Mutant AAV Capsids Evading Antibody Neutralization
Solution Overview
Problem
Recombinant adeno-associated virus (rAAV) vectors face challenges such as neutralization by serum antibodies, limited tissue dispersion, poor infection of non-permissive cell types, and finite transgene carrying capacity, which hinder their effectiveness in gene delivery.
Innovation Solution
Development of mutant AAV vectors with altered capsid properties, including reduced binding to neutralizing antibodies and altered heparin binding, to enhance infectivity and evade neutralization, allowing for improved gene delivery to specific cell types and tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type AAV vectors are used for gene delivery, then they are safe and can deliver genes efficiently, but they are neutralized by serum antibodies in a significant fraction of the population
Solution Approach 1:
The patent applies parameter changes by mutating specific amino acid residues in the AAV capsid protein (e.g., VP1, VP2, or VP3) to alter the capsid's binding properties. These mutations change the capsid's interaction with neutralizing antibodies and cell surface receptors, thereby reducing neutralization while maintaining or enhancing gene delivery efficiency to target cells.
2Reliability
If AAV serotypes using heparan sulfate as a receptor are used, then they achieve efficient gene delivery, but they have limited tissue dispersion
Solution Approach 1:
The patent applies local quality by creating capsid variants with differentiated binding affinities for different cell surface receptors. By mutating specific regions of the capsid protein, the invention enables selective binding to different receptors (e.g., heparan sulfate, integrins, or other cell surface molecules) depending on the target tissue, thereby achieving both efficient delivery and controlled tissue dispersion.
3Reliability
If standard AAV vectors are used, then they can infect permissive cell types, but they fail to infect non-permissive cell types such as stem cells
Solution Approach 1:
The patent applies universality by generating capsid mutants capable of binding to multiple different cell surface receptors. These multi-functional capsids can infect diverse cell types including permissive cells, non-permissive cells, and stem cells by utilizing different receptor interactions, thereby achieving broad cell type specificity while maintaining high infection efficiency.
Data Source
AI summary
The present invention provides mutant adeno-associated virus (AAV) that exhibit altered capsid properties, e.g., reduced binding to neutralizing antibodies in serum and/or altered heparin binding and/or altered infectivity of particular cell types. The present invention further provides libraries of mutant AAV comprising one or more mutations in a capsid gene. The present invention further provides methods of generating the mutant AAV and mutant AAV libraries, and compositions comprising the mutant AAV. The present invention further provides recombinant AAV (rAAV) virions that comprise a mutant capsid protein. The present invention further provides nucleic acids comprising nucleotide sequences that encode mutant capsid proteins, and host cells comprising the nucleic acids. The present invention further provides methods of delivering a gene product to an individual, the methods generally involving administering an effective amount of a subject rAAV virion to an individual in need thereof.