Department of Biomedical Sciences - Iowa State University

Host:  Marit Nilsen-Hamilton

"A Novel Approach to Correct Splicing Defects in Humans"

Pre-mRNA splicing is a fundamental process by which eukaryotes generate messenger RNAs (mRNAs) that code for proteins.  Alternative pre-mRNA splicing enhances the coding potential of genome by making multiple mRNAs from a single gene.  Pre-mRNA splicing also generates circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs). However, functions of most circRNAs and lncRNAs remain elusive.  Up to 50% of all pathogenic mutations in humans are linked to aberrant pre-mRNA splicing.  A sizeable fraction of the splicing-associated mutations has potential to be corrected if appropriate targets are identified.  We employ Survival Motor Neuron (SMN) gene as a model system to correct aberrant splicing associated with Spinal muscular atrophy (SMA), which is one of the leading genetic diseases linked to infant mortality.  We discovered Intronic Splicing Silencer N1 (ISS-N1) as the prominent regulatory element that promotes skipping of SMN2 exon 7.

This discovery led to the development of an antisense oligonucleotide (ASO)-based drug, Spinraza, which targets ISS-N1.  United States Food and Drug Administration (FDA) and European Drug enforcement agency have approved Spinraza as the first drug for the treatment of SMA.  We have recently discovered a novel approach of splicing correction through activation of a unique cryptic splice site.  The approach takes advantage of the engineered U1 small nuclear ribonucleoprotein (U1 snRNP) that targets specific sequence within an intron.  While pivotal role of U1 snRNP in coupling between transcription and splicing machineries are known, our findings support a novel function of U1 snRNP through long-distance interaction.  Our proposed approach could be employed for a broad range of splicing mutations affecting a host of genetic diseases.

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