Amino-Acid-Modified AAV Capsids for Deeper Retinal Transduction
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Solution Overview
Problem
Current AAV-based gene therapy for retinal diseases faces challenges in effectively targeting and transducing deeper cell types of the retina, limiting its therapeutic efficacy.
Innovation Solution
Development of variant AAV capsid proteins with specific amino acid modifications that enhance the infectivity and transduction capabilities of retinal cells, including photoreceptor cells, retinal ganglion cells, glial cells, bipolar cells, amacrine cells, horizontal cells, and retinal pigmented epithelium cells, through directed evolution techniques.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type AAV vectors are used for gene delivery to the retina, then the delivery system is well-characterized and relatively simple to implement, but the transduction efficiency of deeper retinal cell types 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 altered properties. Specifically, the patent describes generating AAV capsid variants with modified amino acid sequences that enhance transduction of deeper retinal cell types while maintaining the overall capsid structure and function. This approach allows optimization of transduction efficiency without completely redesigning the vector system.
Solution Approach 2:
The patent implements local quality by introducing specific amino acid modifications at particular positions within the capsid protein sequence. The variant capsids contain targeted amino acid changes that locally alter the capsid surface properties to improve interaction with deeper retinal cells, while the rest of the capsid structure remains intact to maintain stability and function.
2Reliability
If directed evolution techniques are used to generate AAV variants, then transduction capabilities are enhanced, but the development process becomes more complex and time-consuming
Solution Approach 1:
The patent applies preliminary action by pre-selecting and characterizing specific AAV capsid variants with desired transduction properties before clinical application. The directed evolution process is used to generate and screen multiple capsid variants in advance, identifying those with superior retinal transduction profiles. This preliminary characterization allows selection of optimized variants for further development, reducing the need for extensive optimization during clinical trials.
Solution Approach 2:
The patent implements feedback through iterative rounds of capsid variant generation, screening, and selection based on transduction performance. The directed evolution process involves cycling between generating genetic diversity in capsid sequences, packaging variants, testing transduction efficiency in retinal models, and selecting the best performers for the next round of optimization. This feedback loop systematically improves transduction capabilities while providing data to guide further development decisions.
Data Source
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AI summary
Provided herein are variant adeno-associated virus (AAV) capsid proteins having one or more modifications in amino acid sequence relative to a parental AAV capsid protein, which, when present in an AAV virion, confer increased infectivity of one or more types of retinal cells as compared to the infectivity of the retinal cells by an AA V virion comprising the unmodified parental AAV capsid protein. Also provided are recombinant AAV virions and pharmaceutical compositions thereof comprising a variant AAV capsid protein as described herein, methods of making these rAAV capsid proteins and virions, and methods for using these rAAV capsid proteins and virions in research and in clinical practice, for example in, e.g., the delivery of nucleic acid sequences to one or more cells of the retina for the treatment of retinal disorders and diseases.