OBJECTIVE: Spinal muscular atrophy (SMA) manifests with progressive motor neuron degeneration, leading to muscle weakness. Onasemnogene abeparvovec is a US Food and Drug Administration-approved gene replacement therapy for SMA. This study aimed to present short-term data of children in the United Arab Emirates (UAE) treated with onasemnogene abeparvovec, particularly in the context of children requiring invasive ventilatory support via tracheostomy.
METHODS: A retrospective analysis was performed on 60 children who received onasemnogene abeparvovec. All these children received corticosteroids. They were followed up for up to 3 months. Motor function assessments were performed before and after the gene therapy. Comprehensive clinical evaluations, including pulmonary functions, were performed at baseline and the 3-month mark.
RESULTS: Forty-three percent were male, and the mean age at the time of infusion was 29.6 months (SD ± 17.2). The mean weight was 10.1 kg (SD 2.6). All children demonstrated marked improvements in motor function within 3 months of gene therapy administration. No adverse effects attributable to corticosteroid therapy were observed. Positive clinical outcomes, including increased ventilator-free intervals, reduced antibiotic dependency, and fewer hospital admissions, were reported among children with invasive ventilation via tracheostomy.
CONCLUSIONS: This study demonstrates the favorable tolerability and promising responses to onasemnogene abeparvovec in invasively ventilated pediatric patients. Early improvements in motor function, as observed within 3 months post-treatment, suggest its potential as a viable therapeutic option for this vulnerable patient population.

UNASSIGNED: Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by mutations in the survival motor neuron 1 (SMN1) gene. In clinical studies, gene replacement therapy with onasemnogene abeparvovec (formerly AVXS-101, Zolgensma®, Novartis) was efficacious in improving motor functioning in children with SMA. However, its effects on cognitive and language skills are largely unknown.
UNASSIGNED: This longitudinal observational study evaluated changes in motor and neurocognitive functioning over a 1-year period after administration of onasemnogene abeparvovec in 12 symptomatic SMA type 1 patients with two copies of SMN2 aged 1.7-52.6 months at administration. Motor functioning was measured using the Children\'s Hospital of Philadelphia Infant Test for Neuromuscular Disorders (CHOP-INTEND) while neurocognitive assessment was measured using Griffiths III. Motor milestones and language ability were also assessed at each timepoint.
UNASSIGNED: Statistically significant increases in median CHOP-INTEND scores from baseline were observed at 1, 3, 6, and 12 months after onasemnogene abeparvovec administration (all p ≤ 0.005). Most (91.7%) patients were able to roll over or sit independently for >1 min at 12 months. Significant increases in the Griffiths III Foundations of Learning, Language and Communication, Eye and Hand Coordination, and Personal-Social-Emotional subscale scores were observed at 12-months, but not in the Gross Motor subscale. Speech and language abilities progressed in most patients. Overall, most patients showed some improvement in cognitive and communication performance after treatment with onasemnogene abeparvovec in addition to significant improvement in motor functioning and motor milestones. Evaluation of neurocognitive function should be considered when assessing the global functioning of patients with SMA.

Bulbar function in spinal muscular atrophy has been defined as the ability to meet nutritional needs by mouth while maintaining airway protection and communicate verbally. The effects of disease-modifying treatment on bulbar function are not clear. A multidisciplinary team conducted post-hoc analyses of phase 3 SPR1NT trial data to evaluate bulbar function of infants at risk for spinal muscular atrophy who received one-time gene replacement therapy (onasemnogene abeparvovec) before symptom onset. Three endpoints represented adequate bulbar function in SPR1NT: (1) absence of physiologic swallowing impairment, (2) full oral nutrition, and (3) absence of adverse events indicating pulmonary instability. Communication was not assessed in SPR1NT. We descriptively assessed numbers/percentages of children who achieved each endpoint and all three collectively. SPR1NT included infants <6 postnatal weeks with two (n = 14) or three (n = 15) copies of the survival motor neuron 2 gene. At study end (18 [two-copy cohort] or 24 [three-copy cohort] months of age), 100% (29/29) of patients swallowed normally, achieved full oral nutrition, maintained pulmonary stability, and achieved the composite endpoint. When administered to infants before clinical symptom onset, onasemnogene abeparvovec allowed children at risk for spinal muscular atrophy to achieve milestones within published normal ranges of development and preserve bulbar function.

BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disorder arising from biallelic non-functional survival motor neuron 1 (SMN1) genes with variable copies of partially functional SMN2 gene. Intrathecal onasemnogene abeparvovec administration, at fixed, low doses, may enable treatment of heavier patients ineligible for weight-based intravenous dosing.
OBJECTIVE: STRONG (NCT03381729) assessed the safety/tolerability and efficacy of intrathecal onasemnogene abeparvovec for sitting, nonambulatory SMA patients.
METHODS: Sitting, nonambulatory SMA patients (biallelic SMN1 loss, three SMN2 copies, aged 6-<60 months) received a single dose of intrathecal onasemnogene abeparvovec. Patients were enrolled sequentially into one of three (low, medium, and high) dose cohorts and stratified into two groups by age at dosing: younger (6-<24 months) and older (24-<60 months). Primary endpoints included safety/tolerability, independent standing ≥3 seconds (younger group), and change in Hammersmith Functional Motor Scale Expanded (HFMSE) from baseline (older group) compared with historic controls.
RESULTS: Thirty-two patients were enrolled and completed the study (medium dose, n = 25). All patients had one or more treatment-emergent adverse events, with one serious and related to treatment (transaminase elevations). No deaths were reported. One of 13 patients (7.7%) in the younger group treated with the medium dose achieved independent standing. At Month 12 for the older group receiving the medium dose, change from baseline in HFMSE was significantly improved compared with the SMA historic control population (P < 0.01).
CONCLUSIONS: Intrathecal onasemnogene abeparvovec was safe and well-tolerated. Older patients treated with the medium dose demonstrated increases in HFMSE score greater than commonly observed in natural history.

BACKGROUND: Spinal muscular atrophy (SMA) is a rare neuromuscular disorder leading to early death in the majority of affected individuals without treatment. Recently, targeted treatment approaches including Onasemnogene Abeparvovec (OA) were introduced. This study describes the first real-world experience with OA in Switzerland.
METHODS: Prospective observational case series study using data collected within the Swiss Registry for Neuromuscular Disorders from SMA patients treated with OA. Development of motor, bulbar and respiratory function, appearance of scoliosis, and safety data (platelet count, liver function, and cardiotoxicity) were analyzed.
RESULTS: Nine individuals were treated with OA and followed for 383 ± 126 days: six SMA type 1 (of which two with nusinersen pretreatment), one SMA type 2, and two pre-symptomatic individuals. In SMA type 1, CHOP Intend score increased by 28.1 from a mean score of 20.5 ± 7.6 at baseline. At end of follow-up, 50% of SMA type 1 patients required nutritional support and 17% night-time ventilation; 67% developed scoliosis. The SMA type 2 patient and two pre-symptomatically treated individuals reached maximum CHOP Intend scores. No patient required adaptation of the concomitant prednisolone treatment, although transient decrease of platelet count and increase of transaminases were observed in all patients. Troponin-T was elevated prior to OA treatment in 100% and showed fluctuations in 57% thereafter.
CONCLUSIONS: OA is a potent treatment for SMA leading to significant motor function improvements. However, the need for respiratory and especially nutritional support as well as the development of scoliosis must be thoroughly evaluated in SMA type 1 patients even in the short term after OA treatment.

OBJECTIVE: This systematic review aimed to assess mid- and long-term (at least 12 months) real-world study data from all types of spinal muscular atrophy (SMA) patients treated with any of the approved drugs or combination therapies.
METHODS: A systematic literature search was carried out in five databases. Two authors selected the studies based on pre-defined selection criteria and independently graded the risk of bias at study level.
RESULTS: Five hundred forty-six records were identified in the literature search and 22 studies (in 26 publications) were included in the analysis. Nusinersen, onasemnogene abeparvovec and combination therapies improved motor endpoints in SMA type 1 patients. SMA type 2 to type 4 patients treated with nusinersen showed stabilisation or small improvements in motor endpoints with some deterioration observed. Quality of life endpoints, such as respiratory and nutritional support were poorly reported on. Drug-related adverse events occurred rarely in all types of SMA patients with all assessed drugs. Mid- and long-term studies on risdiplam could not be identified.
CONCLUSIONS: The large quantity of missing data and heterogeneity of studies hinder comparability. Although stability and further improvement on the long-term is still uncertain, the results from the included evidence, as well as from pivotal trials show a striking contrast to the natural progression of the disease.

This study characterizes motor function responses after early dosing of AVXS-101 (onasemnogene abeparvovec) in gene replacement therapy in infants with severe spinal muscular atrophy type 1 (SMA1).
This study is a follow-up analysis of 12 infants with SMA1 who received the proposed therapeutic dose of AVXS-101 in a Phase 1 open-label study (NCT02122952). Infants were grouped according to age at dosing and baseline Children\'s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores: (1) early dosing/low motor, dosed age less than three months with scores <20 (n = 3), (2) late dosing, dosed at age three months or greater (n = 6), and (3) early dosing/high motor, dosed age less than three months with scores ≥20 (n = 3).
Early dosing/low motor group demonstrated a mean gain of 35.0 points from a mean baseline of 15.7, whereas the late dosing group had a mean gain of 23.3 from a mean baseline of 26.5. The early dosing/high motor group quickly reached a mean score of 60.3, near the scale maximum (64), from a mean baseline of 44.0. Despite a lower baseline motor score, the early dosing/low motor group achieved sitting unassisted earlier than the late dosing group (mean age: 17.0 vs 22.0 months). The early dosing/high motor group reached this milestone earliest (mean age: 9.4 months).
The rapid, significant motor improvements among infants with severe SMA1 treated with AVXS-101 at an early age highlight the importance of newborn screening and early treatment and demonstrate the therapeutic potential of AVXS-101 regardless of baseline motor function.