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Hereditary angioedema attacks are caused by too much of a molecule called bradykinin, which makes blood vessels leak. KLKB1 makes a protein several steps upstream in the chain that produces it. Remove that protein and the chain cannot run — which is why an editing therapy aims at KLKB1 rather than at the gene that is actually mutated in the disease.
KLKB1, at 4q35.2, encodes plasma prekallikrein, which is activated to kallikrein and cleaves high-molecular-weight kininogen to release bradykinin. In hereditary angioedema, C1-inhibitor deficiency leaves this pathway unrestrained. Hepatic KLKB1 knockout removes the substrate rather than replacing the missing inhibitor — an instructive example of targeting a pathway rather than the mutated gene.
Sources
- New England Journal of Medicine (Cohn et al.) · 2024
CRISPR-based therapy for hereditary angioedema ↗