# Underlying Mechanisms in CADASIL

> **NIH NIH U01** · NORTHWESTERN UNIVERSITY · 2021 · $654,979

## Abstract

Brain microvascular ischemic disease is a common cause of leukoencephalopathy, leading to cognitive
impairment, dementia, and stroke. CADASIL (cerebral autosomal dominant arteriopathy with subcortical
infarcts and leukoencephalopathy) is the most frequent mendelian cause of cerebral small vessel
disease. Over two decades ago, disease-causing CADASIL mutations were identified in the receptor
NOTCH3. These mutations result in progressive degeneration of vascular smooth muscle cells in
arterioles. While systemic in nature, the clinical deficits associated with CADASIL manifest primarily in
the brain as a vascular disease, leading to multifocal ischemia with progressive cognitive decline. Despite
its devastating impact on patients, our knowledge of the disease is limited, restricting targeted
therapeutic strategies. A major impediment to progress has been the wide variability in disease
manifestation and a lack of agreement as to whether CADASIL results from a gain or loss of function in
NOTCH3 signaling.
Through a collaborative effort with the NIH Clinical Center, we have made significant strides towards
defining a broader range of clinical read-outs to improve diagnosis and prognosis of CADASIL. We also
gained novel information on molecular changes associated with specific disease-causing mutations
which, at least partially, bring clarity into the broad phenotypic variation. In fact, our findings indicate that
some mutations in NOTCH3 result in suppression of the pathway, while others lead to hyperactivation of
Notch signaling. The objective of this U01 application is to further expand the information related to
clinical presentation, advance the characterization of disease-causing mutations and determine the chief
molecular alterations resulting from these mutations. Furthermore, we will validate animal models to
explore potential avenues for treatment. While a clinical trial is the eventual long-term goal of this
research, a comprehensive understanding of genotype-phenotype relationships with the support of our
colleagues at the NIH Clinical Center is the necessary first step towards this goal. Thus, here our
objective is to test the hypothesis that CADASIL is a broad pleotropic disease caused by both loss and
gain of function mutations in NOTCH3 which mechanistically explain the wide clinical outcomes
associated with vascular degeneration. To test this hypothesis, we present three specific aims: (1) To
develop a robust, multi-organ, longitudinal evaluation of disease progression in a large number of
patients and establish genotype-phenotype relationships; (2) To fully characterize the molecular outcome
of CADASIL mutations as gain or loss of function and associate them with specific molecular read-outs
(3) To explore recently generated animal models representative of both genotype spectra and validate
their utility as potential platforms for therapeutic exploration.

## Key facts

- **NIH application ID:** 10156199
- **Project number:** 1U01HL151203-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Manfred Boehm
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $654,979
- **Award type:** 1
- **Project period:** 2021-04-20 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10156199

## Citation

> US National Institutes of Health, RePORTER application 10156199, Underlying Mechanisms in CADASIL (1U01HL151203-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10156199. Licensed CC0.

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