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SMN protein. Nusinersen, an antisense oligonucleotide therapy. ASOs are short, synthetic, single-stranded, chemically modified nucleic acids designed to complementarily bind to a specific mRNA target. ASOs exert their final effect by promoting RNA degradation, interfering with pre-mRNA processing, blocking RNA binding motifs, or disrupting target mRNA structure (143) (Figure 4). Nusinersen is an 18-mer modified 2 -O-2-methoxyethyl phosphorothioate ASO that blocks the binding of hnRNP A1 to the ISS-N1 motif, thereby promoting exon 7 inclusion in SMN2 (80). The first preclinical studies in severe SMA mice treated with nusinersen showed its impressive effects on SMN protein levels (exon 7 inclusion higher than 90% in SMN2 transcripts), increased survival, and improved muscle physiology (77, 143), which led to expedited approval of the SMN2 ASO (ISIS SMNRx) and the initiation of the first clinical trial (NCT01494701). Since its introduction into clinical practice on December 23, 2016, nusinersen has been commercialized under the name Spinraza (Ionis Pharmaceuticals and Biogen) and is the only treatment licensed by the US Food and Drug Administration and European Medicines Agency for all types of SMA in pediatric and adult patients. Encouraging results from the ENDEAR 244 Wirth et al. Annu. Rev. Genom. Hum. Genet. 2020.21:231-261. Downloaded from www.annualreviews.org Access provided by 2600:1700:3c30:a3d0:89dc:b3d1:ac73:5085 on 01/23/22. For personal use only. Table 2 Spinal muscular atrophy therapies undergoing clinical development studies Type of therapy Strategy Drug name Organization Identifier(s) Current clinical stage SMN dependent SMN2 modulators SMN2 ISS-N1– targeting ASO Nusinersen (Spinraza) Biogen/Ionis NCT02386553 (NURTURE) NCT02052791 NCT02865109 NCT01780246 NCT02462759 NCT01703988 NCT02193074 (ENDEAR) NCT02292537 (CHERISH) NCT01839656 NCT02594124 (SHINE) NCT01494701 Administered to patients SMN2-targeting small molecules Risdiplam (RG7916) Hoffmann–La Roche/Genentech NCT03032172 ( JEWELFISH) NCT02913482 (FIREFISH) NCT02908685 (SUNFISH) NCT02240355 (MOONFISH) NCT02633709 Ongoing phase 3 Branaplam (LMI070) Novartis NCT02268552 Ongoing phase 2 SMN1 gene therapy SMN1 gene transfer Onasemnogene abeparvovec [AVXS-101, Zolgensma (IV)] AveXis/Novartis NCT02122952 (START) NCT03381729 (STRONG) Approved by US Food and Drug Administration SMN independent Neuroprotection Enhancement of mitochondrial function Olesoxime (TRO19622) Hoffmann–La Roche NCT01302600 NCT02628743 (OLEOS) Drug development terminated Muscle enhancement Troponin-dependent increase of muscle contraction Reldesemtiv (CK2127107) Cytokinetics/Astellas NCT02644668 Phase 2 completed Inhibitor of latent myostatin SRK-015 Scholar Rock NCT03921528 (TOPAZ) Ongoing phase 2 Abbreviations: ASO, antisense oligonucleotide; ISS-N1, intronic splicing silencer N1. study (NCT02193074) in infant-onset SMA (53) and the CHERISH study (NCT02292537) in childhood-onset SMA (116) accelerated the approval of Spinraza. Preceding these trials and further supporting the clinical efficacy, tolerability, and safety of Spinraza were two phase 1 and 2 studies (26, 50) and two open-label studies: NURTURE (NCT02386553), a phase 2 trial www.annualreviews.org • 25 Years of Spinal Muscular Atrophy Research 245 Annu. Rev. Genom. Hum. Genet. 2020.21:231-261. Downloaded from www.annualreviews.org Access provided by 2600:1700:3c30:a3d0:89dc:b3d1:ac73:5085 on 01/23/22. For personal use only. DNA/RNA Exon 6 T ISS-N1 Exon 8 Nusinersen (SMN ASO) SMN2 mRNA Protein Exon 6 Exon 7 Exon 8 Exon 6 Exon 8 U Exon 6 Exon 8 Exon 7 Exon 6 Exon 8 U Nusinersen (SMN ASO) Full-length SMN SMNΔ7 U1 snRNP Exon 7 Figure 4 Nusinersen-mediated restoration of SMN2 splicing. The ASO nusinersen (black triangles) blocks the ISS-N1 site in intron 7 (red triangles), impairing the access of negative splicing factors (hnRNP A1/2) and stabilizing the U1 snRNP machinery that recognizes exon 7 in SMN2 pre-mRNA. It thereby promotes exon 7 inclusion in SMN2 mature transcripts and shifts the
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