NTLA-2002: CRISPR/Cas9-mediated gene knockout of KLKB1 to treat hereditary angioedema

Hereditary angioedema (HAE) is a rare genetic disorder characterized by recurrent episodes of debilitating and potentially fatal swelling in various parts the body including face, hand airways. Prophylactic treatment options for HAE patients have dramatically improved recent years, significantly reducing frequency attacks overall disease burden but all require chronic, life-long administration. The emergence genome editing technologies as new therapeutic modality offers promise curing many diseases. To this end, Intellia Therapeutics developing NTLA-2002, an investigational CRISPR/Cas9-based therapy targeting KLKB1 HAE. Guide RNA human- cynomolgus monkey-specific were identified formulated using Intellia’s modular CRISPR/Cas9 lipid nanoparticle (LNP) platform technology. These formulations evaluated humanized mouse model (huKLKB1) monkey. gene editing, plasma kallikrein concentration activity, vascular leakage evaluated. In huKLKB1 mouse, single administration NTLA-2002 resulted robust (∼70%), subsequent reductions total (>90%) abrogation captopril-induced leakage. monkey, cyno-specific LNP formulation (∼70%) both protein activity (>95%). Further, these been maintained at least 15 months ongoing monkey study. A robust, durable reduction supporting further development potential one-time option with