A Conversation with Alberto Kornblihtt.

Abstract

Dr. Kornblihtt: I work on alternative splicing and the coupling with transcription and chromatin, but in partic-ular on recent unpublished results that we obtained in the system of the SMN2 [survival of motor neurons 2] gene in terms of enhancing exon 7 inclusion in the therapy of spinal muscular atrophy [SMA]. My lab has been working for more than 20 years on the coupling between transcription and splicing, focusing mainly on kinetic coupling. We found that slow elongation can increase inclusion of certain exons in the mature mRNA [messen-ger RNA]. More recently, we also found that slow elongation can produce skipping of certain exons. Among the exons that are sensitive to elongation, ∼ 80% respond to the first rule — slow elongation increases inclusion — and 20% respond to the second mode in which slow elongation promotes skipping. This is because it gives more time for inhibitors of exon inclusion to bind to the pre-mRNA.Inthecase of exon 7 of spinal muscular atrophy, humans have two genes. When SMN1 is mutated, SMN2 , which is the backup gene, cannot cope with the lack of SMN protein because it has several mutations that make exon 7 poorly included into the mature mRNA. Adrian Krainer has developed a new drug called Spinraza that is an oligonucleotide that is able to displace the negative factors from the pre-mRNA and allow exon 7 to be more included. This is fantastic, and it has success in every of SMA. we found that exon 7 inclusion also to elongation in the second mode,