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Active immunotherapy reduces NOTCH3 deposition in brain capillaries in a CADASIL mouse model
Daniel V Oliveira1,2, Kirsten G Coupland1, Wenchao Shao1
1Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
Insights
This study developed a novel active immunization therapy for Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL). The therapy successfully reduced NOTCH3 protein buildup in a mouse model, showing promise for future patient treatments.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a genetic small vessel disease with no current treatments.
- CADASIL is caused by NOTCH3 gene mutations, leading to abnormal NOTCH3 receptor accumulation in blood vessels.
Purpose of the Study:
- To develop and evaluate a novel active immunization therapy targeting aggregated NOTCH3 extracellular domain (ECD) in a CADASIL mouse model.
- To assess the efficacy and tolerability of this therapeutic approach.
Main Methods:
- Developed an active immunization therapy targeting aggregated NOTCH3 ECD.
- Immunized CADASIL TgN3R182C150 mice with mutated and wild-type NOTCH3 EGF1-5 repeats for 4 months.
- Assessed NOTCH3 deposition, microglia activation, serum NOTCH3 ECD levels, and general health parameters.
Main Results:
- Achieved a 38-48% reduction in NOTCH3 deposition around brain capillaries.
- Observed increased microglia activation and decreased serum NOTCH3 ECD levels.
- Demonstrated no adverse effects on body weight, behavior, retinal vascular cells, neuronal survival, or renal function.
Conclusions:
- The novel active immunization therapy effectively reduced NOTCH3 accumulation in a CADASIL mouse model.
- The therapy appears tolerable, with no significant adverse effects observed.
- This study provides a foundation for developing clinical applications to benefit CADASIL patients.
Abstract:
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.
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