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

Abstract

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