Mechanism & biology
Why does NOTCH3 misfolding kill vascular smooth muscle cells? What downstream pathways can be targeted? iPSC-derived vascular models, mouse models, and human pathology are converging on testable hypotheses.
Where the science is
CADASIL research
CADASIL has gone from a hand-drawn family pedigree in the 1970s to a precisely defined molecular disease with active therapeutic programs. The next decade will be transformative — if we mobilize patients, clinicians, and resources together.
The fields where progress matters most.
Biomarkers
Plasma neurofilament light (NfL), advanced diffusion-MRI metrics (e.g., PSMD), microbleed counts, and emerging skin-biopsy assays may all serve as objective measures of disease activity and treatment response.
Therapeutics
Antisense oligonucleotides targeting mutant NOTCH3 transcripts, allele-selective approaches, NOTCH3 ectodomain clearance strategies, and small molecules modulating downstream signalling are all in active development.
Natural history & registries
Multi-centre cohorts and registries are essential trial-readiness infrastructure. They define the rate of decline, identify modifiers, and enable rapid recruitment when new trials launch.
Why participate
Patients are the most important part of the research engine.
Every CADASIL family who joins a registry, donates samples, or enrols in a study makes the next therapy more likely. Trial-readiness is built one person at a time.
- Help science define how the disease progresses across diverse populations
- Enable rapid recruitment for clinical trials when they launch
- Improve the data behind clinical guidelines
- Create real-world infrastructure for measuring outcomes
How we got here.
Van Bogaert describes a hereditary leukoencephalopathy
Early case reports lay the groundwork for what would become CADASIL — long before genetic testing existed.
The CADASIL acronym is coined
Tournier-Lasserve, Bousser and colleagues consolidate the clinical entity, naming it Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy.
NOTCH3 is identified
Joutel and colleagues identify NOTCH3 as the causative gene — turning CADASIL into a precisely defined molecular disease.
Granular osmiophilic material
GOM is characterised at the ultrastructural level, providing a tissue-based confirmation pathway and a direct window into pathology.
Mouse models & systems biology
NOTCH3-mutant mouse models recapitulate aspects of human disease; iPSC-derived vascular smooth muscle cells become widely available.
Biomarkers and therapeutic candidates
Plasma NfL emerges as a candidate biomarker. Antisense oligonucleotide and gene-targeted strategies enter early-stage development. Population genomics rewrites our understanding of frequency.
Trial readiness
Registries, natural-history studies, and patient organizations come together to prepare for the first true CADASIL therapeutic trials.
What's being studied right now.
NOTCH3 misfolding
Allele-selective ASOs aiming to reduce mutant NOTCH3 transcripts while sparing wild-type function.
Ectodomain clearance
Strategies to clear extracellular NOTCH3 ectodomain accumulations and prevent vessel-wall toxicity.
Vascular reactivity
Pharmacological probes of cerebral autoregulation as candidate trial endpoints.
Cognitive endpoints
Identifying sensitive cognitive measures that change before frank dementia — the holy grail for early-phase trials.
Imaging biomarkers
Diffusion MRI, peak skeleton of mean diffusivity (PSMD), microbleed kinetics, and cortical thickness change.
Population genomics
Establishing the true population frequency of pathogenic NOTCH3 variants — and the natural history of "milder" variants.
How CADASIL Global Foundation supports research.
Connect
Linking patients to investigators and trials — globally — through curated, vetted referrals.
Translate
Communicating the science clearly to patient and physician audiences, so research is understood and trusted.
Mobilize
Building registry, biobank, and trial-readiness infrastructure with academic and industry partners.