From aberrant splicing mechanisms to innovative therapies for genetic disorders
PhD. Professor of Molecular Biology, University of Ferrara
This is a joint event with the Trento RNA Salon, an initiative to foster RNA-centered networking, knowledge-sharing and events in the Trentino Alto-Adige region, sponsored by the RNA Society and Lexogen
In the gene expression flow, the exon recognition and removal of introns (splicing) is a crucial step. This process, mediated by the spliceosome, is very complex and therefore susceptible to derangements. Not surprisingly a significant, and still underestimated, proportion of disease-causing mutations affects splicing.
We will show how the knowledge of the aberrant splicing mechanisms led to the development of strategies able modulate and correct them for therapeutic purposes. It is worth noting that the intervention at the pre-mRNA level has the remarkable advantage of acting on physiological tissues only and of maintaining the gene regulation. During the presentation we will focus on variants of the spliceosomal U1snRNA, which are able to rescue multiple exon-skipping mutations occurring either at splice sites or within exonic regulatory elements. Their efficacy has been proven on splicing mutations in several cellular and mouse models of human disease. Starting from the pioneer models of coagulation factor disorders we will translate the U1snRNA-based correction approach to other diseases, with particular emphasis to Spinal Muscular Atrophy.