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 method for reducing the severity or extent of deficiency of aspartoacylase in a subject, the method comprising:
 intrathecally, intracerebrally, or intravascularly administering rAAV to the subject, wherein the rAAV comprises a nucleic acid comprising a promoter operably linked with a region encoding aspartoacylase (ASPA), wherein the ASPA is expressed from the nucleic acid in cells transduced by the rAAV.   
     
     
         57 . The method of  claim 56 , wherein the nucleic acid expresses an aspartoacylase (ASPA) mRNA comprising one or more miRNA binding sites for one or more miRNAs that are more abundant in one or more non-CNS tissues in comparison to a CNS tissue. 
     
     
         58 . The method 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 twofold more abundant. 
     
     
         59 . The method of  claim 56 , wherein the rAAV is administered intrathecally to the subject. 
     
     
         60 . The method of  claim 56 , wherein the rAAV is administered intracerebrally to the subject. 
     
     
         61 . The method of  claim 56 , wherein the rAAV is administered intravascularly to the subject. 
     
     
         62 . The method of  claim 56 , wherein the rAAV comprises a capsid of either SEQ ID NO: 7 or 8. 
     
     
         63 . The method of  claim 56 , wherein the rAAV is self-complementary. 
     
     
         64 . The method of  claim 56 , 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. 
     
     
         65 . The method of  claim 56 , wherein oligodendrocytes, astrocytes, microglial cells, ependymal cells, Schwann cells, glial cells, neuronal cells or other central nervous system cells are transduced. 
     
     
         66 . The method of  claim 56 , wherein the dose of rAAV for intrathecal administration is in the range of 10 10  genome copies per kilogram to 10 14  genome copies per kilogram. 
     
     
         67 . The method of  claim 56 , wherein the dose of rAAV for intracerebral administration is in the range of 10 10  genome copies per kilogram to 10 14  genome copies per kilogram. 
     
     
         68 . The method of  claim 56 , wherein the dose of rAAV for intravascular administration is in the range of 10 10  genome copies per kilogram to 10 14  genome copies per kilogram. 
     
     
         69 . The method of  claim 56 , wherein the promoter is inducible. 
     
     
         70 . The method of  claim 56 , wherein the promoter is constitutive. 
     
     
         71 . The method of  claim 56 , wherein the promoter is tissue-specific. 
     
     
         72 . The method of  claim 56 , wherein administration is by both intravascularly and intracerebrally. 
     
     
         73 . A method for reducing the severity or extent of deficiency of aspartoacylase in a subject, the method comprising:
 intrathecally, intracerebrally, or intravascularly administering rAAV to the subject an rAAV comprises (i) a capsid protein having the amino acid sequence of SEQ ID NO: 8 and (ii) a nucleic acid comprising a constitutive promoter operably linked with a region encoding aspartoacylase (ASPA), wherein the ASPA is expressed from the nucleic acid in cells transduced by the rAAV.   
     
     
         74 . The method of  claim 73 , wherein the nucleic acid expresses an aspartoacylase (ASPA) mRNA comprising one or more miRNA binding sites for one or more miRNAs that are more abundant in one or more non-CNS tissues in comparison to a CNS tissue. 
     
     
         75 . The method of  claim 74 , 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 twofold more abundant. 
     
     
         76 . The method of  claim 73 , wherein the rAAV is administered intrathecally to the subject. 
     
     
         77 . The method of  claim 73 , wherein the rAAV is administered intracerebrally to the subject. 
     
     
         78 . The method of  claim 73 , wherein the rAAV is administered intravascularly to the subject. 
     
     
         79 . The method of  claim 73 , wherein the rAAV is self-complementary. 
     
     
         80 . The method of  claim 73 , 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, cereobrospinal fluid (CSF), and interstitial spaces. 
     
     
         81 . The method of  claim 73 , wherein oligodendrocytes, astrocytes, microglial cells, ependymal cells, Schwann cells, glial cells, neuronal cells or other central nervous system cells are transduced. 
     
     
         82 . The method of  claim 73 , wherein the dose of rAAV for intrathecal administration is in the range of 10 10  genome copies per kilogram to 10 14  genome copies per kilogram. 
     
     
         83 . The method of  claim 73 , wherein the dose of rAAV for intracerebral administration is in the range of 10 10  genome copies per kilogram to 10 14  genome copies per kilogram. 
     
     
         84 . The method of  claim 73 , wherein the dose of rAAV for intravascular administration is in the range of 10 10  genome copies per kilogram to 10 14  genome copies per kilogram. 
     
     
         85 . The method of  claim 73 , wherein administration is by both intravascularly and intracerebrally.