Rare Disease Report

New Study Provides Hope for CADASIL Patients

AUGUST 01, 2017
James Radke
A new study published in the Journal of Experimental Medicine is providing insight into how treat cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL); a rare cerebrovascular disease.
The study conducted by Machuca-Parra et al observed that antibodies directed toward Notch3 signaling were effective in reversing some of the symptoms in an animal model. Further studies are still necessary, but this is the first to provide hope for this largely unknown rare disease.
CADASIL is a rare vascular disease, and is the result of a mutation in the Notch3 gene causing a buildup of Notch3 protein in small blood vessels in the brain. Migraine headaches, vision issues, and psychiatric problems can all occur, typically beginning in a person’s 30s. Multiple successive strokes eventually lead to dementia by age 65.

There aren’t currently any treatments for CADASIL that halt the disease process, however, patients can receive symptomatic treatment.
In the study, a mouse model for CADASIL (Notch3 knockout mice) were shown to have numerous pathophysiology traits typical of a CADASIL patient, including a reduction of mural cells.
Further, when the mice were given an agonist Notch3 antibody, the treatment prevented mural cell loss and modifies plasma proteins associated with Notch3 activity, including endostatin/collagen 18α1.
The study was led by Dr. Joseph Arboleda-Velasquez from Schepens Eye Research Institute of Mass Eye and Ear, and Harvard Medical School.
Funding for the study was made in part by contributions from the advocacy group, cureCADASIL. In a news release, Nancy Maurer, president of cureCADASIL said,
“We are excited to see Dr. Joe's work published and proud to have supported his CADASIL research over the past 5 years.”
“Dr. Arboleda-Velasquez’s results are exciting developments for the CADASIL field,” said Dr. Irene Griswold-Prenner, scientific advisory board member of cureCADASIL. “If these results translate from mouse models to humans, they provide an avenue to approach treatment for CADASIL patients. Importantly they also point to a target engagement biomarker to support CADASIL clinical trial development. Since no treatments currently exist for CADASIL patients, this is a significant advance for CADASIL research.”
Below, Swati Sathe, MD, of Rutgers New Jersey Medical School summarizes the natural history and pathophysiology of CADASIL.

Machuca-Parra AI, Bigger-Allen AA, Sanchez AV, et al. Therapeutic antibody targeting of Notch3 signaling prevents mural cell loss in CADASIL. J Exper Med. Published July 11, 2017 ahead of print. DOI: 10.1084/jem.20161715
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