A new CRISPR-based approach could eliminate one of the biggest bottlenecks in cell therapy: manufacturing engineered T cells outside the body. Researchers report a two-vector system that creates functional CAR T cells in vivo by precisely inserting therapeutic genes into a T cell-specific genomic site.
The method combines enveloped delivery vehicles (EDVs) carrying CRISPR-Cas9 with an engineered adeno-associated virus (AAV) that delivers a DNA template. Together, they enable targeted insertion of a CAR gene into the TRAC locus – ensuring controlled, T cell-specific expression. In humanized mouse models, the system generated substantial populations of CAR T cells directly in vivo, reaching therapeutic levels and triggering expected biological effects such as B cell depletion.
Crucially, the team engineered both delivery components for specificity and efficiency: a CD3-targeted EDV to home in on T cells, and a serum-resistant AAV variant that exploits CD7 for improved uptake. The resulting cells showed strong proliferation and anti-tumor activity across leukemia, myeloma, and even solid tumor models – often outperforming conventional viral approaches.
If translated to humans, this strategy could bypass complex ex vivo workflows, dramatically reducing cost and expanding access to CAR T therapies.
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