Hereditary angioedema (HAE) is a rare genetic disease that causes severe and unpredictable swelling attacks due to an overproduction of bradykinin. These attacks often affect the face, airways, abdomen, and extremities and can be life-threatening.

Normally, bradykinin is produced through a process called the contact system, which helps regulate blood flow and inflammation. To keep this system in check, the body uses a protein called C1 inhibitor (C1-INH), which acts like a brake. In HAE, this brake is either missing or does not work properly, resulting in excess bradykinin that causes fluid to leak through blood vessel walls and leads to rapid swelling.

There are three types of HAE. The most common is Type I HAE, which accounts for about 85% of cases and occurs when the body does not make enough C1-INH, leaving it unable to properly regulate the contact system. Type II HAE occurs when the body produces C1-INH, but the protein does not function properly. Both Type I and Type II HAE are caused by mutations in the SERPING1 gene, which encodes the C1-INH protein. The least common form is HAE with normal C1-INH, in which C1-INH levels and function are normal, but other genetic or biological factors lead to excessive bradykinin production and swelling. Although the underlying causes differ, the three forms can have similar clinical presentations.

Together, Types I and II are estimated to affect approximately 1 in 50,000 people and can significantly affect patients’ quality of life and mental health because of the unpredictable and potentially severe nature of attacks. Symptoms usually begin during childhood or adolescence and often worsen after puberty. By age 20, nearly everyone with Type I or Type II HAE has experienced symptoms. It is not always clear what causes an HAE attack, but known triggers can include physical injury or minor trauma, dental procedures, surgery, anxiety or emotional stress, viral infections, and repetitive physical activities such as typing, hammering, or shoveling.

While preventive and on-demand treatments are available, long-term prophylactic (LTP) therapies generally require ongoing treatment to continuously suppress the biological pathways responsible for HAE attacks. Depending on the therapy, this may involve intravenous (IV) or subcutaneous (SC) injections or daily oral medication.

However, a new treatment from Intellia Therapeutics could offer a different approach: a single dose designed to provide long-lasting protection against HAE attacks. Results from its Phase 3 trial demonstrate that the therapy can significantly reduce attacks and improve quality of life.

Lonvo-z: a one-time CRISPR treatment

Lonvoguran ziclumeran (lonvo-z), previously known as NTLA-2002, is an investigational one-time treatment developed by Intellia that uses lipid nanoparticles to deliver CRISPR-Cas9 gene-editing components to liver cells.

Rather than repairing the faulty C1-INH “brake” responsible for Type I and Type II HAE, lonvo-z targets a different part of the pathway that produces bradykinin. The treatment permanently disrupts the kallikrein B1 (KLKB1) gene, reducing production of plasma prekallikrein. This, in turn, reduces the amount of kallikrein available to drive bradykinin production and prevents swelling attacks.

Recent results from Intellia’s Phase 3 HAELO trial showed that a single 50 mg dose of lonvo-z reduced the monthly HAE attack rate by 87% compared with placebo.

The randomized, double-blind study enrolled 80 patients randomized 2:1 (52 lonvo-z, 28 placebo) aged 16 years or older with Type I or Type II HAE. Participants received a single IV infusion of either 50 mg lonvo-z or placebo. Of the total study population, 71% were receiving long-term prophylaxis (LTP) at study entry. Patients taking LTP were required to discontinue those therapies before receiving the study treatment.

During the six-month efficacy evaluation period, from weeks 5 through 28, the mean monthly attack rate was 0.26 among patients receiving lonvo-z, compared with 2.10 in the placebo group — an 87% reduction relative to placebo.

Nearly two-thirds of patients (62%) treated with lonvo-z were entirely attack-free without additional prophylactic treatment from weeks 5-28, compared with 11% of those receiving placebo. Moderate-to-severe attacks were reduced by 91% compared with placebo. Total plasma kallikrein levels fell ~65% by day 15 and reached a ~80% steady-state reduction by week 5 that was maintained through week 28. Patients receiving lonvo-z also reported improvements in quality of life that exceeded clinically meaningful thresholds. As of the data cutoff, all patients who received lonvo-z remained free from LTP.

The safety findings were also encouraging, with no serious adverse events or Grade 3 or higher adverse events reported in the lonvo-z group. The most common adverse events during the primary observation period that occurred more frequently with lonvo-z than placebo included infusion-related reactions, headache, fatigue, back pain, and upper respiratory tract infection.

“As a clinician who has witnessed patients struggle with the unpredictability and emotional toll of HAE, the prospect of offering lasting freedom from attacks and chronic medication with a one-time treatment is incredibly exciting, said Danny Cohn, M.D., Ph.D., Internist, Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, and a HAELO principal investigator. “These results give me confidence that many patients will soon have the potential to enjoy a normal life.”

However, the relatively short follow-up period cannot establish the long-term safety of a permanent gene-editing treatment. Because lonvo-z is designed to permanently alter the KLKB1 gene, patients will need to be followed for years to determine whether its efficacy remains durable and whether any long-term safety concerns emerge, such as late hepatic or coagulation safety signals, off-target effects, or germline modifications.

Building on earlier Phase 2 results

The Phase 3 findings build on encouraging results from Intellia’s earlier randomized Phase 2 trial, in which 27 patients received either 25 mg or 50 mg of lonvo-z or placebo (1).

Compared with placebo, lonvo-z reduced the estimated attack rate by 75% among patients receiving the 25 mg dose and by 77% among those receiving the 50 mg dose. During weeks 1 through 16, 4 of the 10 patients who received 25 mg and 8 of the 11 patients who received 50 mg were attack-free and did not require additional treatment (1).

The Phase 3 trial continued this trend, providing evidence of efficacy in a substantially larger group of patients using the selected 50 mg dose. Although the Phase 3 data do not yet prove multi-year durability, pooled Phase 1/2 data for patients who received the 50 mg dose showed nearly 3 years of efficacy, with up to 97% of patients attack- and long-term prophylaxis-free at the cutoff.

A growing HAE treatment landscape

If approved, lonvo-z would enter an HAE treatment landscape that has expanded considerably in recent years. Patients in the United States now have access to numerous therapies that either treat attacks when they occur or prevent them through long-term prophylaxis (LTP).

On-demand treatments include C1-INH replacement therapies such as Berinert and Ruconest, which are used to treat acute HAE attacks. Another recent addition is Ekterly (sebetralstat), an oral plasma kallikrein inhibitor developed by KalVista Pharmaceuticals and approved by the FDA in July 2025. Unlike preventive therapies, sebetralstat is taken orally when an attack begins.

Several effective options are also available for long-term prevention, including Haegarda and Cinryze, which are plasma-derived C1-INH therapies used prophylactically to replace the deficient or dysfunctional protein underlying Type I and Type II HAE, and are administered every three to seven days.

Takhzyro, also called lanadelumab, developed by Takeda, is a monoclonal antibody that targets plasma kallikrein. Approved by the FDA in 2018, it substantially reduces HAE attacks and is administered subcutaneously every two to four weeks.

Orladeyo, also called berotralstat, developed by BioCryst Pharmaceuticals, is an oral small-molecule plasma kallikrein inhibitor approved in 2020 for HAE prophylaxis. Unlike injectable preventive therapies, it is taken orally once daily but requires continuous adherence.

Andembry, or garadacimab-gxii, developed by CSL, is a first-in-class monoclonal antibody that targets activated factor XII (FXIIa), an upstream component of the pathway that leads to bradykinin production. Approved by the FDA in June 2025 for patients aged 12 years and older, it is administered by subcutaneous injection once a month.

Dawnzera, also known as donidalorsen, is an RNA-targeted antisense oligonucleotide (ASO) that reduces prekallikrein production, targeting the same general pathway as lonvo-z. Approved in the United States in August 2025, it is administered subcutaneously every four or eight weeks and reduced HAE attack rates by approximately 81% compared with placebo in pivotal trial data. Long-term data from the OASISplus OLE cohort showed that at 52 weeks, patients in the 4- and 8-week dosing groups demonstrated a 94% and 95% mean attack reduction from baseline, respectively (2).

It is important to note that the clinical landscape here is not a head-to-head comparison. While Lonvo-z reduced the estimated attack rate by 75%, Dawnzera by 81%, Andembry by ~89% (mean) / >99% (median), and Takhzyro historically by ~87%, each was tested in different trials with different baselines and endpoints. Additionally, while existing prophylactic treatments can provide substantial protection against HAE attacks, their effects depend on continued treatment. Lonvo-z is designed to achieve sustained suppression of plasma kallikrein following a single treatment by permanently editing KLKB1. Lonvo-z’s greatest potential advantage is therefore not simply the magnitude of its reduction in attacks, but the possibility of achieving long-term disease control without chronic medication. A one-time infusion could also reduce the treatment burden associated with repeated injections or daily oral medications and eliminate adherence issues associated with chronic prophylaxis.

However, this advantage comes with a different type of risk. Existing HAE medications are temporary and can generally be discontinued if problems arise. CRISPR gene editing is designed to produce a permanent genetic change. While no serious or Grade 3 or higher adverse events were reported in the lonvo-z group in the Phase 3 trial during the primary observation period, the relatively limited follow-up means its long-term safety and durability have yet to be established.

That concern has previously influenced investor perceptions of the therapy. In 2024, after Intellia published positive Phase 2 data in the New England Journal of Medicine, the company’s shares fell more than 20% as Baird analysts argued that the results were not sufficiently compelling to outweigh perceived risks associated with in vivo gene editing.

Intellia anticipates regulatory approval and a U.S. Launch in the first half of 2027 if the rolling BLA is completed in 2H 2026 and accepted. The therapy has Regenerative Medicine Advanced Therapy (RMAT) status, Orphan Drug designation, and a rolling biologics license application (BLA) that was initiated in April with the FDA.

Future of lonvo-z in HAE treatment

The Phase 3 HAELO results demonstrate the potential of lonvo-z to offer another effective treatment option for HAE by providing long-term protection from attacks after a single treatment. While several effective therapies already exist, they require ongoing treatment, making lonvo-z’s one-time dose a potential advantage. However, because the therapy permanently edits the genome, longer-term follow-up will be critical to establish its durability and identify any potential long-term risks. If approved, lonvo-z could potentially shift the treatment of HAE from a disease requiring lifelong management to one with lasting control after a single intervention.

References:

1. Cohn DM, Gurugama P, Magerl M, Katelaris CH, Launay D, Bouillet L, Petersen RS, Lindsay K, Aygören-Pürsün E, Maag D, Butler JS, Shah MY, Golden A, Xu Y, Abdelhady AM, Lebwohl D, Longhurst HJ. 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.
2. Lumry WR, Tachdjian R, Craig T, Karakaya G, Gelincik A, Stobiecki M, Jacobs JS, Gokmen NM, Reshef A, Manning ME, Grammatikos A, Giardino F, Guilarte M, Baptist AP, Bordone L, Newman KB, Treadwell S, Lin T, Yarlas A, Riedl MA, Cohn DM. Donidalorsen for Long-Term Prophylaxis of Hereditary Angioedema Attacks: Results from the OASISplus Open-Label Extension Cohort at Year 1. J Asthma Allergy. 2026 Feb 23;19:592079. doi: 10.2147/JAA.S592079. PMID: 41767175; PMCID: PMC12948764.

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https://www.nejm.org/doi/10.1056/NEJMoa2512761

Dr. Nicholas Marsten
TIMI Study Group, Brigham and Women’s Hospital

A multiobjective AI model for LNP engineering enhances tissue-selective mRNA delivery
https://www.nature.com/articles/s41587-026-03109-0

Dr. Muye Zhou
University of Toronto

John J. Rossi, Ph.D.
​

Dr. Rossi has had a more than forty year career focusing on the development of nucleic acid-based therapies and RNA interference approaches for the treatment of AIDS, cancer, and other major diseases. He is considered a world leader in this field. In 2011 he was elected as an AAAS fellow in Medical Sciences and in 2019 he received the Outstanding Achievement Award from the American Society of Gene & Cell Therapy. He is also an active participant in graduate education, and is Dean Emeritus of the Irell & Manella Graduate School of Biological Sciences.

He served as a Lidow Family Research Chair and Chair and Professor of the Department of Molecular and Cellular Biology of Beckman Research Institute. In addition, as Director of two biotechnology companies.

He was co-founder of several biotechnology companies, including Dicerna Pharmaceuticals, Inc., MiNA Therapeutics, iSTAT Therapeutics, Apterna, and Calando Pharmaceuticals, Inc. for which he has served as Chairman and is currently a member of the Scientific Advisory Board. He also currently serves or has served as member of the Scientific Advisory Board for six other biotechnology companies (SEKRIS Biomedical, Inc., Arrowhead Research Corporation, Kylin Therapeutics Inc., VIRxSYS Corporation, Benitec Biopharma Limited (also known as Benitec Ltd., Nanoviricides, Inc.). Dr. Rossi is a graduate of the University of New Hampshire and received his PhD in microbial genetics from the University of Connecticut. Following a post-doctoral fellowship in molecular genetics at Brown University Medical School, he has been on the faculty of City of Hope since 1980.

Pieter R. Cullis, Ph.D.
​

Pieter R. Cullis, Professor, Department of Biochemistry and Molecular Biology, University of British Columbia. Dr. Cullis and co-workers have been responsible for fundamental advances in the development of nanomedicines employing lipid nanoparticle (LNP) technology for cancer therapies, gene therapies and vaccines. This work has contributed to five drugs that have been approved by the FDA, the EMA and other regulatory bodies. These include Onpattro (the first RNAi drug to receive regulatory approval) to treat the previously fatal hereditary condition transthyretin-induced amyloidosis (hATTR), as well as Comirnaty, the Pfizer/BioNTech COVID-19 mRNA vaccine.

Dr. Cullis has also co-founded eleven biotechnology companies that now employ over 500 people, has published over 400 scientific articles and is an inventor on over 100 patents. He co-founded two Canadian National Centre of Excellence networks, the Centre for Drug Research and Development (now AdMare) in 2004 and the NanoMedicines Innovation Network in 2019. Dr. Cullis has received many awards including the Order of Canada in 2021 and the VinFuture Prize (Vietnam), the Prince Mahidol Award (Thailand), the Gairdner International Award (Canada) and the Tang Prize (Taiwan) in 2022. Professor Cullis was made a Fellow of the Royal Society (London) in 2023 and was elected to the Canadian Medical Hall of Fame in 2024.

Tim Yu, MD, PhD
Boston Children’s Hospital and Harvard Medical School

Talk Title: Interventional genetics: who’s in the waiting room?

Dr. Yu is a neurogeneticist at Boston Children’s Hospital and Harvard Medical School. He obtained his undergraduate degree in Biochemistry at Harvard College. As a MD-PhD student at UCSF, he used molecular genetics to elucidate basic mechanisms of neuronal attraction and repulsion in the wiring of the C. elegans nervous system, and authored or co-authored papers in Science, Neuron, Nature Neuroscience and Nature Reviews Neuroscience. He then completed neurology residency at Massachusetts General Hospital and Brigham and Women’s Hospital. He joined the faculty in the Division of Genetics and Genomics at Boston Children’s Hospital, and is currently Associate Professor at Harvard Medical School and an Associate Member of the Broad Institute. He leads a cross-disciplinary research group that operates at the intersection of genomics, neurobiology, and bioinformatics. Tim’s group was one of the first in the field to deploy high throughput sequencing methods for human genetics, and today continues to use advanced sequencing and analytics to understand the genetic architecture of autism, and other disorders of brain development. His lab has also translated these tools to the hospital, conducting analyses of rapid-turnaround genomic sequencing in both the neonatal intensive care unit and the newborn nursery. Finally, Tim’s group has pioneered disruptive approaches to accelerating treatments for orphan genetic diseases. Beginning with a young girl with Batten disease (a progressive, fatal, neurodegenerative disorder), his team demonstrated it was possible to go from genetic diagnosis to development, testing, and deployment of a novel investigational drug, using an intrathecally delivered, patient-customized oligonucleotide, in just one year’s time. His laboratory continues to work with clinicians, scientists, industry, policymakers, rare disease advocates, and the FDA to streamline this path as an option for children suffering from rare, orphan diseases, and currently has five clinical therapeutic programs in the IND or pre-IND phase for individuals with ultra-rare, orphan neurogenetic conditions.

Daniel J. Siegwart, PhD
University of Texas Southwestern Medical Center

Talk Title: Development of SORT lipid nanoparticles (LNPs) for genome correction of disease-causing mutations

Daniel J. Siegwart is a Professor in the Department of Biomedical Engineering at the University of Texas Southwestern Medical Center. He holds the W. Ray Wallace Distinguished Chair in Molecular Oncology Research and serves as the Director of the Program in Genetic Drug Engineering and Co-leader of the Chemistry and Cancer Program in the NCI-designated Simmons Comprehensive Cancer Center (SCCC). He received a B.S. in Biochemistry from Lehigh University (2003), and a Ph.D. in Chemistry from Carnegie Mellon University (2008), studying with Professor Krzysztof Matyjaszewski. He also studied as an NSF EAPSI Research Fellow at the University of Tokyo with Professor Kazunori Kataoka (2006). He then completed an NIH NSRA Postdoctoral Fellowship at MIT with Professor Robert Langer (2008-2012). He has been elected as a Fellow to the National Academy of Inventors (NAI), the American Institute for Medical and Biological Engineering (AIMBE) College of Fellows, and the Controlled Release Society (CRS) College of Fellows. He was also recognized as an Emerging Leader in Health and Medicine (ELHM) Scholar by the National Academy of Medicine (NAM). His research laboratory utilizes materials chemistry to enable targeted nanoparticle delivery of genomic medicines. Their efforts led to an understanding of the essential physical and chemical properties of synthetic carriers required for therapeutic delivery of siRNA, miRNA, tRNA, pDNA, mRNA, and gene editors. His lab has been at the forefront in the design of synthetic carriers for gene editing and has applied these technologies for correction of genetic diseases and treatment of cancer. For example, they reported the first non-viral system for in vivo CRISPR/Cas gene editing. They also developed the first strategy for predictable tissue specific mRNA delivery and gene editing, called Selective ORgan Targeting (SORT) lipid nanoparticles (LNPs), which are being utilized in two separate Phase 1b human clinical trials to treat genetic respiratory diseases. They ultimately aspire to utilize chemistry and engineering to make a beneficial impact on human health.

Sonia Vallabh, PhD
Eric Minikel, PhD
The Broad Institute

Talk title: Advancing oligonucleotide therapeutics for prion disease

Sonia Vallabh and Eric Minikel are a wife-husband team who co-run a prion disease research laboratory at the Broad Institute of MIT and Harvard. Their work is driven by a deeply personal mission: in 2010, Sonia watched her 52-year-old mother die of a rapid, mysterious neurodegenerative illness that was later identified as genetic prion disease. When Sonia learned in 2011 that she had inherited the causal mutation—placing her at greater than 90% lifetime risk of developing the same incurable disease—she and Eric made the decision to leave their previous careers and retrain as scientists. With no prior biology training, they earned their PhDs in Biological and Biomedical Sciences from Harvard Medical School in 2019 and now lead a 16-person lab together.

At the Broad Institute, their research spans the full arc of prion disease drug development, from therapeutic discovery and preclinical development to clinical biomarkers and natural history studies. Sonia’s work focuses on lowering prion protein levels in the brain as a treatment strategy, as well as developing the biomarker and natural history tools needed to enable meaningful clinical trials, including in presymptomatic people at risk. Their work helped give rise to Phase 1 clinical trials for ION717 and divalent siRNA for prion disease.