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 fragile surface vessels called telangiectasias, recurrent nosebleeds, iron-deficiency anemia, and larger abnormal artery-to-vein connections—arteriovenous malformations (AVMs)—in the lungs, brain, liver, or digestive tract. Most cases result from a harmful variant in one copy of genes in the BMP9–ALK1–endoglin signaling pathway, especially ENG or ACVRL1; severity varies widely even within families. GeneReviews: HHT (ncbi.nlm.nih.gov)

Prognosis is often good when HHT is recognized early and people receive organized screening for lung and brain AVMs, but untreated AVMs and chronic bleeding can cause stroke, brain abscess, heart failure, severe anemia, or life-threatening hemorrhage. Current care is therefore preventive and symptom-focused: surveillance and embolization of suitable pulmonary AVMs, individualized management of brain and liver disease, iron replacement or transfusion when needed, nasal moisturizing and local procedures for nosebleeds, and systemic drugs for refractory bleeding. These interventions can be highly effective, but they do not correct the underlying inherited vascular defect. Second International HHT Guidelines GeneReviews: HHT (ncbi.nlm.nih.gov)

Scope of Recent Research (2020–present)

Research from 2020 through August 8, 2026 has been increasingly active, with parallel efforts to control bleeding, prevent new AVMs, and restore the disrupted endothelial-cell signaling that causes HHT. The field has produced stronger randomized evidence for drug treatment of nosebleeds and has advanced genuine disease-correction concepts—particularly gene replacement for ACVRL1/ALK1 deficiency—but no therapy has yet demonstrated a durable cure in people. Engasertib trial AAV gene-therapy study (nejm.org)

Major Breakthroughs and Emerging Therapies

The clearest potentially curative strategy is gene replacement. In a 2025 mouse study, investigators at the University of California, San Francisco and Duke University tested an engineered adeno-associated virus (AAV) capsid, AAV.cc84, carrying a functional human ACVRL1/ALK1 gene. Intravenous delivery targeted a high proportion of brain endothelial cells while limiting liver-cell transduction, and reduced the severity of brain AVMs in an endothelial Alk1-deficient mouse model. This is an important proof of principle for HHT type 2, but it remains preclinical and does not yet establish safety, dosing, durability, or applicability to people with ENG, SMAD4, or other genetic forms of HHT. AAV gene-therapy study (pubmed.ncbi.nlm.nih.gov)

Gene editing is also advancing as a research platform rather than a patient treatment. In 2020, researchers generated induced pluripotent stem cells (iPSCs) from a person with an ACVRL1 mutation and used CRISPR-Cas9 to correct that mutation, creating matched corrected cell lines for studying disease biology. More recently, investigators used engineered human stem-cell models, endothelial cells, smooth-muscle cells, and three-dimensional vessel organoids to show that ENG haploinsufficiency can impair vessel structure, cell survival, and endothelial–smooth-muscle interactions. These approaches can identify which cell types and molecular changes must be repaired before gene editing can be considered for systemic treatment. CRISPR-corrected HHT iPSCs HHT vessel-organoid models (pubmed.ncbi.nlm.nih.gov)

Small-molecule pathway correction has become a prominent near-term strategy. HHT-related loss of BMP9–ALK1–endoglin signaling can leave endothelial cells with excessive PI3K–AKT activity, promoting abnormal vessel growth. Engasertib, an oral allosteric inhibitor of AKT, was tested in a placebo-controlled trial and reduced nosebleed frequency and duration over 12 weeks, with rash and reversible hyperglycemia as notable on-target adverse effects. This is a mechanistically targeted treatment and may prove disease-modifying, but it is not gene correction and has not yet shown that it eliminates existing AVMs or permanently prevents new ones. Engasertib trial (nejm.org)

Other experimental approaches aim to normalize abnormal endothelial behavior. A 2024 study found that the approved CDK4/6 inhibitor palbociclib prevented AVM development in mouse models created by blocking BMP9/10 or deleting endothelial Alk1. The result links abnormal endothelial cell-cycle control to AVM formation and offers a repurposing lead, although cancer-drug toxicities and the distinction between preventing new lesions in mice and reversing established human AVMs remain substantial hurdles. Palbociclib in HHT models (pubmed.ncbi.nlm.nih.gov)

Clinical Trials and Experimental Approaches

The strongest recent clinical result is the PATH-HHT phase 2 randomized trial of pomalidomide, an oral immunomodulatory drug. In 144 participants with moderate-to-severe HHT nosebleeds, 24 weeks of pomalidomide produced a clinically meaningful improvement in Epistaxis Severity Score versus placebo, with a between-group difference of −0.94 points; quality-of-life scores also improved. Neutropenia, constipation, and rash were more common with pomalidomide. The trial was funded by the National Heart, Lung, and Blood Institute and completed enrollment early after meeting a prespecified efficacy threshold, but pomalidomide treats bleeding rather than correcting the inherited mutation. PATH-HHT trial PATH-HHT registry record (nejm.org)

Vaderis Therapeutics sponsored the multicenter, placebo-controlled engasertib trial, registered as NCT05406362. Seventy-five participants received engasertib 30 mg, engasertib 40 mg, or placebo daily for 12 weeks; both active-dose groups had larger mean reductions in nosebleed frequency and duration than placebo, while an open-label extension continued. Engasertib trial (nejm.org)

Several repurposed antiangiogenic or pathway-directed drugs remain important experimental options. A 2023 randomized phase 2 trial of intravenous bevacizumab in transfusion-dependent HHT did not meet its primary transfusion endpoint in a small, underpowered sample, but hemoglobin improved at six months and participants receiving higher drug exposure had fewer transfusions. Cure HHT’s low-dose pazopanib phase 2/3 study, NCT03850964, had completed its primary phase on November 21, 2025 and was listed as active but not recruiting in its March 19, 2026 registry update, with study completion then estimated for July 2026; because that estimate has passed as of August 8, 2026, updated results or status are needed before drawing conclusions. A small phase 2 tacrolimus study sponsored by Unity Health Toronto completed in October 2024 after enrolling 10 participants; it tested whether low-dose tacrolimus could reduce bleeding while restoring ALK1-related signaling. Bevacizumab randomized trial Pazopanib phase 2/3 registry record Tacrolimus phase 2 registry record (pubmed.ncbi.nlm.nih.gov)

Methodologies and Scientific Approaches

HHT researchers combine genetically engineered mouse models with patient-derived cells and increasingly sophisticated human vascular models. Conditional deletion of endothelial Alk1, blockade of BMP9/10, and Eng or Smad4 models allow investigators to trigger AVM formation and test whether a treatment prevents or reduces abnormal shunts. These systems have implicated excessive VEGF and PI3K–AKT–mTOR signaling, abnormal endothelial proliferation, altered vessel identity, and inflammatory influences in lesion formation. Preclinical HHT-model update Palbociclib in HHT models (pubmed.ncbi.nlm.nih.gov)

For translation toward a cure, investigators are testing delivery vehicles as carefully as therapeutic genes. The AAV.cc84 work compared engineered viral capsids, intravenous versus intranasal administration, endothelial-cell targeting, off-target liver exposure, organ function, and histologic AVM outcomes. In parallel, isogenic gene-corrected iPSCs and vessel organoids let researchers compare a patient’s mutation-bearing cells with genetically matched corrected cells, improving the ability to identify biomarkers and test therapies in human tissue before clinical trials. AAV gene-therapy study CRISPR-corrected HHT iPSCs HHT vessel-organoid models (pubmed.ncbi.nlm.nih.gov)

Leading Institutions and Funding

Major contributors include Massachusetts General Hospital and its PATH-HHT collaborators; the Cleveland Clinic, Mayo Clinic, Johns Hopkins University, Stanford University, University of California, San Francisco, Duke University, University of Toronto/Unity Health Toronto, and European HHT centers. UCSF and Duke led the recent AAV gene-delivery work, while Massachusetts General Hospital coordinated the pivotal pomalidomide program and Vaderis Therapeutics funded engasertib’s proof-of-concept trial. AAV gene-therapy study PATH-HHT trial Engasertib trial (pubmed.ncbi.nlm.nih.gov)

Cure HHT has played a catalytic funding and infrastructure role, reporting $2.1 million in seed grants, young-investigator awards, and conferences leveraged into more than $51.3 million from NIH, Department of Defense, FDA, and European sources. Its funding portfolio lists $3.64 million in NIH support for PATH-HHT and, for the randomized pazopanib program, $5.24 million from the Department of Defense plus $877,824 from the FDA, alongside Cure HHT support. Cure HHT funding portfolio (curehht.org)

Strengths, Limitations, and Challenges

A major strength of current HHT research is that it now connects genetics, mechanism, animal models, and randomized clinical trials. Pomalidomide and engasertib provide evidence that systemic therapies can improve clinically meaningful bleeding outcomes, while AAV-mediated ALK1 replacement offers a rational route toward treating the cause of at least one genetic subtype. The use of gene-corrected iPSCs and vascular organoids should also improve selection of targets and reduce reliance on any single model. PATH-HHT trial Engasertib trial AAV gene-therapy study HHT vessel-organoid models (nejm.org)

The central limitation is that most clinical progress is still symptomatic, not curative. HHT is genetically and clinically heterogeneous, so replacing ACVRL1 cannot by itself cure people with ENG, SMAD4, or other causal variants. A body-wide gene therapy must reach the relevant endothelial cells in organs such as the nose, lungs, brain, liver, and gastrointestinal tract while avoiding immune reactions, harmful off-target expression, dose-related toxicity, and uncertainty about whether established AVMs can regress. Small trials, variable bleeding measurements, rare-disease recruitment barriers, long-term drug safety, and unequal access to expert HHT centers also complicate the path to definitive evidence. GeneReviews: HHT AAV gene-therapy study Tacrolimus phase 2 registry record (ncbi.nlm.nih.gov)

Outlook and Future Directions

HHT is not close to a proven human cure as of August 8, 2026, but the field has moved beyond purely local bleeding control. The most consequential milestones to watch are publication of the pazopanib phase 2/3 results; confirmation and longer-term follow-up of pomalidomide and engasertib benefits; evidence that targeted drugs can prevent or reverse AVMs rather than only reduce bleeding; and formal safety studies that move endothelial-targeted AAV gene replacement from mice toward people. A realistic first “functional cure” may be durable prevention of new lesions and major bleeding, while a true genetic cure will require safe, long-lasting correction or replacement across the vascular system and across HHT genotypes. Pazopanib phase 2/3 registry record AAV gene-therapy study Engasertib trial (clinicaltrials.gov)

References

• GeneReviews: Hereditary Hemorrhagic Telangiectasia — University of Washington, Seattle, 2026.
• Second International HHT Guidelines — Faughnan et al., 2020.
• AAV gene-therapy study — Yadav et al., 2025.
• CRISPR-corrected HHT iPSCs — Bouma et al., 2020.
• HHT vessel-organoid models — Kuroda et al., 2024.
• Palbociclib in HHT models — Genet et al., 2024.
• Engasertib trial — Al-Samkari et al., 2025.
• PATH-HHT trial — Al-Samkari et al., 2024.
• PATH-HHT registry record — ClinicalTrials.gov, 2026.
• Bevacizumab randomized trial — Dupuis-Girod et al., 2023.
• Pazopanib phase 2/3 registry record — ClinicalTrials.gov, 2026.
• Tacrolimus phase 2 registry record — ClinicalTrials.gov, 2025.
• Preclinical HHT-model update — Tual-Chalot et al., 2022.
• Cure HHT funding portfolio — Cure HHT, 2026.