Aav-abcd1 constructs and use for treatment or prevention of adrenoleukodystrophy (ald) and/or adrenomyeloneuropathy (amn)

Abstract

The present disclosure generally relates to polynucleotides and AAV vectors that provide for the expression of ALD protein in target (e.g., neurons or glial) cells when administered to subjects in need thereof. The present disclosure further relates to compositions comprising such a polynucleotide or vector. These polynucleotides, vectors, and compositions may be used for the treatment and prevention of ALD or AMN in subjects in need thereof.

1 .- 86 . (canceled) 
     
     
         87 . A method of treating adrenoleukodystrophy (ALD) and/or adrenomyeloneuropathy (AMN) in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a recombinant adeno-associated viral (AAV) vector comprising:
 (a) an AAV9 capsid; and   (b) a recombinant AAV vector genome comprising, in a 5′ to 3′ direction, a truncated 5′ AAV2 inverted terminal repeat sequence, a cytomegalovirus enhancer, a chicken beta-actin promoter, a beta-actin exon, a chimeric intron, a rabbit beta-globin exon, a human ATP-binding cassette, sub-family D, member 1 (ABCD1) 5′ untranslated region, a human ABCD1 coding sequence, a human ABCD1 3′ untranslated region, an SV40 polyadenylation signal sequence, a bovine growth hormone polyadenylation signal sequence, and a truncated 3′ AAV2 inverted terminal repeat sequence, wherein the recombinant AAV vector genome does not comprise a woodchuck post-transcriptional regulatory element.   
     
     
         88 . The method of  claim 87 , wherein the truncated 5′ AAV2 inverted terminal repeat sequence comprises the sequence of SEQ ID NO: 11001. 
     
     
         89 . The method of  claim 87 , wherein the cytomegalovirus enhancer comprises the sequence of SEQ ID NO: 11005. 
     
     
         90 . The method of  claim 87 , wherein the chicken beta-actin promoter comprises the sequence of SEQ ID NO: 11007. 
     
     
         91 . The method of  claim 87 , wherein the beta-actin exon comprises the sequence of SEQ ID NO: 11008. 
     
     
         92 . The method of  claim 87 , wherein the chimeric intron comprises the sequence of SEQ ID NO: 11009. 
     
     
         93 . The method of  claim 87 , wherein the rabbit beta-globin exon comprises the sequence of SEQ ID NO: 11085. 
     
     
         94 . The method of  claim 87 , wherein the human ABCD1 5′ untranslated region comprises the sequence of SEQ ID NO: 11010. 
     
     
         95 . The method of  claim 87 , wherein the human ABCD1 coding sequence comprises the sequence of SEQ ID NO: 11012. 
     
     
         96 . The method of  claim 87 , wherein the human ABCD1 3′ untranslated region comprises the sequence of SEQ ID NO: 11013. 
     
     
         97 . The method of  claim 87 , wherein the SV40 polyadenylation signal comprises the sequence of SEQ ID NO: 11014. 
     
     
         98 . The method of  claim 87 , wherein the bovine growth hormone polyadenylation signal comprises the sequence of SEQ ID NO: 11016. 
     
     
         99 . The method of  claim 87 , wherein the truncated 3′ AAV2 inverted terminal repeat sequence comprises the sequence of SEQ ID NO: 11018. 
     
     
         100 . The method of  claim 87 , wherein the administering is by intrathecal injection. 
     
     
         101 . The method of  claim 100 , wherein the intrathecal injection is intrathecal-lumbar (IT-L) injection. 
     
     
         102 . A method of treating ALD and/or AMN in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a recombinant AAV vector comprising: an AAV9 capsid and a recombinant AAV vector genome comprising the sequence of SEQ ID NO: 11050. 
     
     
         103 . The method of  claim 102 , wherein the administering is by intrathecal injection. 
     
     
         104 . The method of  claim 103 , wherein the intrathecal injection is IT-L injection. 
     
     
         105 . A method of treating ALD and/or AMN in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a recombinant AAV vector comprising: an AAV9 capsid and a recombinant AAV vector genome comprising the sequence of SEQ ID NO: 11060. 
     
     
         106 . The method of  claim 105 , wherein the administering is by intrathecal injection. 
     
     
         107 . The method of  claim 106 , wherein the intrathecal injection is IT-L injection.