Klkb1-KO Mouse

Klkb1, encoding plasma prekallikrein, is also known as Fletcher factor or kallikrein B1. Its physiological role is to catalyze the release of kinins and other vasoactive peptides [6]. It is unique as coagulation factor XI (FXI) arose through a duplication of the Klkb1 gene [2]. Klkb1 is associated with multiple biological processes and diseases, including its role in the coagulation cascade, barrier function, platelet activation, inflammation, and the immune response [2].

In the context of hereditary angioedema, NTLA-2002, an in vivo gene-editing therapy based on CRISPR-Cas9, targets Klkb1. In a phase 1 dose-escalation trial, a single dose of NTLA-2002 led to robust, dose-dependent, and durable reductions in total plasma kallikrein levels, with significant decreases in angioedema attacks at all dose levels, and no severe adverse events were observed [1]. In the phase 2 portion of the trial, single doses of 25 mg or 50 mg of NTLA-2002 reduced angioedema attacks and led to sustained reduction in total plasma kallikrein levels [5]. Additionally, Klkb1 has been associated with HDL-mediated cholesterol efflux capacity in a genome-wide association study [3], may be a potential prognostic biomarker for hepatocellular carcinoma [4], and its polymorphisms are associated with pulmonary thromboembolism in the Chinese Han population [7]. It has also been identified as a potential drug target for keloids [8], and its mRNA expression may be a diagnostic biomarker for chronic lymphocytic leukemia [6].

In conclusion, Klkb1 is crucial for the regulation of various biological functions. Studies using gene-editing approaches targeting Klkb1, like NTLA-2002 in hereditary angioedema, have shown promise in understanding its role in disease and potential therapeutic applications. Its associations with multiple diseases highlight its importance in biomedical research, providing potential targets for drug development and disease diagnosis.