Embedded Files
vessels, kidney, spinal cord, and peripheral nerves from animal studies conducted in parallel (132). SMN1 gene replacement. Despite the breakthrough effects of nusinersen in the SMA therapy field, some major limitations remain, including the need for periodic intrathecal administration, the fact that nusinersen does not address the upregulation of SMN in other relevant tissues (e.g., muscle and the NMJ), and the questionable sustainability of low peripheral levels of SMN in the long run. This last item is of crucial importance, considering that approximately 80% of patients with SMA type I carry one or two copies of the SMN2 gene (48). The availability of nusinersen is also contingent on its elevated price and particular hospital specifications. Being a monogenic disorder, SMA offers an excellent constellation for gene replacement therapy. The relatively small SMN1 cDNA can be successfully packed into a nonreplicating scAAV9 vector that can be systemically delivered. Thus, it can efficiently transduce spinal motor neurons, as it can cross the blood–brain barrier, and reach the muscle or other peripheral tissues where the SMN protein is abundantly expressed. Preclinical studies in severe SMA animal models (i.e., mouse and pig) showed that intravenous injection of scAAV9-SMN1 restored SMN levels, extended survival, and restored motor function and neurophysiology (44, 55, 121). This preliminary evidence was foundational for a phase 1 openlabel clinical trial (START, NCT02122952). In this study, a single intravenous dose of AVXS-101 (scAAV9-SMN1, driven by the cytomegalovirus enhancer and the chicken β-actin promoter) was administered to 15 infants with SMA type I carrying a biallelic mutation of SMN1 and two SMN2 copies (113). Patients were stratified in two cohorts that received either a high dose [12 patients, 2.0 × 1014 vector genomes (vg)/kg body weight] or a low dose (3 patients, 6.7 × 1013 vg/kg body weight) of the medication. The scAAV-treated group was matched against historical cohorts from the NeuroNEXT SMA infant biomarker study (94). Patients who received the gene therapy showed, in a dose-dependent effect, superior and sustained achievement of motor milestones and better motor function, in contrast to the motor decline observed in historical cohorts. Specifically, 11 out of 12 patients in the high-dose group were able to sit unaided, 9 could roll over, 11 could be orally fed, and 2 walked independently. Most importantly, all 15 patients were alive and independent of mechanical ventilation at 20 months of age, in contrast to 8% survival in historical cohorts resembling the natural course of the disease 248 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. (113). AVXS-101 (onasemnogene abeparvovec) administration increased liver transaminase levels 35 times above reference levels, probably as a consequence of the massive immune response against viral peptides, which could be successfully reversed by daily glucocorticoid administration (1 mg/kg) for one month. In the long term, the beneficial effect of onasemnogene abeparvovec on motor function appears to be sustained (4, 5, 114). At 3.7 years after the initial gene replacement, all patients from the higher-dose group were alive, and none required permanent ventilation support. Moreover, achieved motor milestones and motor improvements were also sustained over time. At the time of analysis (March 8, 2019), seven patients were not hospitalized or receiving additional care, and three patients had started adjuvant nusinersen therapy (114). Interim results of an ongoing open-label phase 1–2 clinical trial of intrathecal administration of onasemnogene abeparvovec in patients with three SMN2 copies (STRONG, NCT03381729) showed a sustained gain of motor milestones and, as the primary outcome, treatment safety (52). On May 24, 2019, onasemnogene abeparvovec (marketed under the name Zolgensma) became the first gene therapy to be approved in the United States for the treatment of pediatric SMA patients (up to two years of age). The
Report abuse