human kallikrein delivered by recombinant adeno-associated virus

rAAV-HK is an investigational gene therapy product in which a recombinant adeno-associated virus (rAAV) vector is used to deliver and express the human tissue kallikrein (HK) gene. The therapy is designed to achieve stable, long-term expression of human kallikrein, a serine protease that converts kininogen to kinins, which in turn activate bradykinin receptor 2 (B2R), leading to vasodilation and reduced blood pressure. Preclinical studies in animal models (e.g., spontaneously hypertensive rats) demonstrated that rAAV-HK administration led to a sustained reduction in blood pressure, protection against cardiovascular and renal injury, alleviation of organ damage, and reductions in cell apoptosis in the heart, kidney, and aorta[1][2][4]. The mechanism involves not only blood pressure reduction through the kallikrein-kinin system but also anti-apoptotic effects via activation of cell survival pathways (e.g., ERK1/2, PI3K/AKT) and modulation of apoptosis-related proteins (e.g., increased Bcl-2, Bcl-xL; decreased Bax, caspase 3)[1]. rAAV-HK also modulates expression of receptors involved in renal function, including upregulation of bradykinin receptor 2 (B2R) and dopamine D1 receptor (D1R), and downregulation of angiotensin II receptor type 1 (AT1R), endothelin A receptor (ETAR), and vasopressin V2 receptor (V2R)[2]. The rAAV vector allows for stable, long-term transgene expression and low immunogenicity[2][4].