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 65% of the genetically confirmed CdLS cases. The remaining cases exhibit mutations in subunits or regulators of the cohesion complex (SMC3, SMCA1, HDAC8, and RAD21). 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: 1. Developing siRNA induced loss of function models of CdLS mutations including NIPBL, HDAC8, and RAD21 in multiple human cell types. 2. Creating a disease phenoprint by compiling hundreds of significantly changed structural (morphological) parameters after loss of NIPBL, HDAC8, or RAD21. 3. Screen loss of function cellular lines using drug discovery platform to reveal known drugs that significantly reverse the structural disease phenotype. 4. 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 Statement: Public Health Relevance: Loss of function mutations in NIPBL, HDAC8, and RAD21 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.
NIH Spending Category: Brain Disorders; Genetics; Intellectual and Developmental Disabilities (IDD); Neurosciences; Orphan Drug; Pediatric; Rare Diseases
Project Terms: 2,2,6,6-tetramethyl-4-piperidinol-N-oxyl; Accounting; Affect; Alleles; Animal Model; Back; base; Behavioral; Bioinformatics; Biological Assay; Biological Markers; Biological Models; Birth; Bruck-de Lange syndrome; Cavernous Malformation; CCND1 gene; Cell model; cell type; Cells; Cerebrum; Chemicals; Clinic; Clinical; Clinical Research; cohesin; cohesion; Complex; Computer software; Congenital Abnormality; congenital anomaly; CSPG6 gene; Data; Deterioration; developmental disease/disorder; Diagnosis; Disease; disease phenotype; Dose; drug candidate; drug discovery; Drug usage; Evaluation; Exhibits; Face; Fingerprint; fluorescence imaging; Functional disorder; gastrointestinal; Gene Expression; Gene Expression Regulation; Genes; Genetic; Grant; Hereditary Disease; Human; Immunologic Deficiency Syndromes; improved; In Vitro; in vivo; in vivo Model; Inherited; knock-down; Lead; Libraries; Life; loss of function; loss of function mutation; malformation; Measurement; Measures; Mediation; medical complication; Mendelian disorder; Methods; Modeling; Mus; Mutation; new technology; Newborn Infant; Organ; Organelles; Other Genetics; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phenotype; Population; postnatal; Preclinical Drug Evaluation; prevent; protein expression; Proteins; public health relevance; Publishing; Quality of life; Rare Diseases; response; RNA Interference; Roberts-SC phocomelia syndrome; Role; Safety; screening; Shapes; Sister Chromatid; Small Business Innovation Research Grant; Small Interfering RNA; spatial relationship; stroke; success; Symptoms; Syndrome; System; Techniques; Technology; Texture; Therapeutic; Vitamin D
