Unlike other mutations that cause Cornelia de Lange Syndrome, little is known about SMC3 mutations as they only comprise of < 2% of the cases.
Create SMC3-CdLS animal models (especially one that mimics the A485del mutation)
Characterize the phenotype of a SMC3-CdLS animal model with respect to:
Structural or functional abnormalities, including similarities or differences with existing NIPBL-animal models.
Whether the causal SMC3 mutant allele behaves as a loss-of-function or gain-of-function allele, and the extent to which SMC3 is a haplosufficient gene.
Molecular pathways that are dys-regulated in SMC3-CdLS (e.g. transcriptional abnormalities, disruptions of signaling pathways)
Investigate therapeutic approaches that can potentially be borrowed and tested from other transcriptomopathies (e.g. gene editing, gene replacement, protein replacement, RNA editing, RNA trans-splicing, etc)
Investigate the effects of pharmacological agents (e.g. HDAC inhibitors, WNT activators, etc) on SMC3-CdLS animals or cells.
Identify relevant signals or pathways that could be affected by drugs.
Identify cells in which genetic intervention (e.g., gene editing, antisense oligonucleotides, etc.) would need to be carried out to achieve therapeutic benefit.
Use models of SMC3-CdLS for pre-clinical research to test potential pharmacological or genetic interventions (Anti-sense oligos, CRISPR etc)