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balance toward increased full-length SMN protein levels. Abbreviations: ASO, antisense oligonucleotide; hnRNP, heterogeneous nuclear ribonucleoprotein; ISS-N1, intronic splicing silencer N1; snRNP, small nuclear ribonucleoprotein. in presymptomatic infants (38), and SHINE (NCT02594124), an ongoing phase 3 study that aims to assess the long-term clinical effects of Spinraza treatment (for a summary of studies, see Table 3). The treatment protocol includes an initial loading dose period consisting of four 12-mg intrathecal injections over two months, followed by a maintenance period with drug injections every four months (73). In general, nusinersen has been found to be safe and well tolerated (64, 73). The reported side effects are consistent with either the expected symptomatology of SMA or the related effects of a lumbar puncture. To date, more than 10,000 patients have undergone therapy with nusinersen worldwide. Small molecules. Small-molecule therapies that modulate SMN2 splicing are being developed and will be a key part of the future clinical landscape of SMA. Perhaps the most significant benefit of these molecules is their ease of administration, as they are orally bioavailable and, unlike nusinersen, have systemic distribution, targeting not only the central nervous system but also other organs. The latter is of crucial importance, considering the contribution of peripheral organs and tissues to the pathology of SMA (76, 78). Besides the limited ability of these molecules to effectively cross the blood–brain barrier, their major drawback is the potential risk of off-target effects (18). To circumvent the unspecificity of small molecules, PTC Therapeutics and Hoffmann–La Roche performed a high-throughput chemical screening of SMN2 splicing modifiers and identified two molecules, RG7800 and RG7916, that selectively shifted SMN2 splicing by stabilizing the U1 snRNP complex and, remarkably, were able to cross the blood–brain barrier (128, 137). Oral administration to severe SMA mice extended their life spans, led to increased SMN levels, protected the NMJ, and improved motor function (128, 140, 141). The first phase 1 clinical trial (MOONFISH, NCT02240355), which aimed to test the safety, tolerability, and pharmacological properties of RG7800 in pediatric and adult SMA, was terminated soon after the enrollment phase due to the eye toxicity detected in long-term tolerability studies. 246 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 3 Overview of important nusinersen clinical trials Study Design and objective Patients Time period Primary outcome Observations SMA type I NURTURE (NCT02386553) Phase 2, open label, single group assignment Assess the efficacy, safety, tolerability, and pharmacokinetics of multiple doses of nusinersen Infants (six weeks or younger) genetically diagnosed with presymptomatic SMA with two or three SMN2 copies 2015–2022a Time to death or respiratory intervention (i.e., ventilation for six or more hours per day continuously for seven or more days or tracheostomy) All infants were alive and none required respiratory intervention after one year of nusinersen delivery. All showed improved HINE motor milestones and appropriate age-related developmental gains (38). SHINE (NCT02594124) Phase 3, open label, nonrandomized, parallel assignment Evaluate the long-term safety and tolerability of nusinersen SMA patients who previously participated in investigational studies of nusinersen (ENDEAR) 2015–2023a Adverse events and/or serious adverse events based on neurological examination, laboratory assessment, coagulation parameters, and weight and 12-lead ECG abnormalities Interim evaluation: Treatment was safe and well tolerated. Motor skills improved in all patients, with greater motor and developmental improvements in patients who started nusinersen therapy in ENDEAR. ENDEAR (NCT02193074) Phase 3, randomized, sham-procedure controlled Assess the clinical efficacy and safety of intrathecaladministered nusinersen
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