Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of familial small vessel disease; no preventive or curative therapy is available. CADASIL is caused by mutations in the NOTCH3 gene, resulting in a mutated NOTCH3 receptor, with aggregation of the NOTCH3 extracellular domain (ECD) around vascular smooth muscle cells. In this study, we have developed a novel active immunization therapy specifically targeting CADASIL-like aggregated NOTCH3 ECD. Immunizing CADASIL TgN3R182C150 mice with aggregates composed of CADASIL-R133C mutated and wild-type EGF1-5 repeats for a total of 4 months resulted in a marked reduction (38-48%) in NOTCH3 deposition around brain capillaries, increased microglia activation and lowered serum levels of NOTCH3 ECD. Active immunization did not impact body weight, general behavior, the number and integrity of vascular smooth muscle cells in the retina, neuronal survival, or inflammation or the renal system, suggesting that the therapy is tolerable. This is the first therapeutic study reporting a successful reduction of NOTCH3 accumulation in a CADASIL mouse model supporting further development towards clinical application for the benefit of CADASIL patients.

Alzecure Foundation Huddinge Sweden

Alzecure Pharma Huddinge Sweden

Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden

Department of Cell and Molecular Biology Karolinska Institutet Stockholm Sweden

Department of Cell Biology Faculty of Science Charles University Prague Czech Republic

Department of Clinical Genetics Leiden University Medical Center Leiden The Netherlands

Department of Neurobiology Care Sciences and Society Karolinska Institutet Stockholm Sweden

Department of Neurodegenerative Disease UCL Institute of Neurology Queen Square London UK

Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology The Sahlgrenska Academy at the University of Gothenburg Mölndal Sweden

Hong Kong Center for Neurodegenerative Diseases Clear Water Bay Hong Kong China

Sinfonia Biotherapeutics Huddinge Sweden

UK Dementia Research Institute at UCL London UK

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