Gene therapy for treating mucopolysaccharidosis type ii

Abstract

A co-therapeutic regimen comprising AAV9-mediated intrathecal/intracisternal and/or systemic delivery of an expression cassette containing a hIDS gene and two or more immunosuppressants is provided herein. Also provided are methods and kits containing these vectors and compositions useful for treating Hunter syndrome and the symptoms associated with Hunter syndrome.

1 . An aqueous suspension comprising replication deficient recombinant adeno-associated virus (rAAV) which comprise an AAV9 capsid and a vector genome which comprises a nucleic acid sequence encoding human iduronate-2-sulfatase (hIDS) under the control of regulatory sequences which direct expression of the hIDS (rAAV9.hIDS), wherein the suspension is formulated for intrathecal injection to a human in need thereof at a dose of 1.3×10 10  GC rAAV9.hIDS/g brain mass or about 6.5×10 10  GC rAAV9.hIDS/g brain mass. 
     
     
         2 . The suspension according to  claim 1 , for use in co-therapy with (i) at least a first immunosuppressive agent selected from at least one of a corticosteroid, an antimetabolite, a T-cell inhibitor, a macrolide, or a cytostatic agent: and (ii) at least a second immunosuppressive agent selected from at least one of a corticosteroid, an antimetabolite, a T-cell inhibitor, a macrolide, or a cytostatic agent, wherein dosing of the immunosuppressive agents begins prior to or on the same day as delivery of the AAV vector; and wherein dosing with at least one of the immunosuppressive agents continues for at least 8 weeks post-vector administration. 
     
     
         3 . The suspension according to  claim 1 , wherein the suspension is administrable to a human patient which has been diagnosed with mucopolysaccharidosis II (MPS II) or severe Hunter syndrome. 
     
     
         4 . The suspension according to  claim 1 , wherein the vector genome is a nucleic acid molecule comprising a 5′ AAV inverted terminal repeat (ITR) sequence, an expression cassette having a nucleic acid sequence of nucleotides 199 to 1928 of SEQ ID NO: 14, and a 3′ AAV ITR. 
     
     
         5 . The suspension according to  claim 1 , wherein the rAAV9.hIDS has a vector genome selected from:
 (a) SEQ ID NO: 3;   (b) SEQ ID NO: 11; or   (c) SEQ ID NO: 14.   
     
     
         6 . A method of treating a patient in need thereof, the method comprising administering to the patient a replication deficient recombinant adeno-associated virus (rAAV) which comprises a heterologous nucleic acid encoding human iduronate-2-sulfatase (hIDS) packaged in an AAV9 capsid at a dose of about 1.3×10 10  GC rAAV9.hIDS/g brain mass or about 6.5×10 10  GC rAAV9.hIDS/g brain mass by intrathecal injection. 
     
     
         7 . The method according to  claim 6 , wherein the patient has been diagnosed with mucopolysaccharidosis II (MPS II) or severe Hunter syndrome. 
     
     
         8 . The method according to  claim 6 , wherein the vector genome is a nucleic acid molecule comprising a 5′ AAV inverted terminal repeat (ITR) sequence, an expression cassette having a nucleic acid sequence of nucleotides 199 to 1928 of SEQ ID NO: 14, and a 3′ AAV ITR. 
     
     
         9 . The method according to  claim 6 , wherein the vector genome is selected from:
 (a) SEQ ID NO: 3;   (b) SEQ ID NO: 11; or   (c) SEQ ID NO: 14.   
     
     
         10 . The method according to  claim 6 , further comprising administering two or more immunosuppressive agents to the subject.