In CADASIL patients, the variability in age at onset and progression of clinical symptoms, including the major symptoms of stroke and cognitive decline, limits their use as an outcome measure in clinical trials, because of the large number of patients that would have to be included to detect a treatment effect within a typical trial-timeframe of 2 years. įor therapeutic development, feasible clinical outcome measures and biomarkers are imperative, both in mouse disease models and in patients. For example, this would be the case for antisense therapeutic strategies targeting mutated pre-mRNA, a therapeutic approach which is being developed for increasing numbers of CNS disorders. However, this model is less suitable as a translational CADASIL model due to the species difference, which creates an additional hurdle in bringing therapeutic compounds to clinical trials. Only the mouse model that expresses mutant rat Notch3 protein from a genomic DNA construct shows early onset vascular Notch3 accumulation with subsequent development of brain parenchymal lesions. The first and often only sign of CADASIL in these models is the presence of NOTCH3 accumulation in the vasculature, and in all human NOTCH3 transgenic models, the NOTCH3 accumulation only becomes apparent at a high age. Available models include transgenic models overexpressing human NOTCH3 from a cDNA construct or rat Notch3 from a genomic construct, and models in which a mutation was introduced into the endogenous Notch3 gene. The hitherto available CADASIL mouse models have important limitations with respect to their feasibility for testing such therapeutic strategies. NOTCH3 targeting therapies are in the pre-clinical phase of development (Rutten et al., unpublished, patent no. To date, there is no therapy to prevent or delay symptoms in CADASIL. This causes recurrent ischemic strokes and cognitive decline, starting at a mean age of 45–50 years. The arteriopathy is systemic but most pronounced in the brain where it leads to degeneration of VSMCs and a disturbed cerebral blood flow regulation. In addition, electron dense deposits (granular osmiophilic material, GOM) are seen in close vicinity to the vascular smooth muscle cells (VSMCs). CADASIL is characterized by accumulation of the extracellular domain of the NOTCH3 protein (NOTCH3 ECD) in the media of small- to medium-sized arterioles. This novel, translational CADASIL mouse model is a suitable model for pre-clinical testing of therapeutic strategies aimed at delaying or reversing NOTCH3 accumulation, using the NOTCH3 score as a biomarker.Ĭerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) is a hereditary small vessel disease caused by mutations in the NOTCH3 gene, leading to mid-adult onset stroke and dementia. This score proved to be a robust and sensitive method to assess the progression of NOTCH3 accumulation, and a feasible biomarker for pre-clinical therapeutic testing. This finding was the basis for developing the ‘NOTCH3 score’, a quantitative measure for the NOTCH3 accumulation load. Immunohistochemistry on brain sections shows characteristic vascular human NOTCH3 accumulation in all four mutant strains, with human NOTCH3 RNA expression levels correlating with age at onset and progression of NOTCH3 accumulation. The four mutant strains we generated have respective human NOTCH3 RNA expression levels of 100, 150, 200 and 350 % relative to endogenous mouse Notch3 RNA expression. We generated transgenic mice in which we overexpressed the full length human NOTCH3 gene from a genomic construct with the archetypal c.544C > T, p.Arg182Cys mutation. To facilitate pre-clinical therapeutic interventions for CADASIL, we aimed to develop a novel, translational CADASIL mouse model. There is no therapy for CADASIL, and therapeutic development is hampered by a lack of feasible clinical outcome measures and biomarkers, both in mouse models and in CADASIL patients. The accumulation is systemic but most pronounced in the brain vasculature where it leads to clinical symptoms of recurrent stroke and dementia. CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a hereditary small vessel disease caused by mutations in the NOTCH3 gene, leading to toxic NOTCH3 protein accumulation in the small- to medium sized arterioles.
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