Cns targeting aav vectors and methods of use thereof

Abstract

The invention in some aspects relates to recombinant adeno-associated viruses useful for targeting transgenes to CNS tissue, and compositions comprising the same, and methods of use thereof. In some aspects, the invention provides methods and compositions for treating CNS-related disorders.

1 - 55 . (canceled) 
     
     
         56 . A recombinant adeno-associated virus (rAAV), comprising: (a) a nucleic acid molecule, comprising a promoter operably linked with a region encoding an aspartoacylase (ASPA); and (b) a capsid protein having the amino acid sequence of SEQ ID NO: 8. 
     
     
         57 . The rAAV of  claim 56 , wherein the nucleic acid comprises an aspartoacylase (ASPA) messenger ribonucleic acid (mRNA), wherein the ASPA mRNA comprises one or more micro-RNA (miRNA) binding sites for one or more miRNAs that are more abundant in one or more non-central nervous system (CNS) tissues in comparison to a CNS tissue. 
     
     
         58 . The rAAV of  claim 57 , wherein the one or more miRNAs that are more abundant in one or more non-CNS tissues in comparison to the CNS tissue are at least two-fold more abundant. 
     
     
         59 . The rAAV of  claim 56 , wherein the rAAV is self-complementary. 
     
     
         60 . The rAAV of  claim 56 , wherein the promoter is a inducible promoter, a constitutive promoter, or a tissue-specific promoter. 
     
     
         61 . A composition, comprising: the rAAV of  claim 56  and a pharmaceutically acceptable carrier. 
     
     
         62 . A method for reducing the severity or extent of deficiency of aspartoacylase in a subject, the method comprising: intrathecally, intraventricularly, or intravascularly administering the rAAV of  claim 56  to the subject. 
     
     
         63 . The method of  claim 62 , wherein the rAAV is administered in an amount in the range of about 10 9  genome copies per subject to about 10 16  genome copies per subject. 
     
     
         64 . The method of  claim 62 , wherein the rAAV is administered intravascularly to the subject. 
     
     
         65 . The method of  claim 62 , wherein the rAAV is administered intrathecally to the subject. 
     
     
         66 . The method of  claim 62 , wherein the rAAV is administered intraventricularly to the subject. 
     
     
         67 . The method of  claim 62 , wherein the rAAV is delivered to an area of the subject selected from the group consisting of brain tissue, meninges, neuronal cells, glial cells, astrocytes, oligodendrocytes, microglial cells, ependymal cells, Schwann cells, cerebrospinal fluid (CSF), and interstitial spaces. 
     
     
         68 . The method of  claim 62 , wherein upon administration, the rAAV transduces oligodendrocytes, astrocytes, microglial cells, ependymal cells, Schwann cells, glial cells, neuronal cells and/or other central nervous system cells in the subject. 
     
     
         69 . The method of  claim 62 , wherein upon administration, the ASPA is expressed oligodendrocytes, astrocytes, microglial cells, ependymal cells, Schwann cells, glial cells, neuronal cells and/or other central nervous system cells in the subject. 
     
     
         70 . The method of  claim 62 , wherein the subject has Canavan disease. 
     
     
         71 . The method of  claim 70 , wherein the method comprises treating Canavan disease in the subject. 
     
     
         72 . The method of  claim 71 , wherein the method comprises extending the lifespan of the subject. 
     
     
         73 . The method of  claim 71 , wherein the method comprises improving one or more symptoms of Canavan disease in the subject.