Raise the Roof: Boosting the Efficacy of a Spinal Muscular Atrophy Therapy  Nicholas J. Kramer, Aaron D. Gitler  Neuron  Volume 93, Issue 1, Pages 3-5 (January 2017) DOI: 10.1016/j.neuron.2016.12.029 Copyright © 2017 Elsevier Inc. Terms and Conditions

Figure 1 The SMN Locus and Proposed Antisense Therapies to Boost SMN Protein Levels in Spinal Muscular Atrophy (A) In healthy people, the SMN1 gene produces sufficient SMN protein for normal function. Humans have another gene homologous to SMN1 called SMN2 that has a nucleotide substitution (T instead of C) in exon 7, which causes this exon to usually be skipped during pre-mRNA splicing and results in a much less stable protein. (B) Spinal muscular atrophy (SMA) is caused by loss-of-function mutations in SMN1. Low levels of SMN protein produced from SMN2 can only partially compensate for these mutations. Copy number variations in SMN2 inversely correlate with SMA clinical phenotypes; therefore, strategies to boost SMN protein levels derived from the SMN2 gene have been proposed as therapeutics. Antisense oligonucleotides (ASOs) are “drug-like” DNA-based molecules that act to reduce mRNA levels or modify splicing events by complementary base-paring to target RNAs. (C) Top: splice-switching oligonucleotides (SSOs) are a type of ASO currently in clinical trials for SMA that act to correct the aberrant splicing of SMN2 with the goal of boosting SMN protein levels derived from SMN2. However, this strategy is limited by the starting amount of SMN2. The long non-coding RNA SMN-AS1 acts as a negative regulator of SMN2 transcription. Bottom: strategies to reduce SMN-AS1 levels using another ASO de-repress SMN2 transcription, thereby further boosting SMN protein levels. A combination antisense therapy targeting both SMN-AS1 and SMN2 splicing with SSOs might alleviate the ceiling effect of the SSO therapy alone and improve SMA outlook. Neuron 2017 93, 3-5DOI: (10.1016/j.neuron.2016.12.029) Copyright © 2017 Elsevier Inc. Terms and Conditions