) Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant genetic disorder characterized by the development of potentially life-threatening vascular anomalies in several organs in the form of arteriovenous malformations (AVMs). HHT mutations are mostly found in the ALK1 and ENG genes and lead to a loss-of- function in the BMP9/10-ALK1-ENG signaling cascade. Evidence suggests that HHT arise from aberrant reactivation of angiogenesis and endothelial cell (EC)-driven hypervascularization. The overall goal of this program is to implement a screening and characterization strategy aimed at identifying FDA-approved drugs with disease-modifying properties and therapeutic potential in novel cellular and mouse models of HHT. We have screened the NIH clinical collections of FDA-approved drugs to identify molecules capable of activating ALK1 signaling in reporter cells. The immunophilin ligand tacrolimus (FK506) was identified as the most potent ALK1 activator. In preliminary studies, we confirmed that tacrolimus, as well as its analog sirolimus, are potent ALK1 signaling activators in ECs. Of significance, the two analog drugs prevented retinal vascular pathology in the transmammary model of BMP9/10-immunoblocking, an HHT mouse model recently developed in our laboratory. In addition, we determined that tacrolimus efficiently triggered ALK1 activation in primary ECs derived from an HHT patient carrying the well-described disease-causing ALK1-T372fsX mutation. Based on these results, we propose in Aims 1 and 2 of this application to assess and compare the therapeutic potential of tacrolimus and sirolimus in the transmammary model of BMP9/10-immunoblocking and in a new knockin mouse line expressing the HHT ALK1-T372fsX mutation. We will also generate a mini-bank of HHT patient- derived primary ECs, which will be used to delineate the mechanisms by which tacrolimus and sirolimus control ALK1 signaling (Aim 3). We believe that this comprehensive approach in relevant and powerful models of HHT not only will increase our understanding of the molecular underpinnings of the disease, but also will motivate new clinical investigations for HHT.
Hereditary hemorrhagic telangiectasia (HHT) is a highly debilitating genetic bleeding disorder for which no effective treatment or cure is currently available. In this application, we propose to determine whether drugs already approved for other conditions could have disease-modifying properties in HHT models. This drug repurposing strategy has the potential to fast-track new clinical investigations for HHT.