Modified AAV Capsids for Retinal Transduction Under Antibody Barriers
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Recombinant adeno-associated virus (AAV) vectors face challenges in efficiently transducing retinal cells and eliciting an immunogenic response, particularly due to neutralizing antibodies and physical barriers in the eye, limiting effective gene therapy for ocular disorders.
Innovation Solution
Modified AAV capsid proteins with specific insertions and mutations, such as Y447F, T494V, and Y733F, enhance transduction efficiency and reduce immunogenicity, particularly for retinal cells, by improving viral tropism and stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If neutralizing antibodies are present in the vitreous, then immune response is reduced, but transduction efficiency decreases
Solution Approach 1:
The patent applies parameter changes by modifying the capsid protein amino acid sequence (specifically substituting tyrosine residues with phenylalanine at positions 447, 733, and other variants) to alter the physical-chemical properties of the virus surface. This modification changes how the capsid interacts with neutralizing antibodies, reducing antibody binding affinity while maintaining transduction capability, thereby resolving the contradiction between immune response and transduction efficiency
Solution Approach 2:
The invention applies local quality by making specific localized modifications to the capsid protein structure at particular amino acid positions (such as Y447F, Y733F substitutions) rather than altering the entire capsid. These localized changes specifically address antibody binding sites while preserving the overall capsid function and transduction mechanism, allowing the virus to evade neutralizing antibodies without losing its ability to infect retinal cells
2Duration of action of stationary object
If AAV capsid is engineered to improve stability, then virus longevity increases, but transduction efficiency may decrease
Solution Approach 1:
The patent applies parameter changes by substituting serine and threonine amino acids with valine residues, and lysines with glutamic acid. These substitutions modify the capsid's physical-chemical parameters (charge, hydrophobicity, stability) to enhance virus longevity through reduced proteasomal degradation, while the modifications are carefully selected to maintain or improve transduction efficiency rather than compromise it
3Adaptability or versatility
If AAV vector is designed for broad cell infection, then tropism increases, but specificity for retinal cells decreases
Solution Approach 1:
The invention applies local quality by making specific localized modifications to the capsid protein at particular amino acid positions that are critical for retinal cell recognition and entry. These targeted substitutions (such as Y447F, Y733F, and other position-specific variants) enhance affinity for retinal cell surface receptors while maintaining the overall broad infection capability of the AAV vector, thereby achieving both versatility and specificity
Data Source
AI summary
The present invention relates to modified recombinant adeno-associated virus (AAV) capsid proteins and AAV particles thereof. In one aspect, the modified recombinant AAV particles provide for increased transduction of retinal cells when compared to the effect of a recombinant AAV particle that does not comprise the modification. The present invention also relates to nucleic acids encoding the modified AAV capsid proteins and AAV particles thereof.