# Modeling and Therapeutic Approaches for Genetic Vasculopathies

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $696,219

## Abstract

Summary
Smooth Muscle Dysfunction Syndrome is a rare disease with less than 50 known cases worldwide. It is caused
by a specific genetic mutation in the ACTA2 gene that affects smooth muscle cells. Smooth muscle cells are
found in many different organs in the body. These include the large blood vessels that carry blood around the
body (aorta), brain blood vessels, lungs, eye pupil muscles, gut, bladder and even the womb in women. The
children affected by this specific ACTA2 mutation have very complex medical problems involving many body
systems. Patients experience repeated strokes as blood vessels supplying the brain are abnormal in shape and
narrowed. As adolescents, the aorta can weaken and dissect, requiring major surgery. Some children have
need respiratory support or home oxygen. These children suffer from a severe complex disease that can result
in progressive neurological disability. Our aim is to develop a gene therapy for children with ACTA2 disease
that can treat all the different organs affected. In this proposal we will extensively characterize in vitro
ACTA2R179H smooth muscle cell function (AIM1), evaluate the neurovascular and subsequent behavioral
consequences of the ACTA2R179H mutation in a novel mouse model (AIM2), and finally use the
ACTA2R179H mouse model to study the ischemic strokes (AIM3). To investigate therapeutic options
throughout the proposal we will utilize a novel CRISPR-cas9 system with custom guide RNAs to revert (base
editing) or destroy (allele targeting) the ACTA2R179H allele, delivering the system in vitro and in vivo, and
quantitatively measuring the phenotypic consequences of gene targeting

## Key facts

- **NIH application ID:** 10520200
- **Project number:** 1R01NS125353-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** MARK E LINDSAY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $696,219
- **Award type:** 1
- **Project period:** 2022-09-20 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10520200

## Citation

> US National Institutes of Health, RePORTER application 10520200, Modeling and Therapeutic Approaches for Genetic Vasculopathies (1R01NS125353-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10520200. Licensed CC0.

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