Rescue of central and peripheral neurological phenotype of friedreich's ataxia by intravenous delivery

Abstract

Described herein are compositions and methods for treating Friedreich's Ataxia (FA) using adeno-associated virus (AAV) to deliver therapeutics agents.

We claim: 
     
         1 . An adeno-associated virus (AAV) particle comprising a neurotropic capsid and a viral genome, wherein said viral genome comprises a polynucleotide sequence encoding Frataxin and one or more microRNA binding sites. 
     
     
         2 . The AAV particle of  claim 1 , wherein the capsid is AAVvoy. 
     
     
         3 . The AAV particle of  claim 2 , wherein the amino acid sequence of the neurotropic capsid comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 2. 
     
     
         4 . The AAV particle of  claim 3 , wherein the amino acid sequence of the neurotropic capsid comprises an amino acid sequence that is at least 99% identical to SEQ ID NO: 2. 
     
     
         5 . The AAV particle of  claim 4 , wherein the amino acid sequence of the neurotropic capsid comprises SEQ ID NO: 2. 
     
     
         6 . The AAV particle of  claim 1 , wherein nucleic acid sequence of the viral genome comprises SEQ ID NO: 1. 
     
     
         7 . The AAV particle of  claim 1 , wherein Frataxin derives from a species selected from the group consisting of  homo sapiens, macaca mulatta  and  macaca fascicularis.    
     
     
         8 . The AAV particle of  claim 7 , wherein Frataxin is  macaca fascicularis  Frataxin. 
     
     
         9 . The AAV particle of  claim 7 , wherein Frataxin is  macaca mulatta  Frataxin, 10, The AAV particle of  claim 7 , wherein the amino acid sequence of Frataxin comprises a sequence selected from the group consisting of SEQ ID NO: 10-12. 
     
     
         11 . The AAV particle of  claim 1 , wherein the microRNA is miRNA-122, 
     
     
         12 . The AAV particle of  claim 11 , wherein the viral genome comprises one, two, or three copies of miRNA-122 binding sites. 
     
     
         13 . The AAV particle of  claim 11 , wherein the miRNA-122 binding sites in the viral genome are located 3′ to the polynucleotide sequence encoding Frataxin. 
     
     
         14 . A method for treating, ameliorating, and/or preventing a neurological disease in a subject stemming from a loss or partial loss of frataxin protein in the subject, wherein the method comprises: administering to the subject a therapeutically effective amount of a composition comprising an AAV particle of any of  claims 1 - 13 .  15 , The method of  claim 14 , wherein the AAV particle is administered by intravenous (IV) administration. 
     
     
         16 . The method of  claim 14 , wherein the AAV particle is administered by intracerebral (IC) administration. 
     
     
         17 . The method of  claim 14 , wherein the AAV particle is administered by IV and IC administration. 
     
     
         18 . The method of any one of  claims 14 - 17 , wherein the AAV particles transduce nervous system structures following administration, wherein the nervous system structures are one or more regions selected from the group consisting of cerebellum or dorsal root ganglia (DRG). 
     
     
         19 . The method of any one of  claims 14 - 18 , wherein the composition is administered at a dose selected from the group consisting of 2,00×10 12  vg/kg, 6.32×10 12  vg/kg, 7.00×10 12 , and 2.00×10 13  vg/kg. 
     
     
         20 . The method of any one of  claims 14 - 19 , wherein the subject is treated for the central neurological phenotype of Friedreich's Ataxia (FA). 
     
     
         21 . The method of any one of  claims 14 - 19 , wherein the subject is treated for the peripheral neurological phenotype of Friedreich's Ataxia (FA). 
     
     
         22 . The method of any one of  claims 14 - 21 , wherein the subject is treated after the onset of symptoms. 
     
     
         23 . The method of any one of  claims 14 - 22 , wherein the effect of treatment lasts longer than 6 months. 
     
     
         24 . The method of any one of  claims 14 - 22 , wherein the effect of treatment lasts longer than 10 months. 
     
     
         25 . A pharmaceutical composition comprising an AAV particle of any one of  claims 1 - 13 .