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Objective. The North Star Assessment for limb-girdle type muscular dystrophies (NSAD), a clinician-reported outcome measure (ClinRO) of motor performance, was initially developed and validated for use in dysferlinopathy, an autosomal recessive form of limb-girdle muscular dystrophy (LGMD R2/2B). Recent developments in treatments for limb-girdle muscular dystrophies (LGMD) have highlighted the urgent need for disease-specific ClinROs. The purpose of this study was to understand the ability of the NSAD to quantify motor function across the broad spectrum of LGMD phenotypes. Methods. Assessments of 130 individuals with LGMD evaluated by the physical therapy teams at Nationwide Children's Hospital and the John Walton Muscular Dystrophy Research Centre were included in the analysis. NSAD, 100-m timed test (100MTT), and Performance of Upper Limb 2.0 assessment data were collected. Psychometric analysis with Rasch measurement methods was used to examine the NSAD for suitability and robustness by determining the extent to which the observed data 'fit' with predictions of those ratings from the Rasch model. The NSAD score was correlated with the 100MTT and Performance of Upper Limb 2.0 assessment scores for external construct validity. Results. The NSAD demonstrated a good spread of items covering a continuum of abilities across both individuals who had LGMD and were ambulatory and individuals who had LGMD and were weaker and nonambulatory. Items fit well with the construct measured, validating a summed total score. The NSAD had excellent interrater reliability [intraclass correlation coefficient (ICC) = 0.986, 95% CI = 0.981-0.991] and was highly correlated with the 100MTT walk/run velocity (Spearman rho correlation coefficient of [r.sub.s](134) = .92). Conclusion. Although LGMD subtypes may differ in age of onset, rate of progression, and patterns of muscle weakness, the overall impact of progressive muscle weakness on motor function is similar. The NSAD is a reliable and valid ClinRO of motor performance for individuals with LGMD and is suitable for use in clinical practice and research settings. Impact. Recent developments in potential pharmacological treatments for LGMD have highlighted the urgent need for disease-specific outcome measures. Validated and meaningful outcome measures are necessary to capture disease presentation, to inform expected rates of progression, and as endpoints for measuring the response to interventions in clinical trials. The NSAD, a scale of motor performance for both individuals who have LGMD and are ambulatory and those who are nonambulatory, is suitable for use in clinical and research settings. Keywords: Clinician-Reported Outcome Measure, Limb-Girdle Muscular Dystrophy, Motor Performance, Neuromuscular Diseases, Rasch Methods, Introduction Limb-girdle muscular dystrophies (LGMD) are a group of progressive, rare, genetically and clinically heterogeneous neuromuscular conditions. All forms of LGMD are characterized by muscle weakness involving the pelvic and/or [...]

Limb-girdle muscular dystrophy 2E/R4 is caused by mutations in the β-sarcoglycan (SGCB) gene, leading to SGCB deficiency and consequent muscle loss. We developed a gene therapy approach based on functional replacement of the deficient SCB protein. Here we report interim results from a first-in-human, open-label, nonrandomized, phase 1/2 trial evaluating the safety and efficacy of bidridistrogene xeboparvovec, an adeno-associated virus-based gene therapy containing a codon-optimized, full-length human SGCBtransgene. Patients aged 4–15 years with confirmed SGCBmutations at both alleles received one intravenous infusion of either 1.85 × 1013vector genome copies kg−1(Cohort 1, n= 3) or 7.41 × 1013vector gene copies kg−1(Cohort 2, n= 3). Primary endpoint was safety, and secondary endpoint was change in SGCB expression in skeletal muscle from baseline to Day 60. We report interim Year 2 results (trial ongoing). The most frequent treatment-related adverse events were vomiting (four of six patients) and gamma-glutamyl transferase increase (three of six patients). Serious adverse events resolved with standard therapies. Robust SGCB expression was observed: Day 60 mean (s.d.) percentage of normal expression 36.2% (2.7%) in Cohort 1 and 62.1% (8.7%) in Cohort 2. Post hoc exploratory analysis showed preliminary motor improvements using the North Star Assessment for Limb-girdle Type Muscular Dystrophies maintained through Year 2. The 2-year safety and efficacy of bidridistrogene xeboparvovec support clinical development advancement. Further studies are necessary to confirm the long-term safety and efficacy of this gene therapy. ClinicalTrials.gov registration: NCT03652259.

Single exon duplications account for disease in a minority of Duchenne muscular dystrophy patients. Exon skipping in these patients has the potential to be highly therapeutic through restoration of full-length dystrophin expression. We conducted a 48-week open label study of casimersen and golodirsen in 3 subjects with an exon 45 or 53 duplication. Two subjects (aged 18 and 23 years) were non-ambulatory at baseline. Upper limb, pulmonary, and cardiac function appeared stable in the 2 subjects in whom they could be evaluated. Dystrophin expression increased from 0.94 % ±0.59% (mean±SD) of normal to 5.1% ±2.9% by western blot. Percent dystrophin positive fibers also rose from 14% ±17% at baseline to 50% ±42% . Our results provide initial evidence that the use of exon-skipping drugs may increase dystrophin levels in patients with single-exon duplications.

X-linked myotubular myopathy (XLMTM) is a life-threatening congenital myopathy that, in most cases, is characterized by profound muscle weakness, respiratory failure, need for mechanical ventilation and gastrostomy feeding, and early death. We aimed to characterize the neuromuscular, respiratory, and extramuscular burden of XLMTM in a prospective, longitudinal study. Thirty-four participants <  4 years old with XLMTM and receiving ventilator support enrolled in INCEPTUS, a prospective, multicenter, non-interventional study. Disease-related adverse events, respiratory and motor function, feeding, secretions, and quality of life were assessed. During median (range) follow-up of 13.0 (0.5, 32.9) months, there were 3 deaths (aspiration pneumonia; cardiopulmonary failure; hepatic hemorrhage with peliosis) and 61 serious disease-related events in 20 (59%) participants, mostly respiratory (52 events, 18 participants). Most participants (80%) required permanent invasive ventilation (>16 hours/day); 20% required non-invasive support (6–16 hours/day). Median age at tracheostomy was 3.5 months (95% CI: 2.5, 9.0). Thirty-three participants (97%) required gastrostomy. Thirty-one (91%) participants had histories of hepatic disease and/or prospectively experienced related adverse events or laboratory or imaging abnormalities. CHOP INTEND scores ranged from 19–52 (mean: 35.1). Seven participants (21%) could sit unsupported for≥30 seconds (one later lost this ability); none could pull to stand or walk with or without support. These parameters remained static over time across the INCEPTUS cohort. INCEPTUS confirmed high medical impact, static respiratory, motor and feeding difficulties, and early death in boys with XLMTM. Hepatobiliary disease was identified as an under-recognized comorbidity. There are currently no approved disease-modifying treatments.

Children with many types of motor dysfunction have problems maintaining postural stability. Because maintenance of postural stability is an integral part of all movements, therapists evaluate and treat to improve postural stability in these children. This article reviews current pediatric assessment tools for postural stability and issues affecting testing this construct in children. The tests and measurements are classified according to their testing purpose and the National Center for Medical Rehabilitation Research disablement framework, focusing on the impairment and functional limitation dimensions. Postural stability is defined from a systems perspective with tests related to the sensory, motor, and biomechanical systems described. Reliability and validity information on the measurements is discussed. Relatively few measurements of postural stability in children are available that have acceptable reliability and validity documentation. Suggestions for research on test development in this area are discussed., [Westcott SL. Lowes LP, Richardson PK. Evaluation of postural stability in children: current theories and assessment tools. Phys Ther. 1997;77:629-645.] Key Words: Balance, Evaluation, Motor dysfunction, Pediatrics, Postural stability, Tests [...]

X-linked myotubular myopathy (XLMTM) is a life-threatening, congenital myopathy characterized by extreme hypotonia, weakness, delayed motor milestones, and respiratory failure, often resulting in pediatric mortality. This study evaluated the content validity and psychometric performance of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders as a measure of neuromuscular functioning in children with X-linked myotubular myopathy. This study was conducted in two phases. Phase I assessed the content validity of the measure for use in an XLMTM pediatric population through: literature review, clinical expert interviews, caregiver interviews, and a modified-Delphi panel among clinicians. Phase II assessed psychometric performance based on the INCEPTUS observational clinical study and the ASPIRO interventional gene therapy study, including tests of reliability (internal consistency, test-retest, and interrater), validity (construct and criterion), and responsiveness based on observational and interventional clinical trial data analyses. Data established construct validity and reliability of the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders among XLMTM patients before administration of resamirigene bilparvovec, and sensitivity to study drug administration as evidenced by the significant post-administration response in ASPIRO. Findings support the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders as an appropriate neuromuscular functioning assessment in a pediatric X-linked myotubular myopathy patient population.

IMPORTANCE: This ongoing study assesses long-term safety and durability of response in infants with spinal muscular atrophy (SMA) type 1 after dosing with onasemnogene abeparvovec gene replacement therapy. OBJECTIVE: The primary objective of this ongoing study is to assess safety. The secondary objective is to determine whether developmental milestones achieved in the START phase 1 clinical trial were maintained and new milestones gained. DESIGN, SETTING, AND PARTICIPANTS: This study is an ongoing, observational, follow-up study for continuous safety monitoring for 15 years in patients from the START phase I study (conducted May 5, 2014, through December 15, 2017) at Nationwide Children’s Hospital in Columbus, Ohio. Participants were symptomatic infants with SMA type 1 and 2 copies of SMN2 previously treated with an intravenous dose of onasemnogene abeparvovec (low dose, 6.7 × 1013 vg/kg; or therapeutic dose, 1.1 × 1014 vg/kg) in START. Thirteen of 15 original START patients are included in this analysis; 2 patients’ families declined follow-up participation. Data were analyzed from September 21, 2017, to June 11, 2020. EXPOSURES: Median time since dosing of 5.2 (range, 4.6-6.2) years; 5.9 (range, 5.8-6.2) years in the low-dose cohort and 4.8 (range, 4.6-5.6) years in the therapeutic-dose cohort. MAIN OUTCOMES AND MEASURES: The primary outcome measure was the incidence of serious adverse events (SAEs). RESULTS: At data cutoff on June 11, 2020, 13 patients treated in START were enrolled in this study (median age, 38.9 [range, 25.4-48.0] months; 7 females; low-dose cohort, n = 3; and therapeutic-dose cohort, n = 10). Serious adverse events occurred in 8 patients (62%), none of which resulted in study discontinuation or death. The most frequently reported SAEs were acute respiratory failure (n = 4 [31%]), pneumonia (n = 4 [31%]), dehydration (n = 3 [23%]), respiratory distress (n = 2 [15%]), and bronchiolitis (n = 2 [15%]). All 10 patients in the therapeutic-dose cohort remained alive and without the need for permanent ventilation. Prior to baseline, 4 patients (40%) in the therapeutic-dose cohort required noninvasive ventilatory support, and 6 patients (60%) did not require regular ventilatory support, which did not change in long-term follow-up. All 10 patients treated with the therapeutic dose maintained previously acquired motor milestones. Two patients attained the new milestone of “standing with assistance” without the use of nusinersen. CONCLUSIONS AND RELEVANCE: The findings of this ongoing clinical follow-up of patients with SMA type 1 treated with onasemnogene abeparvovec supports the long-term favorable safety profile up to 6 years of age and provides evidence for sustained clinical durability of the therapeutic dose. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03421977.

Background and purpose. The purpose of this study was to examine the validity of the Peabody Developmental Gross Motor Scale (PDMS-GM) as an evaluative measure of infants receiving physical therapy. Subjects and Methods. Infants who attended an early intervention program (N=124) were grouped by diagnosis.- cerebral palsy, Down syndrome, hydrocephalus, preterm with developmental delay, full term with developmental delay, and other. The PDMS-GM was administered to each infant three times over a 6-month period by a therapist who did not provide treatment. Results. Mean scaled scores and age-equivalent scores increased for each group. Individual change was examined using the reliable change index. The results indicated that the change in total raw score for 62% of the infants was greater than what could be attributed to measurement error. When minimal clinically important change was defined as 10 scaled score points, the index of responsiveness was equal to 0.5. This finding indicates that a sample size of 68 subjects per group would be needed when the PDMS-GM is used as an outcome measure in research. Conclusion and Discussion. The mean change scores for each group support the use of the PDMS-GM as an evaluative measure. For many infants, particularly infants with cerebral palsy, the PDMS-GM was not responsive to change over a 6-month period. The index of responsiveness suggests that the PDMS-GM should be used only as an outcome measure in large clinical trials. The PDMS-GM is not recommended for evaluating the direct effects of physical therapy but is recommended for providing a global measure of change in motor development as part of a multidimensional assessment. [Palisano RJ, Kolobe TH, Haley SM, et al. Validity of the Peabody Developmental Gross Motor Scale as an evaluative measure of infants receiving physical therapy. Phys Ther. 1995;75:939-951.], Selection of a developmental assessment should be dependent on the ability of the physical therapist to identify the purpose of assessment and to critically review published information for evidence of [...]

Background and Purpose. Despite evidence of weakness in children with cerebral palsy, the use of strength training in this population remains controversial. Subjects. Fourteen children with spastic diplegia, ranging in [...]

Duchenne muscular dystrophy (DMD) is a rare, X-linked, fatal, degenerative neuromuscular disease caused by DMDgene mutations. A relationship between exon skipping and dystrophin production in exon 51-amenable patients treated with eteplirsen (EXONDYS 51 ®) is established. Once-weekly eteplirsen significantly increased dystrophin, with slower decline in ambulatory function compared to baseline. Long-term treatment with eteplirsen leads to accumulation of dystrophin over time and observed functional benefits in patients with DMD. Compare long-term ambulatory function in eteplirsen-treated patients versus controls. Study 201/202 included 12 eteplirsen-treated patients assessed twice/year for ambulatory function over 4 years. Ambulatory evaluations (6-minute walk test [6MWT], loss of ambulation, and North Star Ambulatory Assessment [NSAA]) were compared with matched controls from Italian Telethon and Leuven registries. At Years 3 and 4, eteplirsen-treated patients demonstrated markedly greater mean 6MWT than controls (difference in change from baseline of 132 m [95% CI (29, 235), p = 0.015] at Year 3 and 159 m [95% CI (66, 253), p = 0.002] at Year 4). At Year 4, a significantly greater proportion of eteplirsen-treated patients were still ambulant versus controls (10/12 vs 3/11; p = 0.020). At Year 3, eteplirsen-treated patients had milder NSAA decline than controls (difference in change from baseline of 2.6, 95% CI [-6, 11]), however, the difference was not statistically significant; Year 4 control NSAA data were not available. Eteplirsen resulted in attenuation of ambulatory decline over a 4 year observation period, supporting long-term benefit in patients with DMD.

IMPORTANCE: Micro-dystrophin gene transfer shows promise for treating patients with Duchenne muscular dystrophy (DMD) using recombinant adeno-associated virus serotype rh74 (rAAVrh74) and codon-optimized human micro-dystrophin driven by a skeletal and cardiac muscle-specific promoter with enhanced cardiac expression (MHCK7). OBJECTIVE: To identify the 1-year safety and tolerability of intravenous rAAVrh74.MHCK7.micro-dystrophin in patients with DMD. DESIGN, SETTING, AND PARTICIPANTS: This open-label, phase 1/2a nonrandomized controlled trial was conducted at the Nationwide Children’s Hospital in Columbus, Ohio. It began on November 2, 2017, with a planned duration of follow-up of 3 years, ending in March 2021. The first 4 patients who met eligibility criteria were enrolled, consisting of ambulatory male children with DMD without preexisting AAVrh74 antibodies and a stable corticosteroid dose (≥12 weeks). INTERVENTIONS: A single dose of 2.0 × 1014 vg/kg rAAVrh74.MHCK7.micro-dystrophin was infused through a peripheral limb vein. Daily prednisolone, 1 mg/kg, started 1 day before gene delivery (30-day taper after infusion). MAIN OUTCOMES AND MEASURES: Safety was the primary outcome. Secondary outcomes included micro-dystrophin expression by Western blot and immunohistochemistry. Functional outcomes measured by North Star Ambulatory Assessment (NSAA) and serum creatine kinase were exploratory outcomes. RESULTS: Four patients were included (mean [SD] age at enrollment, 4.8 [1.0] years). All adverse events (n = 53) were considered mild (33 [62%]) or moderate (20 [38%]), and no serious adverse events occurred. Eighteen adverse events were considered treatment related, the most common of which was vomiting (9 of 18 events [50%]). Three patients had transiently elevated γ-glutamyltransferase, which resolved with corticosteroids. At 12 weeks, immunohistochemistry of gastrocnemius muscle biopsy specimens revealed robust transgene expression in all patients, with a mean of 81.2% of muscle fibers expressing micro-dystrophin with a mean intensity of 96% at the sarcolemma. Western blot showed a mean expression of 74.3% without fat or fibrosis adjustment and 95.8% with adjustment. All patients had confirmed vector transduction and showed functional improvement of NSAA scores and reduced creatine kinase levels (posttreatment vs baseline) that were maintained for 1 year. CONCLUSIONS AND RELEVANCE: This trial showed rAAVrh74.MHCK7.micro-dystrophin to be well tolerated and have minimal adverse events; the safe delivery of micro-dystrophin transgene; the robust expression and correct localization of micro-dystrophin protein; and improvements in creatine kinase levels and NSAA scores. These findings suggest that rAAVrh74.MHCK7.micro-dystrophin can provide functional improvement that is greater than that observed under standard of care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03375164

Duchenne muscular dystrophy (DMD) patients experience skeletal muscle degeneration, including respiratory muscles. Respiratory decline in glucocorticoid-treated DMD patients, measured by percent predicted forced vital capacity (FVC% p), is typically 5% annually in patients aged 10 to 18 years. Evaluate the effects of eteplirsen on FVC% p annual change in 3 trials versus matched Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG DNHS) controls. Eteplirsen studies 201/202 evaluated eligible ambulatory DMD patients for at least 4 years, study 204 evaluated primarily non-ambulatory DMD patients for 2 years, and ongoing study 301 is evaluating ambulatory DMD patients for 2 years (interim analysis is included). Eteplirsen-treated patients (n = 74) were amenable to exon 51 skipping and were receiving glucocorticoids. Three CINRG DNHS cohorts included: glucocorticoid-treated patients amenable to exon 51 skipping (Exon 51 CINRG DNHS; n = 20), all glucocorticoid-treated CINRG patients (All CINRG DNHS; n = 172), and all glucocorticoid-treated genotyped CINRG DNHS patients (Genotyped CINRG DNHS; n = 148). FVC% p assessments between ages 10 and <18 years were included for all patients; mixed-model analyses characterized FVC% p annual change. FVC% p annual change was greater for CINRG DNHS Exon 51 controls (– 6.00) versus patients in studies 201/202, study 204, and study 301 (– 2.19, P < 0.001; – 3.66, P0.004; and – 3.79, P0.017, respectively). FVC% p annual change in all eteplirsen studies suggested treatment benefit compared with the Genotyped CINRG DNHS (– 5.67) and All CINRG DNHS (– 5.56) cohorts (P < 0.05, all comparisons). Significant, clinically meaningful attenuation of FVC%p decline was observed in eteplirsen-treated patients versus CINRG DNHS controls.

Spinal muscular atrophy type 1 (SMA1) is the leading genetic cause of infant mortality for which therapies, including AVXS-101 (onasemnogene abeparvovec, Zolgensma®) gene replacement therapy, are emerging. This study evaluated the effectiveness of AVXS-101 in infants with spinal muscular atrophy type 1 (SMA1) compared with a prospective natural history cohort and a cohort of healthy infants. Twelve SMA1 infants received the proposed therapeutic dose of AVXS-101 (NCT02122952). Where possible, the following outcomes were compared with a natural history cohort of SMA1 infants (n = 16) and healthy infants (n = 27) enrolled in the NeuroNEXT (NN101) study (NCT01736553): event-free survival, CHOP-INTEND scores, motor milestone achievements, compound muscle action potential (CMAP), and adverse events. Baseline characteristics of SMA1 infants in the AVXS-101 and NN101 studies were similar in age and genetic profile. The proportion of AVXS-101–treated infants who survived by 24 months of follow-up was higher compared with the NN101 study (100% vs 38%, respectively). The average baseline CHOP-INTEND score for NN101 SMA1 infants was 20.3, worsening to 5.3 by age 24 months; the average baseline score in AVXS-101–treated infants was 28.2, improving to 56.5 by age 24 months. Infants receiving AVXS-101 achieved motor milestones, such as sitting unassisted and walking. Improvements in CMAP peak area were observed in AVXS-101–treated infants at 6 and 24 months (means of 1.1 and 3.2 mV/s, respectively). In this study, AVXS-101 increased the probability of survival, rapidly improved motor function, and enabled motor milestone achievement in SMA1 infants.

The NeuroNEXT SMA Infant Biomarker Study, a two year, longitudinal, multi-center study of infants with SMA type 1 and healthy infants, presented a unique opportunity to assess multi-site rater reliability on three infant motor function tests (MFTs) commonly used to assess infants with SMA type 1. To determine the effect of prospective MFT rater training and the effect of rater experience on inter-rater and intra-rater reliability for the Test of Infant Motor Performance Screening Items (TIMPSI), the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) and the Alberta Infant Motor Scale (AIMS). Training was conducted utilizing a novel set of motor function test (MFT) videos to optimize accurate MFT administration and reliability for the study duration. Inter- and intra-rater reliability of scoring for the TIMPSI and inter-rater reliability of scoring for the CHOP INTEND and the AIMS was assessed using intraclass correlation coefficients (ICC). Effect of rater experience on reliability was examined using ICC. Agreement with ‘expert’ consensus scores was examined using Pearson’s correlation coefficients. Inter-rater reliability on all MFTs was good to excellent. Intra-rater reliability for the primary MFT, the TIMPSI, was excellent for the study duration. Agreement with ‘expert’ consensus was within predetermined limits (≥85%) after training. Evaluator experience with SMA and MFTs did not affect reliability. Reliability of scores across evaluators was demonstrated for all three study MFTs and scores were reproducible on repeated administration. Evaluator experience had no effect on reliability.

Duchenne muscular dystrophy (DMD) is a rare, degenerative, X-linked genetic disease that results in progressive muscle loss and premature death, most commonly from respiratory or cardiac failure. DMD is primarily caused by whole exon deletions, resulting in a shift of the dystrophin mRNA reading frame that prevents production of functional dystrophin protein. Eteplirsen, a phosphorodiamidate morpholino oligomer (PMO), is designed to skip exon 51, restore the reading frame, and induce production of internally shortened dystrophin in patients with mutations amenable to such treatment. Describe lung function assessed throughout eteplirsen studies 201/202. Studies 201/202 included 12 patients treated with eteplirsen over 5 years. Pulmonary function tests included forced vital capacity (FVC), maximum expiratory pressure (MEP), and maximum inspiratory pressure (MIP). With no long-term placebo control, FVC results were compared with data from the United Dystrophinopathy Project (UDP). MIP and MEP were compared to published natural history. Age-adjusted mixed-model repeated-measures analysis showed decreases of 2.3% and 2.6% annually for FVC% p and MEP% p, and an annual increase of 0.6% for MIP% p for the eteplirsen-treated cohort. Data from the UDP demonstrated a 4.1% decline in FVC% p. The published natural history reports annual declines of at least 2.7% and 3.8% for MEP% p and MIP% p, respectively, in patients with DMD. With eteplirsen treatment, deterioration of respiratory muscle function based on FVC% p was half of that seen in the UDP; MEP% p and MIP% p compared favorably with natural history.

Duchenne muscular dystrophy (DMD) is a severe, progressive, and rare neuromuscular, X-linked recessive disease. Dystrophin deficiency is the underlying cause of disease; therefore, mutation-specific therapies aimed at restoring dystrophin protein production are being explored. We aimed to assess the efficacy and safety of ataluren in ambulatory boys with nonsense mutation DMD.

Sporadic inclusion body myositis, a variant of inflammatory myopathy, has features distinct from polymyositis/dermatomyositis. The disease affects men more than women, most commonly after age 50. Clinical features include weakness of the quadriceps, finger flexors, ankle dorsiflexors, and dysphagia. The distribution of weakness is similar to Becker muscular dystrophy, where we previously reported improvement following intramuscular injection of an isoform of follistatin (FS344) by AAV1. For this clinical trial, rAAV1.CMV.huFS344, 6 × 1011vg/kg, was delivered to the quadriceps muscles of both legs of six sporadic inclusion body myositis subjects. The primary outcome for this trial was distance traveled for the 6-min walk test. The protocol included an exercise regimen for each participant. Performance, annualized to a median 1-year change, improved +56.0 m/year for treated subjects compared to a decline of −25.8 m/year (p = 0.01) in untreated subjects (n = 8), matched for age, gender, and baseline measures. Four of the six treated subjects showed increases ranging from 58–153 m, whereas two were minimally improved (5–23 m). Treatment effects included decreased fibrosis and improved regeneration. These findings show promise for follistatin gene therapy for mild to moderately affected, ambulatory sporadic inclusion body myositis patients. More advanced disease with discernible muscle loss poses challenges.

Limb-girdle muscular dystrophy type 2E/R4 (LGMD2E/R4) is caused by β-sarcoglycan (SGCB) gene mutations, resulting in loss of functional protein and dystrophin-associated protein complex disruption. LGMD2E/R4 symptoms include hip/shoulder muscle weakness, cardiac involvement, and elevated creatine kinase (CK). Here, we report initial findings of a Phase 1/2 open-label, systemic gene transfer trial (NCT03652259) of rAAVrh74.MHCK7.hSGCB (SRP-9003), designed to restore functional SGCB, in patients with LGMD2E/R4. Six patients (aged 4–15 years, negative for rAAVrh74 antibodies, 100-meter timed test >40%) received a single SRP-9003 IV infusion of 1.85×1013 vg/kg (Cohort 1, n=3) or 7.41×1013 vg/kg (Cohort 2, n=3). Prednisone (1 mg/kg/day) was initiated 1 day before (30–60 days taper). Endpoints: safety (primary), SGCB expression (secondary), others: North Star Assessment of Limb-girdle Muscular Dystrophies (NSAD), timed functional tests. SRP-9003 is well tolerated with no unexpected immunologic responses observed. All patients demonstrated efficient transduction and robust SGCB expression post-infusion, with subsequent sarcoglycan complex reconstitution and CK reduction. Six months after SRP-9003 infusion, both patient cohorts experienced functional improvements. Cohort 1 had data available up to 18 months indicating NSAD and timed test improvements were maintained over time. These data suggest long-term efficacy of SRP-9003 gene-transfer therapy, supporting advancement of the clinical development program.jrichardson@sarepta.com90

To describe and report the effect of an 8-week individualized, progressive, treadmill training program on the ambulatory ability of a 4-year-old child with myelomeningocele without functional ambulation.

These are initial findings of ongoing, phase 1 multiple ascending-dose gene transfer trial of ≤9 LGMD2E patients who received rAAVrh74.MHCK7.SGCB (NCT03652259). Participants: patients 4–15y, confirmed β-sarcoglycan (SGCB) mutation (both alleles), negative for rAAVrh74 antibodies, >40%n on 100-meter timed test. Patients received single IV infusion of 5x1013 vg/kg rAAVrh74.MHCK7.SGCB. Prednisone 1 mg/kg/day was initiated 1d before gene delivery, tapering after 30d. Primary endpoints: ≥20% SGCB-positive fibers (Day-60 muscle biopsy) and safety (Day 270). Secondary endpoints: CK decrease and functional endpoints (Day 270). First 3 patients enrolled (age 13[n=2]; age 4[n=1]): robust SGCB expression observed by immunohistochemistry (IHC), with a mean of 51% SGCB positive fibers (range 42–63%) expressing a mean 47% intensity (range 38–57%). Co-localization of β-sarcoglycan observed (IHC). Western blot showed a mean 36.1% SGCB expression vs normal (range 34–39%). Mean CK levels reduced by 82%, suggesting slowed muscle destruction. Two patients had elevated liver enzymes (1 serious) and 1 had elevated bilirubin following oral steroid taper, which returned to baseline. Two patients had transient mild nausea, corresponding with increased steroid dosing. No other clinically significant lab findings. Gene transfer in LGMD2E patients following rAAVrh74.MHCK7.SGCB infusion was positive for defined endpoints, demon- strating potential benefits of a rationally designed delivery system.jrichardson@sarepta.com

Extracorporeal membrane oxygenation (ECMO) is a life-support technique used with neonates in acute respiratory distress. It uses a lung or heart and lung bypass system to oxygenate the blood. Developmental outcome studies have reported morbidity rates between 20 and 25. Developmental problems were identified in the areas of movement, speech, and cognition. Additional possible complications include growth abnormalities, chronic lung disease, hearing loss, and seizures. Pediatric physical therapists, working in a variety of settings, may intervene with infants who received ECMO. In addition to direct neonatal intervention and consultation, physical therapists can contribute to follow-up evaluations to identify infants who would benefit from early intervention. Children who received ECMO may also be referred to physical therapy at school age for motor incoordination or sensory processing impairment. Finally, physical therapists may play a role in clinical research to document developmental outcome, identify the need for intervention, and determine best treatment practices for children who received ECMO.

The Americans with Disabilities Act of 1990 (ADA) is an important piece of civil rights legislation that can assist pediatric physical therapists in maximizing the opportunities afforded the children and adolescents they serve. The four sections of the ADA with particular relevance to children and adolescents with disabilities are: employment, public and private accommodations, transportation, and telecommunications. An overview of the regulations governing each of these areas and examples relevant to children and adolescents will be given. An understanding of the provisions of the ADA will assist a therapist in designing a treatment plan that will help prepare children and adolescents with disabilities for their transition into leading productive, fulfilling lives as adults. This plan should include functionally based approaches to treatment, child and family education, and advocacy training. Knowledge of the provisions of the ADA and the implications for children with disabilities will assist therapists in their efforts to optimize their client's independence.