On March 18, 2026 Azalea Therapeutics, Inc., a biotechnology company redefining precision genomic medicines in vivo, reported the publication of foundational research in Nature describing in vivo site-specific genomic integration to reprogram T cells. The research originated as an academic collaboration between the Eyquem laboratory at the University of California, San Francisco and the Doudna laboratory at the University of California, Berkeley. Three of the study’s authors – Justin Eyquem, Ph.D., Jenny Hamilton, Ph.D. and Jennifer Doudna, Ph.D. – subsequently co-founded Azalea Therapeutics to advance precise, programmable in vivo cell engineering toward the development of next-generation in vivo CAR T and other cell-based therapies.
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The publication, titled "In vivo site-specific engineering to reprogram T cells," demonstrates that stable and cell-specific transgene expression can be achieved through in vivo integration of large DNA payloads using a two-vector system consisting of enveloped delivery vehicles (EDVs) and adeno-associated viruses (AAVs). In preclinical models, the approach enabled targeted integration of a promoterless chimeric antigen receptor (CAR) transgene at the TRAC locus, resulting in physiologic CAR expression, robust T cell expansion and durable anti-tumor activity.
The research shows that placing CAR expression under control of the endogenous T cell receptor alpha (TRAC) promoter produces regulated CAR expression compared to conventional approaches relying on random integration or constitutive exogenous promoters. In humanized mouse models of B cell aplasia and hematologic malignancies, in vivo-generated TRAC-CAR T cells achieved therapeutic levels of CAR-positive T cells and sustained tumor control.
"This work demonstrates that stable, cell-specific transgene expression can be achieved through in vivo site-specific integration," said Justin Eyquem, Ph.D., co-founder of Azalea Therapeutics and associate professor of medicine at UCSF. "By integrating a promoterless CAR into the TRAC locus, we place expression under control of the endogenous T cell promoter, resulting in physiologic regulation and durable functional activity in preclinical models. These findings establish a foundation for precise in vivo T cell engineering without ex vivo manufacturing."
The research further describes optimization of both delivery components, including evolution of an AAV variant for improved T cell targeting and incorporation of an anti-CD3-targeted EDV to enhance specificity and activation. In humanized mouse models, the optimized system enabled generation of TRAC-CAR T cells representing up to ~20% of splenic T cells following a single administration, accompanied by complete B cell aplasia and tumor clearance.
"The research described in this publication establishes the scientific foundation for precise, programmable CAR insertion directly inside the body," said Jenny Hamilton, Ph.D., co-founder, president and chief executive officer of Azalea Therapeutics. "At Azalea, we are building on these findings with our proprietary EDV-based platform to advance in vivo CAR T programs toward clinical development. Our goal is to generate physiologically regulated, durable CAR T cells in patients through targeted genomic integration, while avoiding the complexity of ex vivo cell manufacturing."
Azalea is advancing TRAC-targeted in vivo CAR T programs toward IND-enabling studies, building on the foundational work described in this publication, which is available online in Nature.
(Press release, Azalea Therapeutics, MAR 18, 2026, View Source [SID1234663733])