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.