Viral gene therapy as treatment for cholesterol storage disease or disorder

Abstract

Provided herein are compositions and methods for the viral gene therapy (e.g., AAV-directed gene therapy) of cholesterol storage diseases or disorders, such as Niemann-Pick disease, Type C.

1 . A nucleic acid construct comprising:
 (1) a viral vector sequence; and   (2) an NPC1 gene sequence under control of a mini-calmodulin promoter or a mini-elongation factor 1 α ( mini EF1α) promoter.   
     
     
         2 . The nucleic acid construct of  claim 1 , wherein the viral vector is an adeno-associated viral (AAV) vector. 
     
     
         3 . The nucleic acid construct of  claim 1 , wherein the nucleic acid construct comprises a sequence selected from the group consisting of SEQ ID NO: 1 and SEQ ID NO: 7. 
     
     
         4 . A method for treating or preventing a cholesterol storage disease or disorder in a subject, the method comprising:
 administering a composition comprising the nucleic acid construct of  claim 1  and a pharmaceutically acceptable viral carrier to a subject,   thereby treating or preventing the cholesterol storage disease or disorder in the subject.   
     
     
         5 . The method of  claim 4 , wherein the cholesterol storage disease or disorder is Niemann-Pick disease, Type C. 
     
     
         6 . (canceled) 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 4 , wherein the subject is a mammal. 
     
     
         9 . The method of  claim 4 , wherein the nucleic acid construct is encapsidated with an AAV serotype 9 capsid. 
     
     
         10 . The method of  claim 4 , wherein the concentration of the nucleic acid construct in the composition is at least 5×10 12  gc/ml. 
     
     
         11 . The method of  claim 4 , wherein the pharmaceutically acceptable viral carrier is AAV. 
     
     
         12 . The method of  claim 11 , wherein the AAV is selected from the group consisting of AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV rh8, AAVrh10, AAVrh33, AAV rh34, AAV Anc80, or AAV PHP.B. 
     
     
         13 . The method of  claim 4 , wherein the pharmaceutically acceptable viral carrier comprises a viral capsid selected from the group consisting of AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV rh8, AAVrh10, AAVrh33, AAV rh34, AAV Anc80, or AAV PHP.B viral capsid. 
     
     
         14 . A method for treating Niemann-Pick disease, Type C in a subject by gene therapy comprising administering a composition comprising a therapeutically effective amount of a gene therapy construct comprising (1) a viral vector sequence; and (2) an NPC1 gene sequence under control of a mini-calmodulin promoter or a mini elongation factor 1 α ( mini EF1α) promoter, and a pharmaceutically acceptable carrier. 
     
     
         15 . The method of  claim 14 , wherein the viral vector is an adeno-associated viral (AAV) vector. 
     
     
         16 . The method of  claim 14 , wherein the gene therapy construct comprises a sequence selected from the group consisting of SEQ ID NO: 1 (AAV. mini CaMKII NPC1.RBG) and SEQ ID NO: 7 (pAAV- mini EF1α-NPC1-RBG). 
     
     
         17 . (canceled) 
     
     
         18 . The method of  claim 14 , wherein the subject is a mammal. 
     
     
         19 . The method of  claim 14 , wherein the gene therapy construct is encapsidated with an AAV serotype 9 capsid. 
     
     
         20 . The method of  claim 14 , wherein the composition comprises the gene therapy construct at a concentration of 5×10 12  gc/ml or more. 
     
     
         21 . The method of  claim 14 , wherein the viral vector sequence is AAV. 
     
     
         22 . The method of  claim 21 , wherein the AAV is selected from the group consisting of AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV rh8, AAVrh10, AAVrh33, AAV rh34, AAV Anc80, or AAV PHP.B. 
     
     
         23 . The method of  claim 14 , wherein the gene therapy construct comprises a viral capsid selected from the group consisting of AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV rh8, AAVrh10, AAVrh33, AAV rh34, AAV Anc80, or AAV PHP.B viral capsid. 
     
     
         24 . (canceled) 
     
     
         25 . (canceled)