Hereditary Hemorrhagic Telangiectasia

Overview

Hereditary Hemorrhagic Telangiectasia (HHT), also called Osler-Weber-Rendu syndrome, is an inherited disorder in which blood vessels develop abnormally. It commonly causes recurrent nosebleeds and small fragile surface vessels called telangiectasias, but can also cause arteriovenous malformations (AVMs)—direct, high-flow connections between arteries and veins—in the lungs, brain, liver, and gastrointestinal tract. HHT is usually caused by a disease-causing variant in ENG, ACVRL1, or SMAD4, which disrupts signaling needed to maintain healthy blood-vessel architecture. Severity varies greatly, including within families: some people mainly have nosebleeds, whereas others develop anemia, stroke, brain abscess, heart failure, or dangerous bleeding from organ AVMs. International HHT guidelines

Current care is preventive and complication-focused rather than curative. International guidelines recommend diagnosis using clinical criteria and/or genetic testing; screening for lung and brain AVMs; iron replacement and transfusion when needed; local nasal procedures for bleeding; embolization for suitable lung AVMs; and specialist management of liver, gastrointestinal, and pregnancy-related complications. International HHT guidelines Systemic medicines such as anti-angiogenic drugs may lessen bleeding for selected patients, but they do not correct the inherited vascular-signaling defect. Bevacizumab randomized trial

Scope of Recent Research (2020–present)

HHT research has become more mechanistically focused since 2020, with investigators moving beyond bleeding control toward restoring the defective BMP9/BMP10–ALK1–endoglin signaling network or blocking abnormal downstream pathways such as AKT and mTOR. The field remains small compared with more common genetic diseases, and no curative therapy has reached clinical practice; however, the launch of first-in-human pathway-restoring antibody trials, together with targeted small-molecule trials and increasingly sophisticated gene-therapy models, makes this the most active period yet for disease-modifying HHT research. ALK1–BMPRII agonist preclinical study Harmony-HHT trial

Major Breakthroughs and Emerging Therapies

The most directly disease-targeted approach is restoration of ALK1 signaling. DIAG723 is a bispecific “clustering” antibody designed to bring ALK1 and BMPRII receptors together at the endothelial-cell surface, thereby reactivating downstream SMAD1/5/8 signaling. In HHT-like mouse models, related antibodies prevented retinal AVMs; DIAG723 also reduced AVMs, corrected anemia, and improved survival in a neonatal BMP9/10-blockade model. These findings are important because they suggest that malformed vessels may not merely be prevented but, under some conditions, may remodel after the causal signaling pathway is restored. This remains preclinical evidence, however, and the cited work is currently available as a preprint rather than a peer-reviewed final article. ALK1–BMPRII agonist preclinical study

A second strategy is to restrain excessive growth signaling downstream of the mutated HHT pathway. Endothelial cells in experimental HHT models show increased PI3K–AKT–mTOR activity, which contributes to abnormal vessel growth and AVM formation. In mouse models, genetic reduction or pharmacologic inhibition of mTORC1, including treatment with rapamycin, reduced vascular-malformation severity; the studies also indicate that cells beyond the mutant endothelial cells may influence disease progression. mTORC1 targeting in HHT models This biology has now reached the clinic through engasertib, an oral AKT inhibitor, and ATV-1601, an investigational selective allosteric AKT1 inhibitor. Engasertib phase 1/2 trial Harmony-HHT trial

Anti-angiogenic treatment remains clinically meaningful, but it is best understood as disease control rather than a cure. Bevacizumab blocks vascular endothelial growth factor (VEGF), a major driver of abnormal blood-vessel growth. In a small randomized phase 2 trial involving patients with severe transfusion-dependent bleeding, more bevacizumab-treated participants achieved a major reduction in transfusion needs than placebo-treated participants, and hemoglobin improved at six months; the trial was too small to show a statistically significant difference in its primary transfusion endpoint. Bevacizumab randomized trial Pomalidomide, an immunomodulatory medicine, produced a clinically meaningful reduction in nosebleed severity and improved HHT-specific quality of life in the NHLBI-funded PATH-HHT randomized trial, but it does not repair the responsible gene or eliminate AVMs. PATH-HHT pomalidomide trial

Gene replacement is at an earlier stage. A University of California, San Francisco–Duke University team tested engineered adeno-associated virus (AAV) capsids for delivering a working ALK1 gene to relevant vascular tissues. Intravenous AAV.cc84–Alk1 reduced brain-AVM severity in mice with endothelial Alk1 loss, while the study also assessed liver exposure and organ safety—key obstacles for systemic vascular gene therapy. AAV gene-therapy delivery study No human HHT gene-replacement or gene-editing treatment has yet been reported.

Gene editing is currently more useful as a research platform than as a treatment. Researchers have created genetically matched induced pluripotent stem-cell (iPSC) lines from people with HHT2 and corrected an ACVRL1 variant with CRISPR-Cas9, creating paired patient-derived and corrected cells for studying causal mechanisms and testing therapies. Gene-corrected HHT2 iPSC lines Other investigators have used prime editing to introduce a clinically reported ENG mutation into human iPSCs, enabling endothelial-organoid models that more closely isolate the effects of a single HHT mutation. Prime-edited HHT iPSC model

Clinical Trials and Experimental Approaches

The strongest completed recent randomized evidence is the phase 2 PATH-HHT trial of pomalidomide. The study randomized 144 people with HHT and moderate-to-severe nosebleeds; after 24 weeks, pomalidomide reduced the Epistaxis Severity Score by an additional 0.94 points versus placebo and improved HHT-specific quality of life. Neutropenia, constipation, and rash were more frequent with pomalidomide. PATH-HHT pomalidomide trial Engasertib, developed by Vaderis Therapeutics, was evaluated in a placebo-controlled phase 1/2 study; the published report found decreases in nosebleed frequency and duration, with mostly mild-to-moderate reversible rash and hyperglycemia as notable on-target adverse effects. Engasertib phase 1/2 trial

The most notable ongoing disease-modifying trials as of October 17, 2026 are DIAMOND and Harmony-HHT. DIAMOND is Diagonal Therapeutics’ recruiting first-in-human phase 1/2 study of subcutaneous DIAG723, assessing ascending single and multiple doses of the ALK1–BMPRII agonist antibody in adults with HHT. DIAMOND trial registry record Harmony-HHT is Atavistik Bio’s recruiting randomized, placebo-controlled phase 1/2 study of oral ATV-1601 in approximately 100 adults with moderate-to-severe HHT; its initial blinded treatment period is 16 weeks, followed by an open-label extension. Harmony-HHT trial Neither trial has reported efficacy results.

Methodologies and Scientific Approaches

HHT researchers use complementary models because no single model captures the full human disease. These include endothelial-specific Eng, Acvrl1, Smad4, and related mouse knockouts; neonatal mice treated with BMP9/BMP10-blocking antibodies; zebrafish; patient-derived blood-outgrowth endothelial cells; and human iPSC-derived endothelial cells and vascular organoids. Mouse retinal AVMs are particularly useful for testing whether an intervention prevents or reverses abnormal artery-to-vein connections, while brain, lung, and liver models address organ-specific disease. mTORC1 targeting in HHT models ALK1–BMPRII agonist preclinical study

Scientists are also refining delivery and measurement tools. AAV capsid comparisons test which vectors can reach brain and nasal endothelial cells while minimizing liver exposure, and iPSC systems permit side-by-side comparisons of mutant and gene-corrected cells. AAV gene-therapy delivery study Readouts increasingly include vascular imaging, AVM number and morphology, hemoglobin and anemia measures, endothelial SMAD1/5/8 activation, RNA sequencing, nosebleed frequency and duration, transfusion or iron requirements, and validated patient-reported bleeding and quality-of-life scores. PATH-HHT pomalidomide trial DIAMOND trial registry record

Leading Institutions and Funding

Major academic contributors include the Feinstein Institutes for Medical Research/Northwell Health, University of California, San Francisco, Duke University, Leiden University Medical Center, Massachusetts General Hospital, Mayo Clinic, Cleveland Clinic, and HHT specialty centers participating in multicenter trials. Feinstein investigators and Diagonal Therapeutics have jointly advanced the ALK1–BMPRII clustering-antibody concept from endothelial-cell and mouse studies into the DIAMOND trial. ALK1–BMPRII agonist preclinical study DIAMOND trial registry record

The U.S. National Heart, Lung, and Blood Institute (NHLBI) remains a major public funder. Its grant to the Feinstein Institutes, “Therapeutic Potential of ALK1 Activating Drugs in HHT Models,” supports experiments in mouse models, patient endothelial cells, and transcriptomic analysis; the listed 2026 award amount was $558,494, following $569,892 in 2025. NHLBI ALK1-activating-drugs award NHLBI also funded PATH-HHT, while biotechnology companies including Diagonal Therapeutics, Atavistik Bio, and Vaderis Therapeutics are now financing early clinical development of targeted medicines. PATH-HHT pomalidomide trial Engasertib phase 1/2 trial Harmony-HHT trial

Strengths, Limitations, and Challenges

The principal strength of the current pipeline is that it is increasingly grounded in HHT biology rather than broad bleeding suppression. DIAG723 seeks to re-establish the disrupted receptor signal; AKT/mTOR inhibitors address a repeatedly observed downstream consequence; and gene replacement aims to restore missing function directly. The successful randomized pomalidomide trial also shows that rigorous multicenter HHT trials are feasible and that patient-centered bleeding outcomes can detect clinically meaningful benefit. PATH-HHT pomalidomide trial ALK1–BMPRII agonist preclinical study

The central limitation is translation. AVMs arise in diverse organs over decades, and inherited heterozygous variants can be compounded by local “second-hit” loss of the remaining functional gene copy, making a one-time systemic correction difficult. mTORC1 targeting in HHT models Treatments that reduce bleeding may not prevent strokes, reverse established visceral AVMs, or work equally well across ENG, ACVRL1, and SMAD4 disease. Long-term pathway inhibition can introduce toxicity, as illustrated by neutropenia with pomalidomide and rash or hyperglycemia with AKT inhibition. PATH-HHT pomalidomide trial Engasertib phase 1/2 trial AAV-based approaches must still solve dosing, tissue targeting, immune responses, durability, and the safety of altering vascular signaling throughout the body. AAV gene-therapy delivery study

Outlook and Future Directions

A true cure for HHT is not imminent as of October 17, 2026, because no therapy has yet demonstrated durable correction of the inherited vascular defect and prevention of disease across organs in people. The nearer-term milestone is proof that DIAG723 or ATV-1601 can safely reduce bleeding while showing evidence of vascular pathway engagement and, ideally, regression or prevention of AVMs in clinical studies. Positive results would establish the first plausible disease-modifying treatment class; longer-term progress toward cure will depend on demonstrating durable organ-wide benefit and advancing endothelial-targeted gene replacement or editing beyond cell and animal models. DIAMOND trial registry record Harmony-HHT trial AAV gene-therapy delivery study

References

• International HHT guidelines — Faughnan et al., 2020.
• Bevacizumab randomized trial — Dupuis-Girod et al., 2023.
• PATH-HHT pomalidomide trial — Al-Samkari et al., 2024.
• Engasertib phase 1/2 trial — Al-Samkari et al., 2025.
• ALK1–BMPRII agonist preclinical study — Qutaina et al., 2025.
• DIAMOND trial registry record — Health Canada, 2026.
• Harmony-HHT trial — ClinicalTrials.gov, 2026.
• mTORC1 targeting in HHT models — Ola et al., 2025.
• AAV gene-therapy delivery study — Yadav et al., 2025.
• Gene-corrected HHT2 iPSC lines — Urdaneta et al., 2025.
• Prime-edited HHT iPSC model — Kim et al., 2024.
• NHLBI ALK1-activating-drugs award — U.S. Department of Health and Human Services, 2026.