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.

Keywords: Antisense oligonucleotides; CADASIL; Immunotherapy; NOTCH3; Transgenic mice; iPSC.

Fig. 1

Novel therapeutic approaches under evaluation by in vitro and in vivo models. Growth factors: the administration of hematopoietic growth factors (SCF and G-CSF) in TgNotch3^R90C mice, after irradiation of bone marrow, is effective in (1) preventing VSMCs degeneration in small arteries and loss of cerebral capillaries by inhibition of apoptotic cascade; (2) reducing cerebral thrombosis; and (3) implementing neurogenesis, especially in the subventricular zone. Immunotherapy: agonist antibodies (A13 and 5E1) targeting NOTCH3 domains have been tested in NOTCH3KO and transgenic mice (respectively TgNotch3^C455R and TgNotch3^R169C), showing respectively (1a) increased SMA coverage in retinal arterioles; (1b) increased NOTCH3^ECD/COL18A1/endostatin levels; and (2) restoration of adequate vasodilatory responses and myogenic tone. AONs: exon skipping through AONs excludes mutant EGFRs with no impairment of NOTCH3 structure or function and produces a novel “EGFR fusion domain,” with correctly spaced cysteines, derived from parts of EGFR domains encoded by exons located before and after those skipped through AONs (except for exon 2–3 skipping)