Gene therapy constructs for treating Wilson disease
Inventors
Livingston, Christine • Wadsworth, Samuel
Assignees
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Publication Number
US-12338450-B2
Publication Date
2025-06-24
Expiration Date
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.
Core Innovation
The disclosed invention provides recombinant nucleic acid and recombinant adeno-associated virus (rAAV) constructs for Wilson disease that encode a truncated human copper-transporting ATPase 2 (ATP7B). The truncated ATP7B has metal-binding domains (MBDs) 1-3 deleted while retaining the serine-rich loop including two serine residues (S340 and S341) between MBD3 and MBD4. The recombinant construct includes a 5′-inverted terminal repeat (ITR) sequence, a promoter sequence, and a 3′-ITR sequence.
For the Wilson disease application, the invention further provides an rAAV comprising an AAV capsid and a vector genome packaged therein. The vector genome contains the AAV 5′-ITR and AAV 3′-ITR flanking the promoter sequence and the truncated ATP7B coding sequence that preserves the serine-rich loop with S340 and S341. The disclosed architectures are described within an AAV gene-therapy context and are associated with restoring copper metabolism.
The disclosed rAAV construct configurations are described with additional regulatory elements in certain embodiments, including an enhancer sequence and optionally introns and polyadenylation signals. The document discusses capsid selection and reports technical effects using liver and urine copper measurements and ceruloplasmin activity as readouts. In the described comparisons, the truncated ATP7B construct is associated with improved functional outcomes and rAAV yield relative to fuller-length ATP7B constructs, including capsid-dependent yield differences.
Claims Coverage
The partial content includes three independent claims. Across them, the key inventive features are the specific truncated ATP7B design (MBD1-3 deletion with retention of the serine-rich loop containing S340 and S341) and its incorporation into a recombinant nucleic acid construct and an rAAV for treating Wilson disease, with a further embodiment specifying particular AAV regulatory elements and enhancer/promoter/ITR composition within the packaged vector genome.
5′ and 3′ ITR-flanked truncated ATP7B construct with preserved serine-rich loop
A recombinant nucleic acid construct comprising a 5′-inverted terminal repeat (ITR) sequence, a promoter sequence, a nucleic acid sequence encoding the truncated human copper-transporting ATPase 2 (ATP7B) with metal-binding domains (MBDs) 1-3 deleted but the serine-rich loop including two serine residues (S340 and S341) between MBD3 and MBD4 present, and a 3′-ITR sequence.
Wilson disease rAAV with AAV capsid and vector genome encoding truncated ATP7B with preserved serine-rich loop
A recombinant adeno-associated virus (rAAV) useful for the treatment of Wilson disease, comprising an AAV capsid and a vector genome packaged therein, the vector genome comprising an AAV 5′-ITR sequence, a promoter sequence, a nucleic acid sequence encoding the truncated human copper-transporting ATPase 2 (ATP7B) with metal-binding domains (MBDs) 1-3 deleted but the serine-rich loop including two serine residues (S340 and S341) between MBD3 and MBD4 present, and an AAV 3′-ITR sequence.
Packaged enhancer-promoter regulatory genome using SEQ ID-defined elements with truncated ATP7B
A recombinant adeno-associated virus (rAAV) comprising an AAV capsid and a vector genome packaged therein, the vector genome comprising the AAV 5′-inverted terminal repeat (ITR) sequence of SEQ ID NO:2, the enhancer sequence of SEQ ID NO:3, the promoter sequence of SEQ ID NO:12, a nucleic acid sequence of SEQ ID NO:1 or SEQ ID NO:15 encoding a truncated human copper-transporting ATPase 2 (ATP7B), and the AAV 3′-ITR sequence of SEQ ID NO:2.
Across the independent claims, the coverage centers on an rAAV and corresponding recombinant nucleic acid construct that encode a truncated human ATP7B with MBD1-3 deleted while retaining the serine-rich loop containing S340 and S341, with the coding sequence positioned within an AAV vector genome defined by 5′ and 3′ ITRs and, in one embodiment, specific enhancer and promoter elements using named SEQ ID sequences.
Stated Advantages
Improved efficacy in restoring copper metabolism, including reduced liver and urine copper and increased ceruloplasmin activity.
Improved rAAV manufacturing performance, including higher rAAV yield for the ATP7B Δ1-3 construct versus full-length or ATP7B Δ1-4 comparisons.
Capsid-dependent improved yield, including higher yield with AAV9 capsid versus AAV8.
Documented Applications
Treatment of Wilson disease using an rAAV comprising an AAV capsid and a vector genome encoding the specified truncated ATP7B with preserved serine-rich loop.
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