# Gene therapy for disorders of the extracellular matrix

> **NIH NIH RF1** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2023 · $2,481,348

## Abstract

PROJECT SUMMARY
COL4A1 and COL4A2 mutations cause Gould syndrome (GS) – a multisystem disorder for which clinically
heterogeneous cerebrovascular disease is the major consequence. Cerebrovascular disease in individuals with
GS can range from porencephaly caused by germinal matrix hemorrhages in utero, to infantile seizures, to age-
related cerebral small vessel disease (cSVD) and vascular cognitive impairment and dementia (VCID). Hallmarks
of cSVD observed in individuals with GS include subcortical microbleeds, enlarged perivascular spaces, and
lacunar infarcts. Importantly, Col4a1 mutant mice faithfully model patient phenotypes. Moreover, Col4a1 mutant
mice have age-related cerebrovascular dysfunction including loss of myogenic tone and impaired hyperemic
responses that are thought to be critical to VCID progression.
The extracellular insults resulting from COL4A1 and COL4A2 are heterogeneous and complex, which represents
a significant barrier to mechanism-based interventions. However, because GS is a devastating monogenic
disease with a defined genetic cause, it is an ideal candidate for correction of the root cause of the disease via
genome editing technologies. In this proposal, we will leverage vastly improved CRISPR nucleases, base editors,
and prime editors along with novel viral vectors to test therapeutic approaches using primary GS patient cells
and mouse models of GS. This project will provide important pre-clinical data to develop the first genome editing-
based therapy for this severe monogenic disorder. The successful completion of this work could eventually
provide a one-time, lifelong treatment that prevents both childhood stroke and age-related VCID for GS patients
and create a roadmap for correction of similar diseases.

## Key facts

- **NIH application ID:** 10658481
- **Project number:** 1RF1NS128217-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Douglas Gould
- **Activity code:** RF1 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $2,481,348
- **Award type:** 1
- **Project period:** 2023-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10658481

## Citation

> US National Institutes of Health, RePORTER application 10658481, Gene therapy for disorders of the extracellular matrix (1RF1NS128217-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10658481. Licensed CC0.

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