In genetic rare diseases like the Cockayne syndrome (CS), ageing is dramatically accelerated. Understanding the molecular defects responsible for these premature ageing diseases is critical to develop treatments, which are dramatically missing to date and, importantly, give clues to better understand the not yet resolved mechanisms governing physiological ageing. CS is due to mutations in either CSB or CSA genes, which code for DNA repair factors (CSA and CSB, respectively) of UV-induced DNA damages. Increasing evidences, including from our team, indicate that other molecular defects than DNA repair are responsible for the dramatic precocious ageing and neurodegenerative phenotype of CS. Moreover, the UVSS syndrome, also due to CSA or CSB impairment, displays DNA repair defects but normal ageing, de facto uncoupling the two phenotypes. Based on this paradigm, we believe that discriminating defects present specifically in CS cells (but not in UVSS or WT cells) is key to dissect the mechanism leading to the precocious ageing and degenerative phenotype. We have also identified a molecule that rescues the molecular defects in CS patient cells, and has obtained Orphan Drug Designation for this disease. Importantly, despite mutations in the same gene(s), CS is characterized by a very large clinical heterogeneity, the causes of which are not known, and genetic to phenotypic correlations remain elusive.
The aim of this project is to perform a genome-wide transcriptomic profiling of multiple CS patients with a wide spectrum of clinical severities to help understanding the causes in this monogenic disease. This study includes rare primary cells derived from CS and UVSS patients, as well as healthy aged matched donors, original (WT or CSB deficient) and CRISPR/Cas9 edited isogenic models (immortalized cell lines, reprogrammed iPSCs and derived cerebral organoids), and in the presence of the rescue molecule.
