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Objective This study prospectively assessed putative promising biomarkers for use in assessing infants with spinal muscular atrophy ( SMA). Methods This prospective, multi-center natural history study targeted the enrollment of SMA infants and healthy control infants less than 6 months of age. Recruitment occurred at 14 centers within the NINDS National Network for Excellence in Neuroscience Clinical Trials (Neuro NEXT) Network. Infant motor function scales and putative electrophysiological, protein and molecular biomarkers were assessed at baseline and subsequent visits. Results Enrollment began November, 2012 and ended September, 2014 with 26 SMA infants and 27 healthy infants enrolled. Baseline demographic characteristics of the SMA and control infant cohorts aligned well. Motor function as assessed by the Test for Infant Motor Performance Items ( TIMPSI) and the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders ( CHOP- INTEND) revealed significant differences between the SMA and control infants at baseline. Ulnar compound muscle action potential amplitude ( CMAP) in SMA infants (1.4 ± 2.2 mV) was significantly reduced compared to controls (5.5 ± 2.0 mV). Electrical impedance myography ( EIM) high-frequency reactance slope (Ohms/ MHz) was significantly higher in SMA infants than controls SMA infants had lower survival motor neuron ( SMN) mRNA levels in blood than controls, and several serum protein analytes were altered between cohorts. Interpretation By the time infants were recruited and presented for the baseline visit, SMA infants had reduced motor function compared to controls. Ulnar CMAP, EIM, blood SMN mRNA levels, and serum protein analytes were able to distinguish between cohorts at the enrollment visit. [ABSTRACT FROM AUTHOR]

Background: Spinal muscular atrophy type 1 is a motor neuron disorder resulting in death or the need for permanent ventilation by age 2 years. We aimed to evaluate the safety and efficacy of onasemnogene abeparvovec (previously known as AVXS-101), a gene therapy delivering the survival motor neuron gene (SMN), in symptomatic patients (identified through clinical examination) with infantile-onset spinal muscular atrophy.Methods: STR1VE was an open-label, single-arm, single-dose, phase 3 trial done at 12 hospitals and universities in the USA. Eligible patients had to be younger than 6 months and have spinal muscular atrophy with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes per kg) for 30-60 min. During the outpatient follow-up, patients were assessed once per week, beginning at day 7 post-infusion for 4 weeks and then once per month until the end of the study (age 18 months or early termination). Coprimary efficacy outcomes were independent sitting for 30 s or longer (Bayley-III item 26) at the 18 month of age study visit and survival (absence of death or permanent ventilation) at age 14 months. Safety was assessed through evaluation of adverse events, concomitant medication usage, physical examinations, vital sign assessments, cardiac assessments, and laboratory evaluation. Primary efficacy endpoints for the intention-to-treat population were compared with untreated infants aged 6 months or younger (n=23) with spinal muscular atrophy type 1 (biallelic deletion of SMN1 and two copies of SMN2) from the Pediatric Neuromuscular Clinical Research (PNCR) dataset. This trial is registered with ClinicalTrials.gov, NCT03306277 (completed).Findings: From Oct 24, 2017, to Nov 12, 2019, 22 patients with spinal muscular atrophy type 1 were eligible and received onasemnogene abeparvovec. 13 (59%, 97·5% CI 36-100) of 22 patients achieved functional independent sitting for 30 s or longer at the 18 month of age study visit (vs 0 of 23 patients in the untreated PNCR cohort; p<0·0001). 20 patients (91%, 79-100]) survived free from permanent ventilation at age 14 months (vs 6 [26%], 8-44; p<0·0001 in the untreated PNCR cohort). All patients who received onasemnogene abeparvovec had at least one adverse event (most common was pyrexia). The most frequently reported serious adverse events were bronchiolitis, pneumonia, respiratory distress, and respiratory syncytial virus bronchiolitis. Three serious adverse events were related or possibly related to the treatment (two patients had elevated hepatic aminotransferases, and one had hydrocephalus).Interpretation: Results from this multicentre trial build on findings from the phase 1 START study by showing safety and efficacy of commercial grade onasemnogene abeparvovec. Onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the PNCR natural history cohort. The favourable benefit-risk profile shown in this study supports the use of onasemnogene abeparvovec for treatment of symptomatic patients with genetic or clinical characteristics predictive of infantile-onset spinal muscular atrophy type 1.Funding: Novartis Gene Therapies. [ABSTRACT FROM AUTHOR]

• A novel smartphone sensor-based assessment suite was developed for people with spinal muscular atrophy (SMA). • Tests were reliable, engaging, and easy for most people with SMA to complete. • Tests showed convergent validity with established SMA clinical assessments. • Our study demonstrates potential for digital monitoring of disease in SMA. Spinal muscular atrophy (SMA) is characterized by progressive muscle weakness and paralysis. Motor function is monitored in the clinical setting using assessments including the 32-item Motor Function Measure (MFM-32), but changes in disease severity between clinical visits may be missed. Digital health technologies may assist evaluation of disease severity by bridging gaps between clinical visits. We developed a smartphone sensor-based assessment suite, comprising nine tasks, to assess motor and muscle function in people with SMA. We used data from the risdiplam phase 2 JEWELFISH trial to assess the test–retest reliability and convergent validity of each task. In the first 6 weeks, 116 eligible participants completed assessments on a median of 6.3 days per week. Eight of the nine tasks demonstrated good or excellent test–retest reliability (intraclass correlation coefficients >0.75 and >0.9, respectively). Seven tasks showed a significant association (P < 0.05) with related clinical measures of motor function (individual items from the MFM-32 or Revised Upper Limb Module scales) and seven showed significant association (P < 0.05) with disease severity measured using the MFM-32 total score. This cross-sectional study supports the feasibility, reliability, and validity of using smartphone-based digital assessments to measure function in people living with SMA. [ABSTRACT FROM AUTHOR]

Objective: Infantile-onset spinal muscular atrophy (SMA) is the most common genetic cause of infant mortality, typically resulting in death preceding age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes.Methods: A longitudinal, multicenter, prospective natural history study enrolled 26 SMA infants and 27 control infants aged <6 months. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT (National Network for Excellence in Neuroscience Clinical Trials) Network. Infant motor function scales (Test of Infant Motor Performance Screening Items [TIMPSI], The Children's Hospital of Philadelphia Infant Test for Neuromuscular Disorders, and Alberta Infant Motor Score) and putative physiological and molecular biomarkers were assessed preceding age 6 months and at 6, 9, 12, 18, and 24 months with progression, correlations between motor function and biomarkers, and hazard ratios analyzed.Results: Motor function scores (MFS) and compound muscle action potential (CMAP) decreased rapidly in SMA infants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in SMA infants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in SMA infants. Post-hoc analysis of survival to combined endpoint in SMA infants with 2 copies of SMN2 indicated a median age of 8 months at death (95% confidence interval, 6, 17).Interpretation: These data of SMA and control outcome measures delineates meaningful change in clinical trials in infantile-onset SMA. The power and utility of NeuroNEXT to provide "real-world," prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. Ann Neurol 2017;82:883-891. [ABSTRACT FROM AUTHOR]

Risdiplam is a once-daily oral, survival of motor neuron 2 (SMN2) splicing modifier approved for the treatment of spinal muscular atrophy (SMA). JEWELFISH (NCT03032172) investigated the safety, tolerability, pharmacokinetics (PK), and PK/pharmacodynamic (PD) relationship of risdiplam in non-treatment-naïve patients with SMA. JEWELFISH enrolled adult and pediatric patients (N = 174) with confirmed diagnosis of 5q-autosomal recessive SMA who had previously received treatment with nusinersen (n = 76), onasemnogene abeparvovec (n = 14), olesoxime (n = 71), or were enrolled in the MOONFISH study (NCT02240355) of the splicing modifier RG7800 (n = 13). JEWELFISH was an open-label study with all participants scheduled to receive risdiplam. The most common adverse event (AE) was pyrexia (42 patients, 24%) and the most common serious AE (SAE) was pneumonia (5 patients, 3%). The rate of AEs and SAEs decreased by > 50% from the first to the second year of treatment, and there were no treatment-related AEs that led to withdrawal from treatment. An increase in SMN protein in blood was observed following risdiplam treatment and sustained over 24 months of treatment irrespective of previous treatment. Exploratory efficacy assessments of motor function showed an overall stabilization in mean total scores as assessed by the 32-item Motor Function Measure, Hammersmith Functional Motor Scale-Expanded, and Revised Upper Limb Module. The safety profile of risdiplam in JEWELFISH was consistent with previous clinical trials of risdiplam in treatment-naïve patients. Exploratory efficacy outcomes are reported but it should be noted that the main aim of JEWELFISH was to assess safety and PK/PD, and the study was not designed for efficacy analysis. TRIAL REGISTRATION: The study was registered (NCT03032172) on ClinicalTrials.gov on January 24, 2017; First patient enrolled: March 3, 2017., (© 2024. The Author(s).)

Introduction: Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier for the treatment of patients with spinal muscular atrophy (SMA). The JEWELFISH study (NCT03032172) was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of risdiplam in previously treated pediatric and adult patients with types 1-3 SMA. Here, an analysis was performed after all patients had received at least 1 year of treatment with risdiplam., Methods: Patients with a confirmed diagnosis of 5q-autosomal recessive SMA between the ages of 6 months and 60 years were eligible for enrollment. Patients were previously enrolled in the MOONFISH study (NCT02240355) with splicing modifier RG7800 or treated with olesoxime, nusinersen, or onasemnogene abeparvovec. The primary objectives of the JEWELFISH study were to evaluate the safety and tolerability of risdiplam and investigate the PK after 2 years of treatment., Results: A total of 174 patients enrolled: MOONFISH study (n = 13), olesoxime (n = 71 patients), nusinersen (n = 76), onasemnogene abeparvovec (n = 14). Most patients (78%) had three SMN2 copies. The median age and weight of patients at enrollment was 14.0 years (1-60 years) and 39.1 kg (9.2-108.9 kg), respectively. About 63% of patients aged 2-60 years had a baseline total score of less than 10 on the Hammersmith Functional Motor Scale-Expanded and 83% had scoliosis. The most common adverse event (AE) was upper respiratory tract infection and pyrexia (30 patients each; 17%). Pneumonia (four patients; 2%) was the most frequently reported serious AE (SAE). The rates of AEs and SAEs per 100 patient-years were lower in the second 6-month period compared with the first. An increase in SMN protein was observed in blood after risdiplam treatment and was comparable across all ages and body weight quartiles., Conclusions: The safety and PD of risdiplam in patients who were previously treated were consistent with those of treatment-naïve patients., (© 2023. The Author(s).)

Spinal muscular atrophy (SMA) is an autosomal recessive degenerative neuromuscular disorder characterized by loss of spinal motor neurons leading to muscle weakness and atrophy that is caused by survival motor neuron (SMN) protein deficiency resulting from the biallelic loss of the SMN1 gene. The SMN2 gene modulates the SMA phenotype, as a small fraction of its transcripts are alternatively spliced to produce full-length SMN (fSMN) protein. SMN-targeted therapies increase SMN protein; mRNA therapies, nusinersen and risdiplam, increase the amount of fSMN transcripts alternatively spliced from the SMN2 gene, while gene transfer therapy, onasemnogene abeparvovec xioi, increases SMN protein by introducing the hSMN gene into various tissues, including spinal cord via an AAV9 vector. These SMN-targeted therapies have been found effective in improving outcomes and are approved for use in SMA in the US and elsewhere. This article discusses the clinical trial results for SMN-directed therapies with a focus on efficacy, side effects and treatment response predictors. It also discusses preliminary data from muscle-targeted trials, as single agents and in combination with SMN-targeted therapies, as well as other classes of SMA treatments., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Most children with biallelic SMN1 deletions and three SMN2 copies develop spinal muscular atrophy (SMA) type 2. SPR1NT ( NCT03505099 ), a Phase III, multicenter, single-arm trial, investigated the efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelic SMN1 mutations treated within six postnatal weeks. Of 15 children with three SMN2 copies treated before symptom onset, all stood independently before 24 months (P < 0.0001; 14 within normal developmental window), and 14 walked independently (P < 0.0001; 11 within normal developmental window). All survived without permanent ventilation at 14 months; ten (67%) maintained body weight (≥3rd WHO percentile) without feeding support through 24 months; and none required nutritional or respiratory support. No serious adverse events were considered treatment-related by the investigator. Onasemnogene abeparvovec was effective and well-tolerated for presymptomatic infants at risk of SMA type 2, underscoring the urgency of early identification and intervention., (© 2022. The Author(s).)

SPR1NT ( NCT03505099 ) was a Phase III, multicenter, single-arm study to investigate the efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelic SMN1 mutations treated at ≤6 weeks of life. Here, we report final results for 14 children with two copies of SMN2, expected to develop spinal muscular atrophy (SMA) type 1. Efficacy was compared with a matched Pediatric Neuromuscular Clinical Research natural-history cohort (n = 23). All 14 enrolled infants sat independently for ≥30 seconds at any visit ≤18 months (Bayley-III item #26; P < 0.001; 11 within the normal developmental window). All survived without permanent ventilation at 14 months as per protocol; 13 maintained body weight (≥3rd WHO percentile) through 18 months. No child used nutritional or respiratory support. No serious adverse events were considered related to treatment by the investigator. Onasemnogene abeparvovec was effective and well-tolerated for children expected to develop SMA type 1, highlighting the urgency for universal newborn screening., (© 2022. The Author(s).)

SMA is a genetically determined motor system disorder that results in muscle weakness, selective motor neuron death, muscle atrophy, and impaired functional mobility. In SMA model systems, long-term treatment with 4-aminopyridine (4-AP) has been shown to improve motor function. To assess tolerability and preliminary efficacy of 4-AP on walking ability, endurance and EMG in adult ambulatory SMA patients, we conducted a double blind, placebo control, crossover pilot study with dalfampridine (4-AP, 10 mg BID). The study is comprised of a short-term (2 weeks) treatment arm with 1-week washout and a long-term (6 weeks) treatment arm with a 2-week washout. The primary outcome measure, for which the study was powered, was the 6 min walk test (6MWT, distance and percent fatigue); secondary outcome measures were the Hammersmith Functional Motor Scale Expanded (HFMSE), Manual Muscle Testing (MMT), Myometry with Hand held Dynamometry, HHD) and Quantitative Gait Analyses. We performed electrophysiology, including CMAP and H-reflex, during the short-term treatment trial. The mean age of the 11 participants enrolled was 37.7 ± 11.9 years; 54.5% were male. Dalfampridine was safe and well tolerated and no patient suffered a serious adverse event related to treatment. We observed no statistically significant positive effects of dalfampridine treatment on our primary functional motor outcome (6MWT distance, fatigue). Dalfampridine had a positive effects on H-reflex and H/M ratio but not on CMAP amplitude. The effect on the H-reflex is of interest, as it suggests dalfampridine may enhance neuronal activity, an effect observed in SMA Drosophila and mouse models at doses (mg/kg) not recommended for clinical use. Larger studies with dalfampridine in SMA patients are needed to confirm our findings, especially in light of studies in other populations showing drug effects in only a subset of patients., (Copyright © 2020. Published by Elsevier B.V.)

Purpose: Spinal muscular atrophy (SMA) was added to the Recommended Uniform Screening Panel (RUSP) in July 2018, following FDA approval of the first effective SMA treatment, and demonstration of feasibility of high-throughput newborn screening using a primary molecular assay. SMA newborn screening was implemented in New York State (NYS) on 1 October 2018., Methods: Screening was conducted using DNA extracted from dried blood spots with a multiplex real-time quantitative polymerase chain reaction (qPCR) assay targeting the recurrent SMN1 exon 7 gene deletion., Results: During the first year, 225,093 infants were tested. Eight screened positive, were referred for follow-up, and confirmed to be homozygous for the deletion. Infants with two or three copies of the SMN2 gene, predicting more severe, earlier-onset SMA, were treated with antisense oligonucleotide and/or gene therapy. One infant with ≥4 copies SMN2 also received gene therapy., Conclusion: Newborn screening permits presymptomatic SMA diagnosis, when treatment initiation is most beneficial. At 1 in 28,137 (95% confidence interval [CI]: 1 in 14,259 to 55,525), the NYS SMA incidence is 2.6- to 4.7-fold lower than expected. The low SMA incidence is likely attributable to imprecise and biased estimates, coupled with increased awareness, access to and uptake of carrier screening, genetic counseling, cascade testing, prenatal diagnosis, and advanced reproductive technologies.

Importance: One major advantage of developing large, federally funded networks for clinical research in neurology is the ability to have a trial-ready network that can efficiently conduct scientifically rigorous projects to improve the health of people with neurologic disorders., Observations: National Institute of Neurological Disorders and Stroke Network for Excellence in Neuroscience Clinical Trials (NeuroNEXT) was established in 2011 and renewed in 2018 with the goal of being an efficient network to test between 5 and 7 promising new agents in phase II clinical trials. A clinical coordinating center, data coordinating center, and 25 sites were competitively chosen. Common infrastructure was developed to accelerate timelines for clinical trials, including central institutional review board (a first for the National Institute of Neurological Disorders and Stroke), master clinical trial agreements, the use of common data elements, and experienced research sites and coordination centers. During the first 7 years, the network exceeded the goal of conducting 5 to 7 studies, with 9 funded. High interest was evident by receipt of 148 initial applications for potential studies in various neurologic disorders. Across the first 8 studies (the ninth study was funded at end of initial funding period), the central institutional review board approved the initial protocol in a mean (SD) of 59 (21) days, and additional sites were added a mean (SD) of 22 (18) days after submission. The median time from central institutional review board approval to first site activation was 47.5 days (mean, 102.1; range, 1-282) and from first site activation to first participant consent was 27 days (mean, 37.5; range, 0-96). The median time for database readiness was 3.5 months (mean, 4.0; range, 0-8) from funding receipt. In the 4 completed studies, enrollment met or exceeded expectations with 96% overall data accuracy across all sites. Nine peer-reviewed manuscripts were published, and 22 oral presentations or posters and 9 invited presentations were given at regional, national, and international meetings., Conclusions and Relevance: NeuroNEXT initiated 8 studies, successfully enrolled participants at or ahead of schedule, collected high-quality data, published primary results in high-impact journals, and provided mentorship, expert statistical, and trial management support to several new investigators. Partnerships were successfully created between government, academia, industry, foundations, and patient advocacy groups. Clinical trial consortia can efficiently and successfully address a range of important neurologic research and therapeutic questions.

Introduction: In experimental models, prenatal cocaine exposure has been found to perturb GABA and dopamine development. Clinically, abnormalities in tone, posture and state regulation are noted in early infancy but the evolution of these findings over time is not well described. The current study assesses the longitudinal effects of prenatal cocaine exposure in dose-dependent fashion on developmental & behavioral and neurological trajectories over the first 2 years of life., Methods: Three hundred and eighty infants, 113 cocaine-exposed, were enrolled at birth from an urban hospital from 2000 to 2004. Exposure was determined by maternal interview, segmental hair analyses (RIAH ™ ) in all, and meconium and urine in a subset. Developmental, behavioral and neurological assessments were carried out blind to drug exposure at 6, 12 and 24 months of age in the 306 children who returned in follow-up. Mixed-effects linear modeling (developmental growth curve) assessed change in outcome over time., Results: The mental developmental growth curve showed a negative slope (2.2 points) in adjusted analyses among cocaine-exposed children over the first 2 years of life. (p=.04), while the slope of the motor development growth curve did not. Adjusting for microcephaly at 6 months diminished the strength of the association between cocaine exposure and mental developmental growth curve (effect modification). Cocaine exposure was marginally associated with behavioral outcomes in adjusted analyses. Total Behavior scores and Orientation/Engagement scores improved with age. At 1 year of age, prenatal cocaine exposure was significantly associated with lower motor development scores. High rates of hypertonia (global and diparesis) identified at the 6-month visit dropped dramatically in the first 2 years of life: cocaine-exposed children showed a more rapid rate of resolution of hypertonia than unexposed children, with hypertonia improving 2.2 times faster among those with heavy cocaine exposure., Conclusion: We found differences in mental performance over the first 2 years of life associated with prenatal cocaine exposure that was mediated by microcephaly implying that cocaine exerts a sustained teratogenic effect on brain development. Early neurological (hypertonia) and behavioral findings associated with prenatal cocaine exposure improved over time. Hypertonia did not predict long-term development impairments. Conceivably, the transient nature of neurobehavioral manifestations reflects postnatally a tendency towards homeostasis of cocaine-related embryopathic perturbations of GABA and dopaminergic systems.