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NIH grant 1R01NS147187-01A1: In vivo genome editing for cerebrovascular disorders
Institute: {'code': 'NS', 'abbreviation': 'NINDS', 'name': 'National Institute of Neurological Disorders and Stroke', 'admin_org_id': '12500053', 'admin_funding_url': ''}. PI: David Young Chung. Award: $616126.
Start: 2026-08-26T00:00:00.
PROJECT SUMMARY / ABSTRACT
Cerebral small vessel disease (cSVD) is a leading cause of neurodegeneration and stroke, characterized by
vessel wall thickening, loss of elasticity, and dysfunction of vascular smooth muscle cells (SMCs) and pericytes
that impair cerebral blood flow and metabolism. Individuals with cSVD develop MRI-evident white matter injury
and ischemic infarcts. Although SMC and pericyte dysfunction is well established in human disease, progress
toward therapy has been limited by the absence of models that reproduce the vascular pathology seen in
patients.
To address this gap, we developed a knock-in Acta2 R179H mouse that models one of the most severe
genetic vasculopathies. The ACTA2 R179H mutation disrupts actin polymerization and cytoskeletal function,
leading to abnormal vascular remodeling, reduced cerebral blood flow, blood-brain barrier (BBB) breakdown,
and white matter degeneration, recapitulating key features of cSVD. We have also established an in vivo gene
editing approach that corrects the mutation, restoring arterial elasticity and survival when delivered early in life.
This proposal seeks to define how and when gene editing can restore cerebrovascular and white matter
integrity in ACTA2 R179H mice. In Aim 1, we will determine the effects of early and delayed gene editing on
vascular morphology, hemodynamics, and behavioral outcomes. In Aim 2, we will define how actin dysfunction
causes microvascular pathology and BBB breakdown, using high-field MRI and 3-photon microscopy to identify
imaging biomarkers that can guide translational MRI studies in patients. In Aim 3, we will test how gene editing
restores cerebrovascular reserve and oxygen delivery during vascular stress, providing insight into the
reversibility of small-vessel dysfunction.
This multi-PI, multidisciplinary study integrates molecular, physiological, imaging, and behavioral analyses to link
microvascular rescue to functional recovery. The results will establish when and how restoring SMC and pericyte
function reverses cerebrovascular and white matter injury, laying the foundation for gene-editing therapy in
ACTA2 vasculopathy and offering new mechanistic insights into sporadic cSVD and vascular contributions to
neurodegeneration.document fetched 2026-09-06 02:47