Modified AAV5 Capsids Enhance Liver Transduction
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Solution Overview
Problem
Current AAV-based gene therapy is limited by the presence of pre-existing neutralizing antibodies against recombinant AAV capsids in the human population, which reduces the efficacy of the therapy and restricts its application to patients without these antibodies.
Innovation Solution
Development of modified AAV5 capsid proteins with increased infectivity for human liver cells while maintaining low seroreactivity, achieved through specific mutations such as G257R, Q179R, F417L, S705G, P200S, M469I, and A579T.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If wild-type AAV5 capsid is used, then low seroreactivity is maintained, but transduction efficiency of human liver cells is insufficient
Solution Approach 1:
The patent applies parameter changes by introducing specific amino acid mutations (G257R, Q179R, F417L, S705G, P200S, M469I, A579T) into the AAV5 capsid protein sequence. These mutations alter the physical-chemical properties of the capsid surface, enabling enhanced binding affinity to human liver cell receptors while preserving the overall capsid structure and low immunogenicity characteristics of wild-type AAV5.
2Productivity
If AAV capsids with high infectivity are used, then gene delivery efficiency improves, but binding to pre-existing neutralizing antibodies increases
Solution Approach 1:
The patent applies local quality by making targeted amino acid substitutions at specific positions (257, 179, 417, 705, 200, 469, 579) on the capsid surface. These localized changes modify the interaction properties with neutralizing antibodies and liver cell receptors independently, allowing high infectivity to be achieved without proportionally increasing antibody binding across the entire capsid structure.
Data Source
AI summary
The present invention provides mutant adeno-associated virus serotype 5 (AAV5) that exhibit altered capsid properties, e. g., increased infectivity in human liver cells and/or minimal binding to human neutralizing antibodies. The present invention further provides libraries of mutant AAV5 comprising one or more mutations in a capsid gene. The present invention further provides methods of generating the mutant AAV5 and mutant AAV5 libraries, and compositions comprising the mutant AAV5. The present invention further provides recombinant AAV5 (rAAV5) virions that comprise a mutant capsid protein. The present invention further provides nucleic acids comprising nucleotide sequences that encode mutant capsid proteins.