Understanding and Targeting Pulmonary Arteriovenous Malformations Using Repurposed Drugs
Abstract
Hereditary hemorrhagic telangiectasia (HHT) is a genetic disease that is transmitted in such a way that children have a 50% chance of inheriting the disease from one affected parent. Although labelled as a rare disease, about 1 in 5,000 people have HHT – approximately 65,000 people in the US. Very characteristic of HHT is the presence of arteriovenous malformations (AVMs), which are direct connections between arteries and veins, bypassing the capillary bed. These AVMs can occur in the skin, where they are called telangiectasia – hence the name HHT. When AVMs are present in the mucosa of the nose, severe nosebleeds develop. Nosebleeds are the most common symptom in HHT (95%) resulting in a significantly impaired quality of life and often the inability to work due to persistent and irrepressible bleeding events. While symptoms may be mild in childhood, they usually progress during the lifetime with often severe, daily to weekly, gushing nosebleeds requiring frequent interventions by a sinus center and ENT (eye, nose, throat) physicians. Military service in areas and countries with extreme climates (heat, dry air, cold air) or employments as aviators (high altitude) predisposes military personnel to having increased nosebleeds, causing significant suffering as well as intermitted inability to work. HHT is furthermore frequently complicated by AVMs that develop in other organs. When they develop in the brain (in 1%-10% of all HHT patients), they can cause head bleeds, stroke, and seizures. When they develop in the lung (in 15%-45% of all HHT patients), they are called pulmonary AVMs (PAVMs) and can cause a stroke, brain abscess, migraines as well as life-threatening bleeding complications. Patients with PAVMs should not go diving and should not be exposed to changing atmospheric pressures as they will likely suffer from neurological complications afterwards; therefore, scuba divers, compressed air workers, astronauts, and aviators might face disqualification from their jobs. The current understanding is that PAVMs are congenital, meaning you are born with them. Patient reports though suggest that PAVMs can either form over time or alternatively that very small, previously undetectable PAVMs enlarge with age or due to yet unknown trigger factors. Therapies that would reliably prevent development, stop growth, or induce a size reduction of AVMs would be important for Service members to stay active without major health complications and be able to fulfill their duty without restrictions. To understand better how the disease develops, to find and test novel therapies for HHT is the overall goal of our proposal. Our proposal has three significant aims: (1) We try to better understand AVM development, growth, and regression by looking at the lung vessels with such as high resolution such that individual endothelial cells (the lining of blood vessels) can be followed under the microscope. We will delete the common HHT causing genes (Endoglin, Alk-1, and SMAD4) in these endothelial cells and will study how AVMs form over time – in the mouse embryos, newborn, and adult mice. After successful completion of Aim 1, we will have generated a new mouse model of HHT, which will serve us to test novel treatment approaches. (2) This aim focuses on the identification of drugs that might be beneficial for the treatment of HHT. We will repurpose drugs (meaning we will use them for a different indication than approved) that have been already tested in our laboratory and been found to be potentially beneficial in HHT (FK506 and Enzastaurin). As a second strategy, we will identify new pathways that are abnormal in HHT and that we plan to target with novel drugs, predicted with a computer program – so-called in silico. To identify these novel pathways, we will use a very novel technique in that we take blood cells from patients with HHT mutations, change these cells into stem cells, and then differentiate them into endotheli
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910505
Entities
People
- Edda Spiekerkoetter
Organizations
- Stanford University
- United States Army