Application of an efficient drug repurposing platform to identify treatments for Cornelia De Lange Syndrome

DESCRIPTION provided by applicant Cornelia de Lange Syndrome is a complex congenital malformations syndrome with many post natal progressive medical complications CdLS has a clear genetic cause with loss of function mutations in NIPBL accounting for over of the genetically confirmed CdLS cases The remaining cases exhibit mutations in subunits or regulators of the cohesion complex SMC SMCA HDAC and RAD The pathophysiology of the disease is unclear and the set of symptoms are variable and complex These many complications have prevented the identification of new treatments Recursion Pharmaceuticals has developed a high throughput method for modeling monogenic loss of function diseases such as CdLS in human cellular models This grant expects to find a repurposed drug for treatment of CdLS by Developing siRNA induced loss of function models of CdLS mutations including NIPBL HDAC and RAD in multiple human cell types Creating a disease phenoprint by compiling hundreds of significantly changed structural morphological parameters after loss of NIPBL HDAC or RAD Screen loss of function cellular lines using drug discovery platform to reveal known drugs that significantly reverse the structural disease phenotype Confirm the drug is using its known mechanism of action in CdLS rescued cellular lines Recursion has proven this platform successful with the identification of two known drugs for repurposing in another rare loss of function disease cerebral cavernous malformation CCM PUBLIC HEALTH RELEVANCE Loss of function mutations in NIPBL HDAC and RAD lead to Cornelia de Lange Syndrome CdLS a multiple congenital anomaly that also exhibits multiple progressive developmental disorders While there is no cure for the congenital defects associated with CdLS we will use a human cellular model of CdLS to screen for repurposed drugs that reverse the cellular perturbation cause by decreased gene expression in hopes of improving the progressive symptoms of CdLS