Revolutionizing hereditary angioedema management: a breakthrough

Hereditary angioedema (HAE) is a genetic disorder with the potential for life-threatening consequences, marked by recurring incidents of angioedema1. First recorded in 1882, HAE is identified as an uncommon autosomal dominant disorder characterized by intermittent, spontaneously resolving tissue swelling linked to reduced functional levels of C1 esterase inhibitor (C1-INH)2,3. Marked by repeated, unforeseeable episodes of swelling caused by leaky blood vessels, HAE greatly diminishes the quality of life for affected individuals1,4. Traditional treatment methods, which demand continuous use and raise concerns about effectiveness, have long prompted the search for innovative solutions. The intricate pathophysiology of HAE is primarily driven by a genetic mutation that induces heightened kallikrein synthesis, initiating the liberation of bradykinin, a potent regulator of vascular permeability5. Consequently, these mechanisms precipitate the characteristic vascular swelling episodes associated with HAE, affecting various organs, including the skin, gut, and lungs. Current therapies, spanning plasma kallikrein inhibitors to RNA-silencing methods, necessitate continual, lifelong application5,6. The unpredictable and severe nature of HAE episodes frequently results in a diminished quality of life for those affected. However, a few weeks ago, NTLA-2002 gene therapy, employing the Nobel Prize-winning gene-editing tool CRISPR/Cas9, exhibited encouraging results in a limited clinical trial for HAE, emerging as a beacon of hope in the therapeutic landscape of HAE7. Researchers observed a notable reduction in monthly episodes of swift swelling, typical of angioedemas, following a single dose, with no significant safety issues7,8. Recent advancements in HAE management have been further solidified by the introduction of novel therapies such as berotralstat, approved for routine prevention of HAE attacks9. This orally administered drug targets the plasma kallikrein pathway more specifically, reducing the frequency of HAE episodes without the need for injections, thus offering an improved quality of life for patients. Likewise, according to the latest findings from ongoing research, novel prophylactic treatments like lanadelumab, an injectable monoclonal antibody that selectively inhibits active plasma kallikrein, have been approved10. This therapy has shown substantial efficacy in reducing the attack rate in HAE patients, offering a new ray of hope for those seeking less frequent treatment administrations. NTLA-2002 represents an in vivo gene-editing intervention utilizing CRISPR-Cas9 technology, specifically directed at the kallikrein B1 (KLKB1) gene7. The objective is to achieve sustained management of angioedema episodes throughout one’s life with just a single administration. It employs lipid nanoparticle technology for conveying mRNAs that encode the Cas9 endonuclease and a single guide RNA (sgRNA) to hepatocytes, primarily housing KLKB17. Through deactivating the gene accountable for plasma prekallikrein production, NTLA-2002 aims to offer a singular, enduring resolution HAE. In a meticulously executed Phase I trial conducted at various global locations, NTLA-2002 not only exhibited an impeccable safety record but also displayed noteworthy, dose-dependent decreases in overall plasma kallikrein protein levels7. The reduction in the frequency of angioedema attacks further emphasizes the therapeutic promise inherent in this groundbreaking intervention. Real-world impact echoed through patient testimonials, portraying the transformative effects of the therapy. Participants described the therapy as a ‘medical magic wand’, emphasizing the liberation from the shackles of chronic HAE attacks and the associated physical and mental burdens11. The notable achievements of NTLA-2002 have garnered attention, resulting in its classification as a priority medicine by the European Medicines Agency12. The upcoming pivotal Phase III study on a global scale seeks to further establish its status as a groundbreaking therapy with the potential to redefine the landscape of managing HAE7,8,11. As we move forward, continuous monitoring and long-term follow-up studies are essential to validate the durability and broader applicability of these gene-editing and new pharmacological interventions, ensuring that the promise they hold translates into long-term benefits for patients with HAE. In the pursuit of overcoming HAE, NTLA-2002 emerges as a promising symbol, employing CRISPR-Cas9 to redefine therapeutic strategies. This advancement not only signifies a substantial advancement in meeting the unfulfilled requirements of individuals with HAE but also emphasizes the revolutionary capabilities of gene-editing technologies in the domain of rare genetic disorders. Ethical approval This study does not require ethics approval. Consent Not applicable. Sources of funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Author contribution S.D. and M.N.K.: contributed equally to the conception, design, analysis, and interpretation of data, drafting the manuscript, and critical revision; G.T.B., S.G., D.S., and R.K.S.: contributed to data acquisition, analysis, drafting, and critical revision; M.A., S.R., P.S., and R.S.: contributed to data interpretation, drafting, and critical revision. All authors approved the final version and agreed to be accountable for the work. Conflicts of interest disclosure None. Research registration unique identifying number (UIN) Not Applicable. Guarantor Not Applicable. Data availability statement Not applicable. Provenance and peer review Not Applicable.

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