Researchers at Homology Medicines developed a capsid selection strategy that can allow the use of the best vector to develop gene therapies to treat different genetic diseases including lysosomal storage disorders such as lysosomal acid lipase deficiency (LAL-D).

This approach, the researchers said allows them to “embrace a capsid selection rather than a ‘one-capsid-fits-all’ limitation to best develop disease-specific therapeutics,” as presented at the American Society of Gene and Cell Therapy’s (ASGCT) 2022 Annual Meeting.

Capsid selection is key to the success of gene therapy. In the present study, a team of researchers led by Jacinthe Gingras, PhD, used a panel of 15 naturally occurring adeno-associated viruses (AAVs) isolated from healthy human hematopoietic stem cells (HSCs) to identify key features to develop a capsid selection strategy for rare metabolic and neurological diseases.


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Each so-called AAVHSC differs from each other and from the widely-used AAV9 capsid by 1 to 4 amino acids at different regions such as hypervariable regions, phospholipase domain, basic regions, and glycan-binding sites. These variations give each capsid a unique set of features in terms of tropism, overall immune responses, and transduction kinetics, the researchers said.

Read more about LAL-D overview

“By understanding the relationship of how each variation, based on structural and functional mapping, contributes to the unique characteristics of each capsid, we identify key insights to help guide our AAVHSC program capsid selection strategy,” they wrote.

Capsid selection for each specific requirement is based on features such as vector genome translation, biodistribution, transgene output, translatable biomarkers, access to the blood circulation or cerebrospinal fluid, trafficking, and second-strand synthesis.

LAL-D is a rare lysosomal storage disorder caused by mutations in the LIPA gene, which encodes the acid lipase enzyme that is essential to break down certain fats. Gene therapy for LAL-D is still in its infancy but researchers are working on developing new strategies to use it to treat this incurable disease. The capsid selection strategy presented here could accelerate their quest.

Reference

Smith LJ, Avila N, Behmoiras L, et al. Capsid selection strategy for the development of gene therapies based on structural and functional analyses of a panel of AAVHSCs. Poster presented at: American Society of Gene and Cell Therapy’s (ASGCT) 25th Annual Meeting: May 16-19, 2022; Washington DC.