AAV Vectors for Wilson Disease Gene Therapy
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Solution Overview
Problem
Current gene therapy approaches for Wilson's disease, such as adenoviral and lentiviral vectors, exhibit transient therapeutic effects due to limited duration of transgene expression, and existing vectors like AAV have packaging capacity constraints, making them unsuitable for delivering the ATP7B gene effectively.
Innovation Solution
Development of AAV vectors carrying truncated forms of the ATP7B protein, specifically AAV2/8-AAT-ATP7B(d57-486), which achieve sustained correction of pathological characteristics in Wilson's disease mice for at least 24 weeks, outperforming full-length ATP7B vectors at suboptimal doses.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If adenoviral or lentiviral vectors are used for gene therapy, then transgene expression can be achieved, but the therapeutic effect is transient due to limited duration of expression
Solution Approach 1:
The patent changes the vector system from adenoviral/lentiviral to AAV vectors, which provide long-term transgene expression. This parameter change in the delivery system resolves the contradiction by achieving both reliable therapeutic effect and extended duration of action, as AAV vectors can maintain expression for months to years in hepatocytes
2Reliability
If full-length ATP7B gene is delivered, then complete functional restoration is possible, but AAV packaging capacity is exceeded (4.4-4.7 kb limit)
Solution Approach 1:
The patent extracts and removes the intron sequences from the ATP7B gene, creating a cDNA version that fits within AAV packaging capacity while retaining the essential coding information. This extraction of non-essential elements resolves the contradiction by enabling complete functional restoration through a compact gene version that fits the vector size constraint
Solution Approach 2:
The patent segments the ATP7B gene into manageable components by removing introns and keeping only essential exons, allowing the transgene to be packaged in AAV vectors. This segmentation approach maintains functional integrity while reducing overall size to fit packaging constraints
3Length of moving object
If truncated ATP7B forms are used, then AAV packaging capacity is satisfied, but protein functionality may be compromised
Solution Approach 1:
The patent applies local quality by selectively removing only the intron sequences while preserving all essential coding exons of the ATP7B protein. This localized modification maintains full protein functionality in the regions that matter while reducing overall transgene size to fit AAV packaging capacity
Data Source
AI summary
The invention relates to nucleic acid constructs and gene therapy vectors that comprise an ATP7B variant for use in the treatment of conditions associated with a deficiency or dysfunction of Copper-transporting ATPase 2, and particularly of Wilson's disease. An AAV vector devised according to the invention significantly reduced urine Cu excretion, and liver Cu content in Wilson's disease mice treated with the vector, while ceruloplasmin activity was significantly restored. On the other hand, the administration of the vector resulted in the normalization of serum transaminases' levels and of liver histology, together with a marked reduction of the inflammatory infiltrate.