Dr. Suning Ping, a post-doctoral fellow in Dr. Li-Ru Zhao’s lab at SUNY Upstate Medical University in Syracuse, received a student travel grant from cureCADASIL to present her work entitled “STEM CELL FACTOR AND GRANULOCYTE COLONY-STIMULATING FACTOR PROMOTE BRAIN REPAIR AND COGNITIVE FUNCTION THROUGH VEGF-MEDIATED ANGIOGENESIS IN A MOUSE MODEL OF CADASIL”. Dr. Li-Ru Zhao’s lab has recently demonstrated the efficacy of combining two hematopoietic growth factors. Stem cell factor (SCF) and granulocyte colony-stimulating factor (G-CSF) improve cognitive function, increase brain blood vessel density and increase neural network rewiring in a transgenic mouse model of CADASIL. Dr. Ping demonstrated that a third growth factor, vascular epithelial growth factor (VEGF), is necessary for SCF and G-CSF to function. By blocking VEGF with Avastin, the improvement in cognitive function, enhanced blood vessel density and enhanced neural network rewiring that was observed with SCF and G-CSF does not occur. Dr. Ping’s results shed light on a key mechanism by which hematopoietic growth factors may restrict CADASIL pathology. **Young CADASIL Investigators PI: Dr. Li-Ru Zhao, PhD Fellow: Suning Ping, PhD SUNY Upstate Medical University in Syracuse
The purpose of this summer fellowship funded by cureCADASIL was to understand the dysregulation of NOTCH signaling in CADASIL through immunohistological characterization of brain vasculature from CADASIL subjects and controls. Given the diversity in CADASIL-causing NOTCH3 mutations, our approach was to use a diverse cohort of NOTCH3 mutations to address the hypothesis that CADASIL is a disease caused by loss of function in NOTCH signaling. Utilizing a combination of markers for distinct vascular cell types, classical and novel NOTCH3 signaling targets we characterized the cellular consequences of CADASIL causing NOTCH3 mutations on brain vasculature. This fellowship aided to further advance our understanding of the consequences of NOTCH3 dysregulation in brain vasculature of CADASIL patients and provide preliminary data to support a grant submission to continue this work. **Young CADASIL Investigators/Seed Funding PI: Luisa Iruela-Arispe, MSc, PhD Fellow: Milagros Romay, PhD Student: Margaret Ramirez The Arispe Laboratory University of California at Los Angeles
Funding from cureCADASIL utilized to initiate experiments with animals carrying the R1031C mutation. This analysis is critical for us to examine how many patients could potentially benefit from our modality of treatment: only those with a specific mutation or patients with different mutations associated to different mechanisms. **Research Alliance Joseph Arboleda-Velasquez MD, PhD Schepens Eye Research Institute of Massachusetts Eye and Ear
Funding to support work of a Fellow dedicated to CADASIL Research. Dr. Dorothee Schoemaker will work with cureCADASIL to grow and enrich the registry of CADASIL subjects and will work with members of the medical and research community to increase our understanding of the vascular contributions to cognitive decline. **Research Alliance Joseph Arboleda-Velasquez MD, PhD Schepens Eye Research Institute of Massachusetts Eye and Ear


Funds provided by cureCADASIL have been instrumental in addressing additional experiments suggested by reviewers from the journal considering publication of our in vivo testing of a potential treatment for CADASIL. Specifically, we were able to conduct additional analyses of brain integrity to evaluate vascular leakage and how it can be prevented. We were also able to fund additional experiments to enable another animal trial. Funds were used to generate more animal model mice, determine whether or not they carry the CADASIL mutation and support their maintenance. The latter will include animals with established brain pathology to determine the potential effect of the drug. This will be informative of potential efficacy in patients with moderate to advanced CADASIL. **Research Alliance Joseph Arboleda-Velasquez, MD, PhD Schepens Eye Research Institute of Massachusetts Eye and Ear


Supplemental funding assisted in identifying a roster of blood biomarkers that have the potential to report whether a therapy for CADASIL would be effective in clinical trials. These biomarkers include proteins that are significantly more or less abundant in the presence of CADASIL and revert to their normal levels after treatment with an experimental drug in laboratory models. We are launching a major effort to further develop and validate these biomarkers in blood from CADASIL patients as a necessary step towards the goal of launching a clinical trial that will test the safety and efficacy of experimental treatments for CADASIL. As part of the plan we will 1) develop assays specific for the human proteins, 2) analyze samples already collected from research sites from around the world, and 3) establish the foundation for collection of additional samples in the US. Validation of these biomarkers will enable the design of clinical studies to evaluate modalities of treatment that Dr. Arboleda-Velasquez found to be promising in laboratory models of CADASIL. **Research Alliance Joseph Arboleda-Velasquez, MD, PhD Schepens Eye Research Institute of Massachusetts Eye and Ear

Strategic Initiatives