Gene edited T lymphocytes hold promise as safe and effective living therapies for a wide range of humandiseases, including autoimmune disease. However, viral methods currently employed to engineer cells fortherapy are imprecise, exorbitantly expensive, and have high failure rates. These drawbacks limit developmentof cell therapies and prevent them from penetrating alternative markets, where natural, spontaneous diseasecan be addressed in pre-IND and IND-enabling studies to improve therapeutic outcomes.This proposal is focused on optimizing and advancing the development of a novel, non-viral method for highlyefficient and precise engineering of human T cells. The innovation is a nanoplasmid-based, site-specific geneediting platform that enables tunable manufacturing of human cell therapeutics. Not only will this precise geneediting platform yield a quantum leap forward in cellular engineering, but the resultant product will also providesustained clinical improvements over the standard of care for B cell-mediated autoimmune diseases, for whichno current cell therapies exist. This Phase I proposal is focused on optimizing the efficiency of the GeneWeldsite-specific gene editing platform and demonstrating the in vitro functionality of using GeneWeld to reprogramhuman Chimeric Antigen Receptor (CAR)-T cells for elimination of a targeted B cell population.
Public Health Relevance Statement: NARRATIVE
No precise, plasmid-based, non-viral gene integration platform has achieved scalable, efficient manufacturing
for human cell therapies. This proposal is focused on fulfilling this unmet need with the development of a safe,
non-viral, targeted, and highly efficient genome editing platform for ex vivo programming of primary human T
cells (e.g., CAR-T cells).
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