Aav9-mediated gene therapy for treating mucopolysaccharidosis type i
AssigneeThe Trustees of the University of Pennsylvania
InventorsChristian Hinderer, James M. Wilson
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Abstract
A co-therapeutic regimen comprising AAV9-mediated intrathecal/intracisternal and/or systemic delivery of an expression cassette containing a hIDUA gene and two or more immunosuppressants is provided herein. Also provided are methods useful for treating hIDUA deficiency (MPSI) and the symptoms associated with Hurler, Hurler-Scheie and Scheie syndromes.
Claims19
A therapeutic regimen useful for treatment of an alpha-L-iduronidase deficiency in a human patient, wherein the regimen comprises administering to the patient:
- (a) a recombinant AAV (rAAV) having an AAV9 capsid and a nucleic acid comprising a sequence encoding human α-L-iduronidase (hIDUA) operably linked to regulatory sequences which direct expression thereof, wherein the human hIDUA coding sequence has the nucleotide sequence of nucleotides 1990 to 3948 of SEQ ID NO:
- 3 which encodes a functional hIDUA,
- (b) at least a first immunosuppressive agent selected from at least one of a glucocorticoid, a steroid, an antimetabolite, a T-cell inhibitor, a macrolide, or a cytostatic agent;
- and
- (c) at least a second immunosuppressive agent selected from at least one of a glucocorticoid, a steroid, an antimetabolite, a T-cell inhibitor, a macrolide, or a cytostatic agent,
- wherein administration of at least one immunosuppressive agent begins prior to or on the same day as delivery of the AAV vector;
- and
- wherein administration of at least one of the immunosuppressive agents continues for at least 8 weeks post-vector administration.
A composition comprising a recombinant AAV vector comprising a heterologous nucleic acid encoding human α-L-iduronidase (hIDUA), wherein the human hIDUA coding sequence has the nucleotide sequence of SEQ ID NO:
- 1 or a sequence at least about 80% identical to SEQ ID NO:
- 1 which encodes a functional hIDUA, and wherein the AAV vector is formulated for intrathecal injection to a human subject in need thereof to administer a total flat dose of:
- (a) about 1.2×1012 to about 6.0×1012 GC or about 6.0×1012 to about 3.0×1013 GC to a human subject ≥4 months to <9 months of age;
- or
- (b) about 2×1012 to about 6.0×1013 GC or about 1.0×1013 to about 5.0×1013 GC to a human subject ≥9 months to <18 months of age;
- or
- (c) about 2.2×1012 to about 1.1×1013 GC or about 1.1×1013 to about 5.5×1013 GC to a human subject ≥9 months to <18 months of age.
Dependencies are inferred from the claim text.