# US 12,594,348 B2 · Compositions for treating Friedreich's ataxia > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,594,348 B2 - Document ID: US12594348B2 - Status: Granted - Kind: B2 - Application number: 17/787,013 - Filed: 2020-12-18 - Published: 2023-07-06 - Granted: 2026-04-07 - Earliest claimed: 2019-12-19 - Assignees: The Trustees of the University of Pennsylvania - Applicants: The Trustees of the University of Pennsylvania - Inventors: James M. Wilson; Christian Hinderer; Nimrod Miller - Web page: https://patentgrep.com/patent/US12594348B2 ## CPC - A61K 48/0008: {characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition} - A61K 47/02: Inorganic compounds - A61K 48/005: {characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered} - A61K 48/0075: {characterised by an aspect of the delivery route, e.g. oral, subcutaneous} - A61P 9/00: Drugs for disorders of the cardiovascular 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 - C07K 14/47: from mammals - C12N 15/86: Viral vectors - A01K 2217/075: inducing loss of function, i.e. knock out - A01K 2267/0318: Animal model for neurodegenerative disease, e.g. non- Alzheimer's - C12N 2310/141: MicroRNAs, miRNAs - C12N 2750/14122: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes - C12N 2750/14143: viral genome or elements thereof as genetic vector - C12N 2750/14151: Methods of production or purification of viral material - C12N 2750/14152: relating to complementing cells and packaging systems for producing virus or viral particles - C12N 2830/42: being an intron or intervening sequence for splicing and/or stability of RNA - C12N 2830/50: regulating RNA stability, not being an intron, e.g. poly A signal - 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 - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) - C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00) - A01K: ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS ## Abstract A recombinant adeno-associated virus (rAAV) comprising an AAV capsid and a vector genome comprising a frataxin gene is provided. Also provided is a composition containing an effective amount of rAAV to ameliorate symptoms of Freidreich's ataxia, including, e.g., reduction in progression towards neurocognitive decline and/or cardiomyopathy. ## Claims ### Claim 1 A recombinant adeno-associated virus (rAAV) having an AAV capsid and a vector genome comprising a FXN gene having the sequence of SEQ ID NO: 3 or a sequence 95% identical thereto that encodes human frataxin protein having amino acid sequence of SEQ ID NO: 2, and regulatory sequences which direct expression of the FXN gene in targeted human cells. ### Claim 2 (depends on 1) The rAAV according to claim 1, wherein the vector genome comprises an AAV2 5′ inverted terminal repeat (ITR), a CB7 promoter comprising a cytomegalovirus immediate early (CMV IE) enhancer, a chicken beta-actin promoter, a chimeric intron comprising a chicken beta actin splice donor and a rabbit beta-globin splice acceptor element, the FXN gene, a polyA, and an AAV2 3′ ITR, optionally comprising the sequence of nucleotides 198 to 2737 of SEQ ID NO: 8 or nucleotides 198 to 2736 of SEQ ID NO: 12. ### Claim 3 (depends on 1) The rAAV according to claim 1, wherein the vector genome further comprises at least one, at least two, or at least three tandem repeats of dorsal root ganglion (DRG)-specific miRNA targeted sequences. ### Claim 4 (depends on 3) The rAAV according to claim 3, wherein the at least two or at least three miRNA target sequences are the same. ### Claim 5 (depends on 1) The rAAV according to claim 1, wherein the AAV capsid is an AAVrh91 capsid. ### Claim 6 (depends on 1) The rAAV according to claim 1, wherein the AAV capsid is an AAV clade F capsid. ### Claim 7 (depends on 6) The rAAV according to claim 6, wherein the clade F capsid is an AAVhu68 capsid. ### Claim 8 (depends on 1) An aqueous pharmaceutical composition comprising a formulation buffer and a stock of the rAAV according to claim 1. ### Claim 9 (depends on 8) The pharmaceutical composition according to claim 8, wherein the formulation buffer comprises: an artificial cerebrospinal fluid comprising buffered saline and one or more of sodium, calcium, magnesium, potassium, or mixtures thereof, and a surfactant. ### Claim 10 (depends on 9) The pharmaceutical composition according to claim 9, wherein the surfactant is present at 0.0005% w/w to about 0.001% w/w of the pharmaceutical composition. ### Claim 11 (depends on 8) The pharmaceutical composition according to claim 8, wherein the composition is at a pH in the range of 7.5 to 7.8, or 6.2 to 7.7, or about 7. ### Claim 12 (depends on 1) A regimen comprising dual-route of administration of rAAV, the regimen comprising intravenous administration of a first rAAV according to claim 1 and intraparenchymal (dentate nucleus) administration of a second rAAV according to claim 1. ### Claim 13 (depends on 12) The regimen according to claim 12, wherein the intraparenchymal (dentate nucleus) administration is performed unilaterally. ### Claim 14 (depends on 12) The regimen according to claim 12, wherein the intraparenchymal (dentate nucleus) administration is performed bilaterally. ### Claim 15 (depends on 12) The regimen according to claim 12 wherein the intravenous and intraparenchymal (dentate nucleus) administrations of the rAAV are performed sequentially and within a 24-hour period. ### Claim 16 (depends on 1) A regimen comprising co-administration of a first rAAV according to claim 1 intravenously and a second rAAV according to claim 1 intrathecally. ### Claim 17 (depends on 8) A method of treating FRDA in a subject with FRDA, the method comprising administering the pharmaceutical composition according to claim 8 to the subject. ### Claim 18 A plasmid comprising an expression cassette comprising a FXN gene having the sequence of SEQ ID NO: 3 or a sequence 95% identical thereto that encodes human frataxin protein having amino acid sequence of SEQ ID NO: 2. ### Claim 19 A plasmid comprising the vector genome of SEQ ID NO: 8 or 12, or a sequence at least 95% identical to SEQ ID NO: 8 or 12. ### Claim 20 (depends on 18) A host cell comprising the plasmid according to claim 18. ### Claim 21 (depends on 1) The rAAV according to claim 1, wherein the FXN gene comprises a sequence of SEQ ID NO: 3. ### Claim 22 (depends on 18) The plasmid according to claim 18, wherein the FXN gene comprises a sequence of SEQ ID NO: 3.