AAV Virions with Altered Capsid for Retinal Gene Delivery
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Solution Overview
Problem
Current adeno-associated virus (AAV) vectors inefficiently infect Müller cells in the retina via intravitreal injection, limiting the effectiveness of gene delivery for retinal degenerative diseases.
Innovation Solution
Development of AAV virions with altered capsid proteins, such as the ShH10 variant, which exhibit increased infectivity and specificity for retinal cells, including Müller glial cells, by modifying amino acid sequences to enhance interactions with retinal structures.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type AAV vectors are used for intravitreal injection, then the delivery system is simple and well-established, but the infectivity of Müller cells is insufficient
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of the AAV capsid protein to create variant capsids with enhanced Müller cell infectivity. Specific amino acid substitutions are introduced into the capsid structure to alter its interaction with retinal cells, thereby improving transduction efficiency while maintaining the overall AAV vector system
Solution Approach 2:
The patent implements local quality by making targeted modifications to specific regions of the capsid protein rather than altering the entire structure. By focusing amino acid changes on particular domains of the capsid that interact with retinal cell receptors, the invention achieves enhanced infectivity while preserving other important functions of the capsid
2Productivity
If AAV vectors are modified to enhance retinal cell infectivity, then gene delivery effectiveness improves, but the manufacturing process becomes more complex
Solution Approach 1:
The patent modifies production parameters by changing the amino acid sequence of the capsid protein through site-directed mutagenesis or other molecular biology techniques. These parameter changes enable enhanced gene delivery to retinal cells while using established AAV production platforms, thereby improving productivity without completely overhauling the manufacturing process
3Adaptability or versatility
If naturally occurring AAV variants are used, then different cellular tropisms are achieved, but infectivity of Müller cells remains inefficient
Solution Approach 1:
The patent applies local quality by making targeted amino acid modifications to the capsid protein that specifically enhance Müller cell tropism. Rather than relying on naturally occurring variants with broad but weak tropism, the invention introduces specific local changes to the capsid structure that confer high-affinity binding and efficient transduction of Müller cells
Solution Approach 2:
The patent creates composite capsid structures by combining elements from different AAV serotypes or introducing heterologous peptide sequences into the capsid protein. This composite approach allows the engineered capsid to exhibit enhanced Müller cell specificity while maintaining other desirable properties of AAV vectors
Data Source
AI summary
The present disclosure provides adeno-associated virus (AAV) virions with altered capsid protein, where the AAV virions exhibit greater infectivity of retinal cells compared to wild-type AAV. The present disclosure further provides methods of delivering a gene product to a retinal cell in an individual, and methods of treating ocular disease.