Gene therapy constructs for treating wilson disease
AssigneeUltragenyx Pharmaceutical Inc.
InventorsChristine Livingston, Samuel Wadsworth
Life of this patent
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Abstract
This application relates to adeno-associated viral vectors encoding a truncated yet functional ATP7B for use in gene therapy for treating Wilson disease (WD). The truncated ATP7B described herein has several advantages over the wild-type ATP7B such as higher efficacy and improved manufacturing yield.
Claims77
A recombinant nucleic acid construct comprising:
- (a) a 5′-inverted terminal repeat (ITR) sequence;
- (b) a promoter sequence;
- (c) a nucleic acid sequence encoding a truncated human copper-transporting ATPase 2 (ATP7B) in which metal-binding domains (MBDs) 1-3 have been deleted, but the serine-rich loop including two serine residues (S340 and S341) between MBD3 and MBD4 is present;
- and
- (d) a 3′-ITR sequence.
A recombinant adeno-associated virus (rAAV) useful for the treatment of Wilson disease, said rAAV comprising an AAV capsid and a vector genome packaged therein, said vector genome comprising:
- a. an AAV 5′-inverted terminal repeat (ITR) sequence;
- b. a promoter/enhancer sequence;
- c. a nucleic acid sequence encoding a truncated human copper-transporting ATPase 2 (ATP7B) in which metal-binding domains (MBDs) 1-3 have been deleted, but the serine-rich loop including two serine residues (S340 and S341) between MBD3 and MBD4 is present;
- and
- d. an AAV 3′-ITR.
A recombinant nucleic acid construct comprising:
- a. an AAV 5′-inverted terminal repeat (ITR) sequence of SEQ ID NO:2;
- b. an enhancer sequence of SEQ ID NO:3;
- c. a promoter sequence of SEQ ID NO:12;
- d. a nucleic acid sequence encoding a truncated human copper-transporting ATPase 2 (ATP7B) of SEQ ID NO:1 or SEQ ID NO:15;
- and
- e. an AAV 3′-ITR of SEQ ID NO:2.
A rAAV comprising an AAV capsid and a vector genome packaged therein, said vector genome comprising:
- a. an AAV 5′-inverted terminal repeat (ITR) sequence of SEQ ID NO:2;
- b. an enhancer sequence of SEQ ID NO:3;
- c. a promoter sequence of SEQ ID NO:12;
- d. a nucleic acid sequence encoding a truncated human copper-transporting ATPase 2 (ATP7B) of SEQ ID NO:1 or SEQ ID NO:15;
- and
- e. an AAV 3′-ITR of SEQ ID NO:2.
A recombinant nucleic acid comprising a nucleic acid sequence which is at least 80% identical to SEQ ID NO:14.
Dependencies are inferred from the claim text.