acids [NA] - C12N 2310/3515: Lipophilic moiety, e.g. cholesterol - C12N 2310/531: Stem-loop; Hairpin - C12N 2320/30: Special therapeutic applications - C12N 2320/34: Allele or polymorphism specific uses - 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 - C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13) ## Abstract The present invention relates to the discovery of an effective treatment for a variety of gain-of-function diseases, in particular, Huntington's disease (HD). The present invention utilizes RNA Interference technology (RNAi) against polymorphic regions in the genes encoding various gain-of-function mutant proteins resulting in an effective treatment for the gain-of-function disease. ## Claims ### Claim 1 A composition for treating a subject having or at risk for Huntington's disease caused by a mutation within the htt gene encoding a gain-of-function mutant huntingtin protein, comprising: a vector that expresses an effective amount of an siRNA or an shRNA targeting a non-disease causing heterozygous single nucleotide polymorphism (SNP) within a gene encoding said mutant huntingtin protein located at a site distinct from the expanded CAG region mutation within the htt gene encoding the mutant huntingtin protein. ### Claim 2 (depends on 1) The composition of claim 1, wherein said siRNA or shRNA comprises a first strand comprising about 16-25 nucleotides homologous to a region of the gene comprising the polymorphism and a second strand comprising about 16-25 nucleotides substantially complementary to the first strand such that the first and second strands are capable of annealing together. ### Claim 3 A composition for treating a subject having or at risk for Huntington's disease caused by a mutation within the htt gene encoding a gain-of-function mutant huntingtin protein, comprising a vector that expresses an effective amount of a siRNA or shRNA targeting a heterozygous SNP within a gene encoding said mutant huntingtin protein, wherein the SNP has an allelic frequency of at least 10% in a sample population and is present at a genomic site selected from the group consisting of RS362331, RS4690077, RS363125, RS363075, RS362268, RS362267, RS362307, RS362306, RS362305, RS362304, and RS362303. ### Claim 4 (depends on 1) The composition of claim 1, wherein the vector is a viral vector, retroviral vector, expression cassette, or plasmid. ### Claim 5 (depends on 1) The composition of claim 1, wherein the vector further comprises an RNA Polymerase III or RNA Polymerase II promoter. ### Claim 6 (depends on 5) The composition of claim 5, wherein the RNA Polymerase III promoter is the U6 or H1 promoter. ### Claim 7 (depends on 4) An isolated host cell comprising the vector of claim 4. ### Claim 8 (depends on 7) The isolated host cell of claim 7, which is a mammalian host cell. ### Claim 9 (depends on 8) The isolated host cell of claim 8, which is a non-human mammalian cell. ### Claim 10 (depends on 8) The isolated host cell of claim 8, which is a human cell. ### Claim 11 A composition for treating a subject having or at risk for Huntington's disease characterized or caused by a mutant huntingtin (htt) protein, comprising a vector that expresses an effective amount of a siRNA targeting a heterozygous single nucleotide polymorphism (SNP) within a gene encoding the mutant htt protein, such that RNA silencing of said gene occurs, wherein the siRNA comprises (i) an antisense strand or a variant thereof having sufficient complementarity to the SNP at genomic site RS362307 to direct target-specific RNA interference of the gene encoding the mutant htt protein; and (ii) a sense strand or a variant thereof that is substantially complementary to the antisense strand, such that the sense and antisense strands are capable of annealing together. ### Claim 12 A composition for treating a subject having or at risk for Huntington's disease characterized or caused by a mutant huntingtin (htt) protein, comprising a vector that expresses an effective amount of a siRNA targeting a heterozygous single nucleotide polymorphism (SNP) within a gene encoding the mutant htt protein, such that RNA silencing of said gene occurs, wherein the siRNA comprises (i) an antisense strand or a variant thereof having sufficient complementarity to the SNP at genomic site RS362331 or RS363125 to direct target-specific RNA interference of the gene encoding the mutant htt protein; and (ii) a sense strand or a variant thereof that is substantially complementary to the antisense strand, such that the sense and antisense strands are capable of annealing together.