Abstract
Spinal muscular atrophy (SMA) is a motor neuron disease, typically resulting from loss-of-function mutations in the survival motor neuron 1 (SMN1) gene. Nusinersen/SPINRAZA, a splice-switching oligonucleotide that modulates SMN2 (a paralog of SMN1) splicing and consequently increases SMN protein levels, has a therapeutic effect for SMA. Previously reported small-molecule SMN2 splicing modulators such as risdiplam/EVRYSDI and its analog SMN-C3 modulate not only the splicing of SMN2 but also that of secondary splice targets, including forkhead box protein M1 (FOXM1). Through screening SMA patient-derived fibroblasts, a novel small molecule, designated TEC-1, was identified that selectively modulates SMN2 splicing over three secondary splice targets. TEC-1 did not strongly affect the splicing of FOXM1, and unlike risdiplam, did not induce micronucleus formation. In addition, TEC-1 showed higher selectively on galactosylceramidase and huntingtin gene expression compared to previously reported compounds (e.g., SMN-C3) due to off-target effects on cryptic exon inclusion and nonsense-mediated mRNA decay. Moreover, TEC-1 significantly ameliorated the disease phenotype in an SMA murine model in vivo. Thus, TEC-1 may have promising therapeutic potential for SMA, and our study demonstrates the feasibility of RNA-targeting small-molecule drug development with an improved tolerability profile.
Highlights
Spinal muscular atrophy (SMA) is a motor neuron disease, typically resulting from loss-of-function mutations in the survival motor neuron 1 (SMN1) gene
As a result of these screens, we identified a compound, TEC-1, which increased the form of SMN2 that includes exon 7 (FL-SMN2), and decreased the form that skips exon 7 (Δ7) in a concentration-dependent manner (Fig. 1a,b,e,f)
To improve the clinical tolerability, we simultaneously evaluated the splicing of SMN2 and secondary splice targets (e.g., forkhead box protein M1 (FOXM1)) in SMA patient-derived fibroblasts, which maintain the intrinsic structure of cellular mRNAs
Summary
Spinal muscular atrophy (SMA) is a motor neuron disease, typically resulting from loss-of-function mutations in the survival motor neuron 1 (SMN1) gene. One of the base pair differences causes a translationally silent, single-nucleotide transition in SMN2 at position 6 of exon 7 (c6t), which disrupts binding sites for positive splicing r egulators[1] and creates binding sites for negative splicing regulators[2]. This change (c6t) strengthens an extended inhibitory context[3,4]. Nusinersen/ASO10-27/SPINRAZA, an approved antisense oligonucleotide (ASO) drug for the treatment of SMA, directly targets intronic splicing silencer N1 (ISS-N1) in intron 7 of SMN26,7, which modulates SMN2 splicing, and leads to an increase in SMN protein levels[8]. ASO drugs and gene therapies are generally expensive; the costs of nusinersen for 10 years and a single treatment with AVXS-101 in the United States are approximately $4.1 and $2.1 million, respectively, which imposes an additional burden on the patients
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