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Repurposing drugs to treat Hereditary Hemorrhagic Telangiectasia: identification using a vascularized HHT on-a-chip microphysiological system platform

Award Number: R03NS141038
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2025
PERIOD OF PERFORMANCE END DATE: 11/30/2026

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Repurposing drugs to treat Hereditary Hemorrhagic Telangiectasia: identification using a vascularized HHT on-a-chip microphysiological system platform - PROJECT SUMMARY One in five thousand babies are born with Hereditary Hemorrhagic Telangiectasia (HHT), a rare disease that results in vascular malformations with a high risk of rupture and bleeding. Most patients suffer from recurrent, spontaneous and prolonged (30+ minutes) nose bleeds, leading to anemia and great social anxiety. Arterio- venous malformations (AVM’s) in liver lead to reduced liver function and ultimately high-output heart failure. Lung AVMs circumvent the clot filtering function of lung capillaries leading to increased risk of stroke. Ruptured AVMs in the brain are rapidly fatal. As for many rare diseases treatment options are limited. This proposal will leverage our recently generated in vitro model of HHT to screen a de-risked drug library for compounds that can be developed or re-purposed to treat patients with this debilitating disease. The cause of HHT has been mapped to two genes that account for over 95% of cases. Alk1 (ACVRL1) and endoglin (ENG) form a heterodimer that acts as a receptor for circulating BMP9 and BMP10. Signaling through this complex engages SMAD4 (mutations in which account for the majority of the remaining patients), which then drives a quiescence phenotype in peripheral endothelial cells (EC). Patients are globally heterozygous for mutations in the receptor genes, with local loss-of-heterozygosity leading to over-activation of the EC and lesion development. There is no evidence that lesions are substantially different in different tissues or that their growth is driven by different mechanisms. A 2018 report co-authored by the PI was the first to show that a small molecule VEGFR2 inhibitor (Pazopanib) could reduce bleeding in patients and this has led to a follow-up study. While this drug looks promising it does not appear to be effective on all patients suggesting that a continued search for alternatives is worthwhile. In this study, we will utilize our recently developed in vitro HHT-on-a-chip microphysiological model, which recapitulates vascular lesions of HHT patients, including the small vascular tangles (telangiectasias) and the larger AVMs. Importantly, lesion formation is blocked by pazopanib, mirroring its effects in patients. Our hypothesis is that: the HHT-VMO platform can be used to identify drugs that could be repurposed to treat HHT. To test this hypothesis we will screen a compound library enriched for drugs with known cardiovascular activity. Many of these are either FDA-approved or otherwise de-risked. We will look for drugs that either block lesion formation (and) or regress already-formed lesions. Our Aims are: 1. Optimize protocol with a 5 compound sub-library. 2. Screen a 1000-compound library. 3. Re-screen hits at additional concentrations and timepoints. The patient advocacy organization CureHHT has already pledged to help move any FDA-approved drugs into clinical trials.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $78,500 )
2026	2026	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	2/26/2026	NON-COMPETING CONTINUATION	$78,500
														Subtotal = $78,500

Issue Date FY: 2025 ( Subtotal = $78,500 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/27/2024	NEW	$78,500
														Subtotal = $78,500

Grand Total All Awards = $157,000

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Repurposing drugs to treat Hereditary Hemorrhagic Telangiectasia: identification using a vascularized HHT on-a-chip microphysiological system platform

Award Number: R03NS141038

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/2025

PERIOD OF PERFORMANCE END DATE: 11/30/2026

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