CADASIL from Bench to Bedside: Disease Models and Novel Therapeutic Approaches

Abstract

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic disease caused by NOTCH3 mutations and characterized by typical clinical, neuroradiological, and pathological features. NOTCH3 belongs to a family of highly conserved transmembrane receptors rich of epidermal growth factor repeats, mostly expressed in vascular smooth muscle cells and pericytes, which perform essential developmental functions and are involved in tissues maintenance and renewal. To date, no therapeutic option for CADASIL is available except for few symptomatic treatments. Novel in vitro and in vivo models are continuously explored with the aim to investigate underlying pathogenic mechanisms and to test novel therapeutic approaches. In this scenario, knock-out, knock-in, and transgenic mice studies have generated a large amount of information on molecular and biological aspects of CADASIL, despite that they incompletely reproduce the human phenotype. Moreover, the field of in vitro models has been revolutionized in the last two decades by the introduction of induced pluripotent stem cells (iPSCs) technology. As a consequence, novel therapeutic approaches, including immunotherapy, growth factors administration, and antisense oligonucleotides, are currently under investigation. While waiting that further studies confirm the promising results obtained, the data reviewed suggest that our therapeutic approach to the disease could be transformed, generating new hope for the future.

Effects of different regional cerebral blood flow on white matter hyperintensity in CADASIL patients

“…CADASIL is a common genetic SVD that presents with typical pathological changes of Notch3 ECD deposition and small vessel degeneration [ 23 ] . These marked degenerative changes lead to cerebrovascular dysfunction, which further causes white matter tract damage [ 24 ] . Interestingly, mutant NOTCH3 occurs in both the brain and peripheral arterial vessels [ 8 ] .…”

Perspectives on Cognitive Phenotypes and Models of Vascular Disease

“…With the goal of investigating the CADA-SIL clinical spectrum, CADASIL-specific mouse models have been developed using transgene and knock-in technology based on specific individual human CADASIL variants. 14 However, most models only recapitulate a portion of the CADASIL-related pathology, such as altered vascular smooth muscle cell function, while strokes and white matter changes are not reproduced. There is also a lack of systematic analyses of neurobehavioral studies in mouse models to elucidate CADASIL-specific cognitive impairment.…”

To Be, or Notch to Be: Mediating Cell Fate from Embryogenesis to Lymphopoiesis

“…While the exact mechanism causing CADASIL is unknown, development of vascular smooth muscle cells is impacted, with the disorder primarily manifest by cerebral white matter lesions [73]. Although insightful in understanding the pathology, mouse models with Notch3 mutations or deletions do not fully recapitulate the clinical features of CADASIL [74].…”