Drug Candidates

With CADASIL and its CNS phenotypes arising from vascular integrity issues, the ultimate drug screening platform will be to develop systems that examine the permeability of the blood-brain barrier.  However, NOTCH signaling is so ancient and conserved, even models systems as simple as the C. elegans worm can potentially address the deficiencies caused by cysteine imbalance. We know the orthologs of NOTCH3 in worm, the glp-1 and lin-12 genes, each cause lethality when eliminated. What is not yet known is how well these KO animals can be rescued by gene replacement. We will be testing if the extracellular part of the worm gene (eg. lin-12) can be replaced with human coding sequence and still function.  If so, we will then examine clinical variants for their detrimental effects on lin-12 signaling in the worm. Intriguingly, protein aggregation disorders can be easily modeled in C. elegans and often lead to early-onset locomotion defects (31951916). However, we will be also utilizing iPSC-derived tissue to create a CADASIL Blood-Brain Barrier (BBB) model. The complementarity of the C elegans model (fast) with the iPSC-based BBB model (accurate) is expected to yield modalities with high clinical translatability.  Drug screens to be performed on models will include FDA-approved drug libraries and new entities like novel chemical entities, antisense oligonucleotides and conformation-specific antibodies.