# Modifiers of Disease Severity and Progression in Cerebral Cavernous Malformation

> **NIH NIH U54** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $352,691

## Abstract

Abstract
 Familial cerebral cavernous malformation (FCCM) is a rare autosomal dominant disease caused by
mutations in three CCM genes, and classically diagnosed by multiple lesions on MRI. These leaky vascular
lesions can cause premature hemorrhagic strokes, recurrent seizures, and other disabling deficits. The
mechanisms or events triggering neurological symptoms remain unknown. Further, FCCM patients present with
huge variability in disease burden, even among those with the same gene mutation, family, or age. This variation
presents a difficult conundrum for those managing or living with this lifelong disease. Currently only neurosurgical
treatment options are available. However, several promising therapeutics targeting CCM signaling pathways
(VEGF, RhoA kinase, TGF-ß, inflammation) are under active pre-clinical investigation, and a new Phase 1/2
clinical trial of atorvastatin in CCM patients is underway. In anticipation of Phase 3 clinical trials, we propose to
leverage our considerable progress over the past 9 years to establish, recruit, phenotype, and identify modifiers
of FCCM disease severity and progression to focus on gaps in knowledge and barriers to clinical trial
preparedness in FCCM. Our long-term goal is to identify measurable outcomes and robust biomarkers that will
help select high-risk patients and help monitor drug response in clinical trials.
 In the last project period, we identified brain lesion burden as an important phenotype of FCCM severity, and
that inflammation is a key modifier of lesion burden at both the genetic and mRNA levels. Parallel work in animal
models confirmed the importance of our human findings and revealed an unexpected link to the gut microbiome.
Moreover, recent studies have reported that circulating plasma levels of inflammatory cytokines can be used as
reliable biomarkers to risk-stratify patients. We propose to leverage our prior efforts to now focus on factors that
influence disease progression to clinical symptoms and outcomes, including patient-reported quality of life, and
barriers to phenotyping lesions (Aim 1), investigate a new environmental modifier – the gut microbiome (Aim 2),
and expand our focus on blood biomarker development for clinical trials (Aim 3). The Brain Vascular
Malformations Consortium’s FCCM cohort, the largest of its kind, will be used to accomplish these aims in
collaboration with the Angioma Alliance - patient advocacy group, our 7 BVMC recruitment sites, and the Rare
Diseases Clinical Research Network. Results of our study will characterize quality of life outcomes and identify
modifiers of disease risk and biomarkers useful for stratification or monitoring drug therapy, thus establishing
clinical trial readiness for FCCM patients.

## Key facts

- **NIH application ID:** 10212460
- **Project number:** 5U54NS065705-13
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Helen Kim
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $352,691
- **Award type:** 5
- **Project period:** 2009-09-30 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10212460

## Citation

> US National Institutes of Health, RePORTER application 10212460, Modifiers of Disease Severity and Progression in Cerebral Cavernous Malformation (5U54NS065705-13). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10212460. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*