Prof. Frédéric Allain, ETH Zürich

Abstract

Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality (1/10,000 live birth). The disease is caused by deletion or mutation within the Survival Motor Neuron 1 (SMN1) gene. The SMN2 gene, a nearly identical copy of SMN1, fails to prevent SMA mostly due to a single C-to-U change in SMN2 exon 7 compare to SMN1. This change does not alter an amino acid, but affects binding of a splicing regulator. As a consequence, the majority of the transcripts from SMN2 lacks exon 7, leading to a non functional SMN protein that gets rapidly degraded. Despite the fact that SMN2 has an altered splicing of exon 7, the gene still produces some full-length transcripts (~10%), and hence some SMN protein. In other words, SMA is caused by loss or mutation of SMN1, which is not rescued by the low levels of stable SMN protein produced by SMN2. Consequently, the SMN2 gene is a major modifier of the severity of SMA phenotype and increasing the amount of functional SMN protein by acting on SMN2 splicing seems to be a powerful strategy to treat and possibly cure SMA. Numerous factors responsible for splicing regulation of SMN2 exon 7 have been identified. This includes cis-acting elements and trans-acting factors that have either positive or negative effects on exon 7 inclusion. Taking advantage of this knowledge several different strategies aiming at increasing the levels of functional SMN protein in SMN2 have been investigated by either preventing repressing factors or promoting activating ones.

In this project, we aim at finding small molecules that could increase the level of functional SMN protein produced by SMN2 gene using a drug screening approach and structural informations on key regulators of SMN2 splicing. We will focus on one activator complex of SMN2 involving the proteins Tra2-b1 and hnRNP G. This complex will be characterized structurally by NMR spectroscopy but also screened against a drug library to find small molecule drugs that can stabilize their interactions with SMN2 pre-mRNA. Positive drugs hits will then be further tested for their effect on splicing, placed on the three dimensional structure of the protein-RNA complex and be further improved by rational drug design or a fragment-based approach if several hits are found. If successful, this original approach could be used in many other genetic diseases originating from alternative-splicing defect.