# Therapeutic Potential of ALK1 Activating Drugs in HHT Models

> **NIH NIH R01** · FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH · 2020 · $412,500

## Abstract

PROJECT SUMMARY/ABSTRACT (DESCRIPTION)
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.

## Key facts

- **NIH application ID:** 9840506
- **Project number:** 5R01HL139778-03
- **Recipient organization:** FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
- **Principal Investigator:** PHILIPPE MARAMBAUD
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $412,500
- **Award type:** 5
- **Project period:** 2017-12-15 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9840506

## Citation

> US National Institutes of Health, RePORTER application 9840506, Therapeutic Potential of ALK1 Activating Drugs in HHT Models (5R01HL139778-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9840506. Licensed CC0.

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