Thrombotic Microangiopathy Following Onasemnogene Abeparvovec for Spinal Muscular Atrophy: A Case Series.

Spinal muscular atrophy is treated with onasemnogene abeparvovec, which replaces the missing survival motor neuron 1 gene via an adeno-associated virus vector. As of July 1, 2020, we had identified 3 infants who developed thrombotic microangiopathy following onasemnogene abeparvovec. Early recognition and treatment of drug-induced thrombotic microangiopathy may lessen mortality and morbidity.

Outcome measures in a cohort of ambulatory adults with spinal muscular atrophy.

INTRODUCTION: With the advent of disease-altering therapies for spinal muscular atrophy (SMA), there is a requirement to better characterize outcome measures, particularly in milder forms of disease. METHODS: Maximal voluntary isometric contraction testing and 6-minute walk test (6MWT) performed in ambulatory SMA adults as part of the SMA-VALIANT trial were analyzed. Test-retest reliability and correlation with other candidate biomarkers and outcomes were investigated. RESULTS: Maximal voluntary isometric contraction testing and 6MWT showed good test-retest reliability (intraclass correlation coefficient = 0.98 and 0.85, respectively). Maximal voluntary isometric contraction testing and 6MWT demonstrated very strong correlation (r = 0.83, P <. 0001), and each correlated with the SMA Functional Rating Scale (r = 0.7, P < .0001 and r = 0.65, P = .0001, respectively), lean muscle mass (r = 0.68, P < .0001 and r = 0.56, P = .001, respectively), and ulnar compound muscle action potential (r = 0.57, P = .0008 and r = 0.47, P = .008, respectively). DISCUSSION: Maximal voluntary isometric contraction testing and 6MWT are suitable outcomes for use in ambulatory adults with SMA. Maximal voluntary isometric contraction testing may be preferable because of superior test-retest reliability and closer associations with other outcomes and biomarkers of neuromuscular function.

Natural history of infantile-onset spinal muscular atrophy.

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.

Clinical trial of L-Carnitine and valproic acid in spinal muscular atrophy type I.

INTRODUCTION: The aim of this study was to determine the safety and therapeutic potential of L-carnitine and valproic acid (VPA) in infants with spinal muscular atrophy (SMA). METHODS: Our investigation was an open-label phase 2 multicenter trial of L-carnitine and VPA in infants with SMA type I with retrospective comparison to an untreated, matched cohort. Primary outcomes were: safety and adverse events; secondary outcomes were survival, time to death/>16 hours/day of ventilator support; motor outcomes; and maximum ulnar compound motor action potential amplitude. RESULTS: A total of 245 AEs were observed in 35 of the 37 treated subjects (95%). Respiratory events accounted for 49% of all adverse events, resulting in 14 deaths. Survival was not significantly different between treated and untreated cohorts. DISCUSSION: This trial provides evidence that, in infants with SMA type I, L-carnitine/VPA is ineffective at altering survival. The substantial proportion of infants reaching end-points within 6 months of enrollment underscores the urgent need for pre-symptomatic treatment in SMA type I. Muscle Nerve 57: 193-199, 2018.

Pregnancy and delivery in women with spinal muscular atrophy.

OBJECTIVES: To expand the limited available knowledge about pregnancy and delivery in women with spinal muscular atrophy (SMA) using a cohort of genetically proven SMA patients from USA. METHODS: This was a cross-sectional questionnaire-based study. We mailed questionnaires to 58 women with confirmed SMA. RESULTS: Thirty-two women responded, reporting 35 pregnancies, including 19 women with at least one pregnancy. In this cohort, preterm labor and delivery by cesarean section were more common in mothers with SMA particularly SMA type 2. Seventy-four percent of mothers reported increased weakness during pregnancy that persisted after delivery in 42%. SMA mothers generally had a positive experience and good outcomes and elected to have more than one pregnancy. CONCLUSION: This information regarding pregnancy in women with genetically confirmed 5q SMA will prove useful in guiding future research and in providing counseling to women with SMA.

SMA valiant trial: a prospective, double-blind, placebo-controlled trial of valproic acid in ambulatory adults with spinal muscular atrophy.

INTRODUCTION: An open-label trial suggested that valproic acid (VPA) improved strength in adults with spinal muscular atrophy (SMA). We report a 12-month, double-blind, cross-over study of VPA in ambulatory SMA adults. METHODS: There were 33 subjects, aged 20­55 years, included in this investigation. After baseline assessment, subjects were randomized to receive VPA (10­20 mg/kg/day) or placebo. At 6 months, patients were switched to the other group. Assessments were performed at 3, 6, and 12 months. The primary outcome was the 6-month change in maximum voluntary isometric contraction testing with pulmonary, electrophysiological, and functional secondary outcomes. RESULTS: Thirty subjects completed the study. VPA was well tolerated, and compliance was good. There was no change in primary or secondary outcomes at 6 or 12 months. CONCLUSIONS: VPA did not improve strength or function in SMA adults. The outcomes used are feasible and reliable and can be employed in future trials in SMA adults.

Treatment preferences in spinal muscular atrophy: A swing weighting study for caregivers of patients with SMA types 1 and 2.

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder characterized by skeletal muscle weakness and atrophy. Patients with SMA types 1 and 2 develop severe disabilities conferring substantial patient and caregiver burden. Caregiver treatment characteristic preferences are useful for informing treatment choices and improving adherence. We aimed to identify drivers of SMA treatment preference from the perspective of caregivers of patients with SMA types 1 or 2 in the United States. We quantified the relative importance of different treatment characteristics and compared preferences for hypothetical treatment scenarios. Treatment attributes and attribute levels elicited were based on a literature search and interviews with caregivers and health care professionals. The most important treatment characteristics from the perspective of health care professionals and caregivers were identified and used in a survey to quantify relative importance for caregivers. Caregivers completed surveys regarding their preferences using swing weighting methodology. These results were used to estimate the relative value of four hypothetical SMA treatment scenarios exploring different modes of treatment administration. The swing weighting survey, completed by 20 caregivers, demonstrated that the attributes driving treatment preference were reduction in permanent ventilation needs and risk of severe adverse events, followed by treatment access (including cost coverage and availability), increased ability to sit without support, and less treatment administration burden. The hypothetical SMA treatment scenarios with the highest relative value offered an easier mode of administration, lowest risk of severe adverse events, less need of permanent ventilation, and highest ability of patients to feed and sit without support. Our findings suggest that caregivers prefer a treatment with reduced clinical burden and risk in which the cost is covered and treatment is available in the short term. These results can provide important contextual information for decision-makers and help promote patient-centered care for patients with SMA.

Onasemnogene abeparvovec preserves bulbar function in infants with presymptomatic spinal muscular atrophy: a post-hoc analysis of the SPR1NT trial.

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.

Patients with Spinal Muscular Atrophy Type 1 Achieve and Maintain Bulbar Function Following Onasemnogene Abeparvovec Treatment.

BACKGROUND: Improvement and maintenance of bulbar function are goals of disease-modifying treatments for spinal muscular atrophy (SMA). Lack of standardized measures and a widely accepted definition of bulbar function represents a gap in SMA care. OBJECTIVE: A multidisciplinary team conducted post-hoc analyses of pooled data from one phase 1 (START) and two phase 3 (STR1VE-US, STR1VE-EU) studies to define and evaluate bulbar function of infants with SMA type 1 after receiving one-time gene replacement therapy, onasemnogene abeparvovec. METHODS: We defined bulbar function as the ability to meet nutritional needs while maintaining airway protection and the ability to communicate verbally. Four endpoints represented adequate bulbar function: (1) absence of clinician-identified physiologic swallowing impairment, (2) receiving full oral nutrition, (3) absence of adverse events indicating pulmonary instability, and (4) the ability to vocalize at least two different, distinct vowel sounds. We descriptively assessed numbers/percentages of patients who achieved each endpoint and all four collectively. Patients were followed until 18 months old (STR1VE-US and STR1VE-EU) or 24 months (START) post-infusion. RESULTS: Overall, 65 patients were analyzed for swallowing, nutrition intake, and adverse events, and 20 were analyzed for communication. At study end, 92% (60/65) of patients had a normal swallow, 75% (49/65) achieved full oral nutrition, 92% (60/65) had no evidence of pulmonary instability, 95% (19/20) met the communication endpoint, and 75% (15/20) achieved all four bulbar function components in the composite endpoint. CONCLUSIONS: In these three clinical trials, patients with SMA type 1 who received onasemnogene abeparvovec achieved and maintained the bulbar function criteria utilized within this investigation.

Safety of Onasemnogene Abeparvovec for Patients With Spinal Muscular Atrophy 8.5 kg or Heavier in a Global Managed Access Program.

BACKGROUND: Spinal muscular atrophy is a rare, neurodegenerative disorder caused by biallelic deletions in the survival motor neuron (SMN1) gene. Onasemnogene abeparvovec is a one-time, intravenous gene replacement therapy designed to deliver the SMN1 transgene. Although available in many geographies, it is not approved globally. The Global Managed Access Program (GMAP) expanded treatment access to patients in countries where treatment was not approved. Previous onasemnogene abeparvovec clinical trials included patients with body weight <8.5 kg. Through GMAP, children weighing ≥8.5 kg received onasemnogene abeparvovec. We describe safety data for heavier patients in GMAP. METHODS: GMAP records were reviewed to identify patients weighing ≥8.5 kg at onasemnogene abeparvovec dosing. To obtain corresponding adverse event (AE) data, the Novartis ARGUS safety database was searched using patient identification numbers and birth dates/dosing dates for any reported AE for GMAP patients. RESULTS: As of September 2, 2021, 102 patients weighing ≥8.5 kg at time of dosing were identified. Fifty-four (53%) had one or more reported AEs. Three patients were reported to be deceased. All three deaths were assessed to be secondary to acute respiratory events. Most (62%) AEs were non-serious. The most frequently reported AEs included increases in hepatic laboratory values, decreased platelets and thrombocytopenia, pyrexia, vomiting, and decreased appetite. CONCLUSIONS: Safety findings for patients weighing ≥8.5 kg administered onasemnogene abeparvovec through GMAP were consistent with those described in clinical trials and included hepatotoxicity, thrombotic microangiopathy, and thrombocytopenia.

Reliability of the Modified Hammersmith Functional Motor Scale in young children with spinal muscular atrophy.

INTRODUCTION: The test-retest reliability of the Modified Hammersmith Functional Motor Scale (MHFMS) in children with spinal muscular atrophy (SMA) ≤30 months of age was assessed. The age at which typically developing children (TD) achieve maximum MHFMS scores was also studied. METHODS: Twenty-two children with SMA type II [mean age (SD) = 20 (5) months, range 9-30 months) were tested twice using the MHFMS. Twenty-five TD children [mean age (SD) = 18 (7) months, range 9-30 months) were tested once. RESULTS: The average difference between MHFMS scores for SMA children was 0.18 [first assessment: mean (SD) = 12.8 (9.8); second assessment: mean (SD) = 13.0 (8.8)]. Reliability was excellent (ICC(1,3) = 0.96, SEM 1.86). TD participants had MHFMS scores ranging from 36 to 40 [mean (SD) = 39.2 (1.2)] and achieved maximum test scores at 12 months of age. DISCUSSION: MHFMS scores in young children with SMA type II showed excellent test-retest stability. This suggests that the MHFMS can be used reliably in this younger population for clinical trials and follow-up.

Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy.

INTRODUCTION: This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy. OBJECTIVE: We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data. METHODS: Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign and cardiac assessments, laboratory evaluations, physical examinations, and concomitant medication use. AE reporting and available objective clinical data from postmarketing programs were evaluated. RESULTS: The main target organs of toxicity in mice were the heart and liver. Dorsal root ganglia (DRG) inflammation was observed in NHPs. Patients exhibited no evidence of sensory neuropathy upon clinical examination. In clinical trials, 101/102 patients experienced at least one treatment-emergent AE. In total, 50 patients experienced serious AEs, including 11 considered treatment related. AEs consistent with hepatotoxicity resolved with prednisolone in clinical trials. Transient decreases in mean platelet count were detected but were without bleeding complications. Thrombotic microangiopathy (TMA) was observed in the postmarketing setting. No evidence of intracardiac thrombi was observed for NHPs or patients. CONCLUSIONS: Risks associated with onasemnogene abeparvovec can be anticipated, monitored, and managed. Hepatotoxicity events resolved with prednisolone. Thrombocytopenia was transient. TMA may require medical intervention. Important potential risks include cardiac AEs and DRG toxicity.

The Cure SMA Membership Surveys: Highlights of Key Demographic and Clinical Characteristics of Individuals with Spinal Muscular Atrophy.

BACKGROUND: Cure SMA maintains the largest patient-reported database for people affected with spinal muscular atrophy (SMA). In 2017, Cure SMA initiated annual surveys with their membership to collect demographic and disease characteristics, healthcare, and burden of disease information from patients and caregivers. OBJECTIVE: To summarize results from two large-scale Cure SMA surveys in 2017 and 2018. METHODS: Cure SMA database members were invited to complete surveys; these were completed by caregivers for living or deceased individuals with SMA and/or affected adults. RESULTS: In 2017, 726 surveys were completed for 695 individuals with SMA; in 2018, 796 surveys were completed for 760 individuals with SMA. Data from both survey years are available for 313 affected individuals. Age at symptom onset, distribution of SMN2 gene copy number, and representation of each SMA type in the surveys were consistent with that expected in the SMA population. In the 2018 survey, the average age at diagnosis was 5.2 months for SMA type I and the reported mean age at death for this subgroup was 27.8 months. Between survey years, there was consistency in responses for factors that should not change within individuals over time (e.g., reported age at diagnosis). CONCLUSIONS: Results from the Cure SMA surveys advance the understanding of SMA and facilitate advocacy efforts and healthcare services planning. Longitudinal surveys are important for evaluating the impact of effective treatments on changing phenotypes, and burden of disease and care in individuals with SMA.

Compound muscle action potential and motor function in children with spinal muscular atrophy.

Reliable outcome measures that reflect the underlying disease process and correlate with motor function in children with SMA are needed for clinical trials. Maximum ulnar compound muscle action potential (CMAP) data were collected at two visits over a 4-6-week period in children with SMA types II and III, 2-17 years of age, at four academic centers. Primary functional outcome measures included the Modified Hammersmith Functional Motor Scale (MHFMS) and MHFMS-Extend. CMAP negative peak amplitude and area showed excellent discrimination between the ambulatory and non-ambulatory SMA cohorts (ROC = 0.88). CMAP had excellent test-retest reliability (ICC = 0.96-0.97, n = 64) and moderate to strong correlation with the MHFMS and MHFMS-Extend (r = 0.61-0.73, n = 68, P < 0.001). Maximum ulnar CMAP amplitude and area is a feasible, valid, and reliable outcome measure for use in pediatric multicenter clinical trials in SMA. CMAP correlates well with motor function and has potential value as a relevant surrogate for disease status.

Spinal Muscular Atrophy (SMA) Subtype Concordance in Siblings: Findings From the Cure SMA Cohort.

BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder caused by homozygous survival of motor neuron 1 (SMN1) gene disruption. Despite a genetic etiology, little is known about subtype concordance among siblings. OBJECTIVE: To investigate subtype concordance among siblings with SMA. METHODS: Cure SMA maintains a database of newly diagnosed patients with SMA, which was utilized for this research. RESULTS: Among 303 sibships identified between 1996 and 2016, 84.8% were subtype concordant. Of concordant sibships, subtype distribution was as follows: Type I, 54.5%; Type II, 31.9%; Type III, 13.2%; Type IV, 0.4%. Subtype and concordance/discordance association was significant (Fisher's exact test; p < 0.0001). Among discordant sibships (chi-square test, p < 0.0001), Types II/III (52.2%) and Types I/II (28.3%) were the most common pairs. No association was found between sibling sex and concordance. Our findings show that most siblings with SMA shared the same subtype concordance (most commonly Type I). CONCLUSIONS: These data are valuable for understanding familial occurrence of SMA subtypes, enabling better individual treatment and management planning in view of new treatment options and newborn screening initiatives.

Nusinersen initiated in infants during the presymptomatic stage of spinal muscular atrophy: Interim efficacy and safety results from the Phase 2 NURTURE study.

Spinal muscular atrophy (SMA) is a neurodegenerative disease associated with severe muscle atrophy and weakness in the limbs and trunk. We report interim efficacy and safety outcomes as of March 29, 2019 in 25 children with genetically diagnosed SMA who first received nusinersen in infancy while presymptomatic in the ongoing Phase 2, multisite, open-label, single-arm NURTURE trial. Fifteen children have two SMN2 copies and 10 have three SMN2 copies. At last visit, children were median (range) 34.8 [25.7-45.4] months of age and past the expected age of symptom onset for SMA Types I or II; all were alive and none required tracheostomy or permanent ventilation. Four (16%) participants with two SMN2 copies utilized respiratory support for ≥6 h/day for ≥7 consecutive days that was initiated during acute, reversible illnesses. All 25 participants achieved the ability to sit without support, 23/25 (92%) achieved walking with assistance, and 22/25 (88%) achieved walking independently. Eight infants had adverse events considered possibly related to nusinersen by the study investigators. These results, representing a median 2.9 years of follow up, emphasize the importance of proactive treatment with nusinersen immediately after establishing the genetic diagnosis of SMA in presymptomatic infants and emerging newborn screening efforts.

Recruitment & retention program for the NeuroNEXT SMA Biomarker Study: Super Babies for SMA!

BACKGROUND/AIMS: Recruitment and retention of research participants are challenging and critical components of successful clinical trials and natural history studies. Infants with spinal muscular atrophy (SMA) have been a particularly challenging population to study due to their fragile and complex medical issues, poor prognosis and, until 2016, a lack of effective therapies. Recruitment of healthy infants into clinical trials and natural history studies is also challenging and sometimes assumed to not be feasible. METHODS: In 2011, our group initiated a two-year, longitudinal natural history study of infants with SMA and healthy infant controls to provide data to assist in the analysis and interpretation of planned clinical trials in infants with SMA. The recruitment goal was to enroll 27 infants less than 6 months of age with SMA and 27 age-matched healthy infants within the two-year enrollment period. A detailed recruitment and retention plan was developed for this purpose. In addition, a survey was administered to participant families to understand the determinants of participation in the study. RESULTS: All healthy infants were recruited within the study's first year and 26 SMA infants were recruited within the two-year recruitment period. Thirty-eight participant families responded to the recruitment determinants survey. Nearly half of respondents (18/38, 48%) reported that they first heard of the study from their physician or neurologist. The most common reason to decide to enroll their infant (22/38, 58%) and to remain in the study (28/38, 74%) was their understanding of the importance of the study. Thematic recruitment tools such as a study brochure, video on social media, and presentations at advocacy meetings were reported to positively influence the decision to enroll. CONCLUSIONS: A proactive, thematic and inclusive recruitment and retention plan that effectively communicates the rationale of a clinical study and partners with patients, advocacy groups and the local communities can effectively recruit participants in vulnerable populations. Recommendations for the proactive integration of recruitment and retention plans into clinical trial protocol development are provided.

Homocysteine levels are associated with increased risk of congestive heart failure in patients with and without coronary artery disease.

BACKGROUND: Increased homocysteine (HCY) is associated with increased risk of vascular disease. Whether HCY affects development of congestive heart failure (CHF) independent of coronary artery disease (CAD) is uncertain. We evaluated whether increased HCY predicts low ejection fraction or clinical CHF. METHODS: Patients (n = 2,842) undergoing coronary angiography had HCY measured between 1994 and 1999 and were prospectively studied. Left ventricular dysfunction (LVD) was defined as ejection fraction < or =40%. Multivariable regressions assessed predictive strength of HCY for LVD or LVD/CHF. RESULTS: The average age was 64 +/- 12 years; 69% were men, and 74% had CAD. LVD was present in 12% and the combination of either LVD or clinical CHF was present in 21.9%. Quartiles of HCY were: < or =10.5 (Q1), 10.5-13.2 (Q2), 13.3-17.0 (Q3) and > or =17.1 micromol/l (Q4). LVD and LVD/CHF were more prevalent in Q3 (15, 25%) and Q4 (15, 27%) than in Q1 HCY (8.4, 18%; p < 0.001 vs. Q4). After adjustment, Q3 and Q4 HCY independently predicted LVD (OR = 1.7, 95% CI 1.2-2.5, p = 0.004; OR = 1.8, 95% CI 1.3-2.6, p = 0.002) or LVD/CHF (OR = 1.4, 95% CI 1.04-1.8, p = 0.03; OR = 1.7, 95% CI 1.3-2.2, p < 0.001). Findings did not differ by disease etiology: for Q4 among non-CAD patients, OR = 1.7 for LVD and OR = 1.7 for LVD/CHF. Further, there was no interaction of results with gender. CONCLUSION: High HCY levels (Q3/4 > or =13.3 micromol/l) are associated with LVD and combined endpoint of LVD/clinical CHF. This relationship is independent of CHF etiology and gender. Further research is indicated to distinguish between a causal or noncausal mechanism for this association.

Perspectives on clinical trials in spinal muscular atrophy.

Spinal muscular atrophy is one of the most heterogeneous of the single-gene neuromuscular disorders. The broad spectrum of severity, with onset from the prenatal period to adulthood, presents unique challenges in the design and implementation of clinical trials. The clinical classification of subjects into severe (type 1), intermediate (type 2), and mild (type 3) subtypes has proved useful both in enhancing communication among clinicians internationally and in forging the collaborative development of outcome measures for clinical trials. Ideally, clinical trial design in spinal muscular atrophy must take into account the spinal muscular atrophy type, patient age, severity-of-affection status, nature of the therapeutic approach, timing of the proposed intervention relative to disease progression, and relative homogeneity of the cohort to be studied. Following is an overview of the challenges and opportunities, current and future therapeutic strategies, and progress to date in clinical trials in spinal muscular atrophy.