Microphysiological systems to model vascular malformations

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PROJECT SUMMARY Vascular malformations (VM), including capillary malformations, venous malformations and arteriovenous malformations are generally present at birth and can often develop over time to become life-threatening. Most, if not all, arise from post-zygotic (somatic) mutations and are consequently sporadic, and thereby hard to model. Hereditary hemorrhagic telangiectasia (HHT) is a dominant genetic disorder characterized by the pres- ence of vascular malformations (VMs) in multiple organs, the rupture of which leads to acute hemorrhage and chronic bleeding, as well as stroke, heart failure and liver failure. Its prevalence is 1 in 5-10,000, so it is rare, but that still equates to >30,000 patients in the US. VMs in HHT range from small mucosal and cutaneous capillary malformations (causing acute and chronic bleeding from the nose and gastrointestinal tract), to large arteriovenous malformations (AVM) of the liver, brain and lung, the rupture of which can lead to death. The vast majority of HHT patients have mutations in two genes – ACVRL1 (Alk1, HHT2) and ENG (Endoglin, HHT1). Port-wine stains (PWS) are birthmarks caused by capillary malformations in the skin and occur in approximately 1 in 200 newborns. They can occur anywhere on the body but are common on the face, and neck and persist throughout life. They can be small (Mikhail Gorbachev has a port-wine stain on his forehead), however many are larger and can be grossly disfiguring. Sturge-Weber syndrome (SWS) is a related disease where the malformations occur in the brain. Recently, activating mutations (p.R183Q) in the G-protein GNAQ have been noted to have a strong correlation with both isolated PWS and SWS. Current therapies for either disease are very limited. The focus of this proposal is to leverage our expertise in creating vascularized and perfused tissues in culture to create in vitro models of the vascular malformations HHT, PWS and SWS. In the UG3 phase we will pursue three aims: G1: Develop an MPS disease model for Hereditary Hemorrhagic Telangiectasia (HHT); G2: Develop a microphysiological disease model for Port Wine Stain (PWS); and, G3: Develop tissue-specific micro-physiological models of HHT and PWS. In the UH3 phase we will build on this in three further aims: H1: Demonstrate utility of the platforms for investigating disease biology; H2: Demonstrate utility of the platforms for performing drug screens; and, H3: Demonstrate utility of the platforms for assessment of candidate therapies. Completion of this project will yield platforms with the potential to transform drug discovery and testing for two rare diseases that currently have very little support from the pharmaceutical industry. We hope to make significant advances on behalf of HHT and PWS patients.