Written by Peter Liu
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In hereditary angioedema, gene therapy to downregulate kallikrein is being studied. Phase 2 trials show safety and promising efficacy.
Gene therapy may become a curative option
Gene therapy and gene editing technologies remain an investigational technique to treat disease, but there is mounting evidence that it can benefit patients with many conditions including various cancers, sickle cell disease, immunodeficiencies, and infections such as HIV (PMID: 31365802). It appears hereditary angioedema (HAE) may be another disease this technology has the potential to cure. HAE involves deficiency in C1 inhibitor (C1INH) activity, which results in bradykinin overactivity. While rare, it is common for large-volume inpatient practices in tertiary care centers to see cases of HAE, as well as mimics of HAE, both as new diagnoses and for treatment of acute episodes. Established treatments for HAE involve administration of C1INH, bradykinin antagonists, or kallikrein inhibitors (kallikrein cleaves proenzymes into active bradykinin), usually prescribed and managed with specialty involvement. These therapies are preventive or abortive but only work for short periods of time. A gene therapy approach may offer a curative option. Today’s phase 2 randomized, double-blind, placebo-controlled trial evaluated NTLA-2002, an in vivo CRISPR-based gene-editing therapy to downregulate KLKB1 (the gene coding serum kallikrein) in liver cells. Twenty-seven patients received a single 25mg (n=10) or 50mg (n=11) dose of NTLA-2002 or placebo (n=6). NTLA-2002 arms had lower mean monthly attack rates by 75% (25mg) and 77% (50mg) versus placebo (2.82 attacks/month; 95%CI 0.80–9.89; differences not statistically significant). Follow-up was 16 weeks long. Plasma kallikrein levels declined by 55% (25mg) and 86% (50mg). Only mild or moderate adverse events were noted in the NTLA-2002 arms. These results support further investigation in phase 3 trials.
How does this change my practice?
When I first learned of CRISPR in 2015, I thought it would be twenty years before any application. Ten years later, the findings from the featured study today put HAE on the map as another disease with promising gene therapies. It will be exciting to see longer-term efficacy and safety outcomes in a larger patient population in addition to the frequency of the dosing.
Source
CRISPR-Based Therapy for Hereditary Angioedema. N Engl J Med. 2025 Jan 30;392(5):458-467. doi: 10.1056/NEJMoa2405734. Epub 2024 Oct 24. PMID: 39445704
