The Chan Zuckerberg Initiative today announced $1 million in funding to Fanny Elahi, MD, PhD, Assistant Professor of Neurology, Neuroscience, and Pathology, Molecular and Cell-Based Medicine, and a team of researchers from the Icahn School of Medicine at Mount Sinai. The grant—aimed at enabling patient-partnered collaborations in rare neurodegenerative disease research—will also support collaborative efforts and patient engagement by cureCADASIL, a non-profit organization dedicated to finding a cure for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL).
CADASIL, caused by mutations in a gene called NOTCH3, is a rare inherited disease of the blood vessels that occurs when the thickening of blood vessel walls blocks the flow of blood to the brain. The condition is characterized by migraine headaches, strokes, and dementia. Other symptoms include brain white matter lesions, cognitive deterioration, vision problems, and psychiatric symptoms such as severe depression and changes in behavior.
The funding will allow researchers to employ complementary approaches for modeling disease with molecular analyses of patient-donated blood, brain tissue, and stem cell-derived brain vasculature to recreate the early instigating events of the condition and to longitudinally map disease progression with high precision. This is a unique experimental approach, and one in which patients can participate in research at the bench rather than only in the clinic, making them partners in this truly translational work.
"There is significant unmet need in CADASIL because there are no therapies and we don't fully understand how the genetic mutation leads to complex multicellular dysfunction," said Dr. Elahi, the coordinating Principal Investigator. "Our current mechanistic understanding is based on animal models, but we now have the tools to create meaningful patient-informed models that will enable us to tease apart abnormalities, study interaction between cells, and identify the most impactful targets for intervention. This work may have reached beyond this one rare condition because although the clinical presentation of CADASIL is rare, the underlying genetic mutation is more common, and our research may provide foundational discoveries relevant to chronic vascular disease and poststroke decline."
The CZI funding will be used to build cellular models of CADASIL using patient-derived samples to reverse-engineer the disease and discover new therapeutic targets. The line of inquiry will establish a blueprint for translational research on rare and common diseases, especially genetic diseases, that will enable the team to make connections between patient symptoms and biological mechanisms. The project will work in collaboration with the Chan Zuckerberg Initiative's Rare As One Project, an initiative supporting work by patient communities that accelerates fundamental research and drives progress against rare diseases.
Other Icahn Mount Sinai contributors are Joel Blanchard, PhD, Assistant Professor of Neuroscience, and Cell, Developmental and Regenerative Biology; Towfique Raj, PhD, Assistant Professor of Neuroscience, and Genetics and Genomic Sciences; Miriam Merad, MD, PhD, Director of both the Precision Immunology Institute and the Mount Sinai Human Immune Monitoring Core; and Filip Swirski, PhD, Professor of Medicine (Cardiology), and Diagnostic, Molecular and Interventional Radiology, and Director of the Cardiovascular Research Institute.
"Hard questions require new approaches, and new approaches need multiple areas of expertise—including the lived experience from patients—in order to succeed," said Dr. Elahi. "There are many possible symptoms or targets to tackle in any disease, so researchers and clinicians need patient input about the most important or bothersome symptoms. In addition, patient engagement motivates researchers to overcome the obstacles we encounter and persevere even in the face of challenges. Thanks to this unique network grant from the Chan Zuckerberg Initiative, we are tackling CADASIL at the right time, equipped with the right tools, and with a team that includes patients and their perspectives. We are all deeply grateful to Chan-Zuckerberg for this opportunity."
