AAV Capsid Engineering

Adeno-associated virus (AAV) capsids are useful for gene therapies because they can carry
a DNA payload and are non-pathogenic. The first AAV-delivered gene therapies were recently approved but are still not optimized
for clinical use. They need to become better at targeting specific tissues and less conspicuous to the
immune system. Wyss Institute researchers have developed a new systemactic approach to protein engineering,
applying it to the AAV capsid. They generated a library of every possible single change to the capsid protein sequence,
testing over 200,000 variants. Analyzing the library in mice revealed distinct variant profiles of mutations enhancing
AAV’s tropism for specific tissues. Unexpectedly, the team’s comprehensive approach also uncovered a new protein
encoded by the AAV genome, with potential functions at the cell membrane. A first application generating “deep” multi-mutant AAV variants demonstrated the superior
tissue-targeting potential of these libraries. Wyss researchers are now working to analyze these libraries with machine learning,
for engineering highly efficient, tissue-specific and minimally immunogenic AAV gene therapies.

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