Immunotherapy and improved diagnosis and prognosis of the small vessel disease CADASIL
Awardee: Helena Karlström
Institution: Karolinska Institutet
Grant Amount: $109,856.00
Funding Period: February 1, 2024 - January 31, 2025
Summary:
Cerebral small vessel diseases (SVD) are medical conditions that cause great human suffering and costs for society. SVD cause approximately 20% of all strokes and more than 40% of dementia cases in elderly and are on the rise in an ageing population. SVD are difficult to diagnose, as current imaging modalities only recognize vessels, which are approximately ten times larger than those primarily affected by SVD. It is an emerging notion that the brain vasculature is affected in SVD which contributes to the neurodegenerative process. CADASIL is the most common hereditary form of SVD and to investigate this monogenic variant will be of importance for providing valuable insights into the molecular mechanisms underpinning idiopathic SVD and for development of therapeutic treatment. In this proposal we want to explore ways to restore the brain vascular system in a CADASIL mouse model which has an ongoing pathology (aggregated NOTCH3) by two immunization treatment strategies i.e an active and a passive vaccination approach against aggregated NOTCH3. We have recently shown promising in vivo results with an active immunization study in a CADASIL mouse model where we immunized aggregated NOTCH3 just before pathology onset for four months (preventive study). Our results are very encouraging since we observe that NOTCH3 accumulation around the small vessels in the brain is reduced, but without any Notch3 related side effects (coverage of the vascular tree in the retina, kidney morphology and inflammation status is unaffected). We also observed reduced levels of NOTCH3 ECD in the blood after immunization, which could be of great importance for diagnosis, monitor prognosis and therapeutic efficacy (Oliveira et al EMBO Mol Med, 2023). The results from these will be important novel step towards future therapy development for the disease.