Abstract
Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by mutations in the survival motor neuron 1 (SMN1) gene. All patients have at least one copy of a paralog, SMN2, but a C-to-T transition in this gene results in exon 7 skipping in a majority of transcripts. Approved treatment for SMA involves promoting exon 7 inclusion in the SMN2 transcript or increasing the amount of full-length SMN by gene replacement with a viral vector. Increasing the pool of SMN2 transcripts and increasing their translational efficiency can be used to enhance splice correction. We sought to determine whether the 5′ untranslated region (5′ UTR) of SMN2 contains a repressive feature that can be targeted to increase SMN levels. We found that antisense oligonucleotides (ASOs) complementary to the 5′ end of SMN2 increase SMN mRNA and protein levels and that this effect is due to inhibition of SMN2 mRNA decay. Moreover, use of the 5′ UTR ASO in combination with a splice-switching oligonucleotide (SSO) increases SMN levels above those attained with the SSO alone. Our results add to the current understanding of SMN regulation and point toward a new therapeutic target for SMA.
Highlights
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by loss-of-function mutations in the survival motor neuron 1 (SMN1) gene.[1]
We designed a series of overlapping 20-O-methyl (20-OMe) antisense oligonucleotides (ASOs) in 2-nucleotide increments across the 50 region of the SMN2 transcript, including the upstream open reading frames (uORFs) associated with the putative start codon (Figure 1A)
Transfection of ASOs targeting the 50 untranslated region (50 UTR) in SMA patient-derived fibroblasts resulted in increased SMN protein levels compared to the level of SMN in untransfected patient cells or those treated with a nontargeting control (NTC) ASO (Figures 1B and 1C)
Summary
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by loss-of-function mutations in the survival motor neuron 1 (SMN1) gene.[1]. A complete absence of SMN protein results in embryonic lethality.[9] All SMA patients have at least one copy[10,11] of an SMN1 gene paralog, SMN2, which arose from a duplication of the SMN locus on chromosome 5.1 SMN2 does not fully compensate for the loss of SMN1; due to a C-to-T transition that results in exon 7 skipping in a majority of transcripts, only 10 percent to 20 percent of SMN2 mRNAs encode the fully functional SMN protein.[12,13,14] Clinically, disease severity correlates with SMN2 copy number and full-length SMN2 transcript level.[15,16]
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