Cold Spring Harbor Laboratory, NY, USA
Prof. Adrian R. Krainer´s lab has developed antisense approaches for splicing modulation and for targeted inhibition of nonsense-mediated mRNA decay (NMD), taking advantage of specific features of each RNA-processing pathway.
Nusinersen (Spinraza), the first approved drug for spinal muscular atrophy (SMA), exemplifies a successful path from basic studies of pre-mRNA splicing mechanisms to an effective treatment for a devastating disease. Nusinersen is a splice-switching antisense oligonucleotide (ASO) that efficiently promotes SMN2 exon 7 inclusion and restores SMN protein levels, which are limiting in patient motor neurons. Clinical trials of CSF-administered nusinersen in SMA patients, sponsored by Ionis and Biogen, began at the end of 2011. Based on the striking results of two phase-3 trials in infants with the most severe form of SMA, and in children with an intermediate form of SMA, respectively, Spinraza was approved by the FDA in December 2016, for all SMA types. We are exploring prenatal ASO treatment in SMA mouse models, as it is likely that early intervention will maximize the clinical benefit. Using a similar approach, we also developed an ASO that corrects defective splicing of IKBKAP pre-mRNA, due to a 5’ splice site mutation that causes familial dysautonomia.
Nonsense mutations account for >10% of pathogenic genetic lesions, and can be partially suppressed by translational read-through drugs (RTDs). NMD degrades mRNAs with premature termination codons, and may worsen clinical outcomes by degrading mRNAs that encode semi-functional truncated proteins, or by reducing RTD efficacy. We developed a gene-specific method of NMD inhibition, using ASOs to target exon-junction-complex assembly sites. This method may be clinically useful in the context of genes with certain nonsense or frame-disrupting mutations, or of wild-type isoforms naturally regulated by NMD.
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