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Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, represents a global health challenge due to its complexity and the limitations of current diagnostic techniques. By combining Raman spectroscopy and Artificial Intelligence (AI), we have succeeded in classifying tumor cells. In fact, we have performed a first Raman spectral analysis based on the characterization and differentiation between uncultured primary human liver cells derived from resected HCC tumor tissue and the adjacent non-tumor counterpart. Biochemical analysis of the collected Raman spectra revealed that there is more DNA in the nuclei of the tumor cells than in non-tumor cells. We then develop three machine learning approaches, including multivariate models and neural networks, to rapidly automate the recognition and classification of the Raman spectra of both cells. To evaluate the performance of the developed AI models, we prepared and analyzed two additional cell samples with a ratio of 4:1 and 3:1 between tumor and non-tumor cells and compared the obtained results with the nominal percentages (accuracy of 80 and 60%, respectively). These results confirm that the models are able to make classifications at the level of a single spectrum, indicating the possibility of rapidly analysing and classifying a primary HCC cell.

Objective: Limb-girdle muscular dystrophy R9 (LGMDR9, formerly known as LGMD2I), caused by variants in the fukutin-related protein (FKRP) gene leads to progressive muscle weakness of the shoulder and pelvic limb-girdles and loss of motor function over time. Clinical management and future trial design are improved by determining which standardized clinical outcome assessments (COA) of function are most appropriate to capture disease presentation and progression, informing endpoint selection and enrollment criteria. The purpose of our study was to evaluate the cross-sectional validity and reliability of clinical outcome assessments in patients with FKRP-related LGMDR9 participating in the Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP) natural history study., Methods: Enrolled patients completed a battery of COA on two consecutive days, including the North Star Assessment for limb girdle-type dystrophies (NSAD), the 100-m timed test (100 m), and the Performance of Upper Limb 2.0 (PUL)., Results: A total of 101 patients with FKRP-related LGMDR9 completed COA evaluations. All functional COA were highly and significantly correlated even across constructs, except for the 9-hole peg test. Similarly, all tests demonstrated excellent test-retest reliability across 2-day visits. The NSAD and PUL demonstrate robust psychometrics with good targeting, ordered response thresholds, fit and stability, and limited dependency of items across the scales., Conclusions: This study has determined the suitability of several functional COA, cross-sectionally, in LGMDR9 to inform future trial design and clinical care., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Aim: To evaluate the psychometric properties and measurement quality of the Patient-Reported Outcomes Measurement Information System Parent Proxy (PROMIS PP) Mobility item bank (v1.0, 23 items) for children with Duchenne muscular dystrophy (DMD), through Rasch statistical analysis., Method: De-identified PROMIS PP Mobility items were completed by the caregivers of male patients with DMD, aged 4 to 12 years, as part of standard clinical care at the Nationwide Children's Hospital clinic; data were mined retrospectively from electronic health records. Rasch analysis was used to assess the internal functioning of the measure and items., Results: Overall, 151 observations were available for the Rasch analysis, equally split between patients aged 4 to 7 years and 8 to 12 years. After removing clinically irrelevant items and regrouping response options for specific items, the resulting 19-item measure demonstrated overall good fit to Rasch model expectations and the ability to discriminate between respondents with different mobility levels (Person Separation Index = 0.95, excellent reliability)., Interpretation: The customized PROMIS PP Mobility measure demonstrated good fit and may be a reliable option for mobility assessment in children with DMD. Rasch analysis can be used by other researchers to improve the sensitivity of patient-reported outcomes in their field of interest., (© 2024 The Author(s). Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Conducting functional assessments remotely can help alleviate the burden of in-person assessment on patients with Duchenne muscular dystrophy and their caregivers. The objective of this study was to evaluate whether scores from remote functional assessment of patients with Duchenne muscular dystrophy correspond to in-person scores on the same functional assessments. Remote live stream versus in-person scores on the North Star Ambulatory Assessment (including time [seconds] to complete the 10-meter walk/run and time to rise from the floor [supine to stand]) were assessed using statistical analyses, including intraclass correlation coefficient, and Pearson, Spearman, and Bland-Altman analyses. The remote and in-clinic assessments had to occur within 2 weeks of one another to be considered for this analysis. This analysis included patients with Duchenne muscular dystrophy, aged 4 to 7 years. Participants in this analysis received delandistrogene moxeparvovec (as part of SRP-9001-101 [Study 101; NCT03375164] or SRP-9001-102 [Study 102; NCT03769116]) or were randomized to receive placebo (in Part 1 of Study 102). This study evaluates score reproducibility between live stream remote scoring versus in-person functional assessments as determined by intraclass correlation coefficient, and Pearson, Spearman, and Bland-Altman analyses. The results showed that scores from remote functional assessment of patients with Duchenne muscular dystrophy strongly correlated with those obtained in person. These findings demonstrate congruence between live stream remote and in-person functional assessment and suggest that remote assessment has the potential to reduce the burden on a family by supplementing in-clinic visits., Competing Interests: The authors of this paper have read the journal’s policy and have the following competing interests: Linda P Lowes reports receiving salary support from Sarepta Therapeutics, Inc. through Nationwide Children’s Hospital to subsidize training and quality control activities for ongoing clinical trials and licensing fees for natural history data. Lindsay N Alfano reports receiving salary support from Sarepta Therapeutics, Inc. through Nationwide Children’s Hospital to subsidize training and quality control activities for their ongoing clinical trials. Megan A Iammarino reports no conflicts of interest. Natalie F Reash reports receiving salary support from Sarepta Therapeutics, Inc. for Clinical Evaluator training for ongoing and upcoming clinical trials. Kathryn Giblin is an employee of Eli Lilly and was previously an employee of Sarepta Therapeutics, Inc. and may have stock options. Lixi Yu, Shufang Wang, and Rachel Salazar are employees of Sarepta Therapeutics, Inc. and may have stock options. Larry Hu was an employee of Sarepta during the execution of this work. Jerry R Mendell received study funding from Sarepta Therapeutics while at Nationwide Children’s Hospital at the time of the study, and is currently an employee of Sarepta Therapeutics. Jerry R Mendell is a co-inventor of AAVrh74.MHCK7.micro-dys technology. The authors confirm that this does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 P. Lowes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: This single-arm prospective cohort study aimed to evaluate the feasibility and utility of in-home body weight support harness system (BWSS) use in children treated for spinal muscular atrophy (SMA)., Methods: Individuals with 2 or 3 copies of SMN2 who received pharmacotherapeutic treatment, had head control, and weight <50lbs were enrolled. Families were provided a BWSS and documented use. Motor outcome assessments were completed at baseline, month 3 and month 6. Families provided feedback in an end of study survey., Results: All 32 participants (2.9 (SD 1.9) yrs), improved or remained stable on all outcomes. Average reported frequency of use was 4.1(2.3) hrs/week. Controlling for other covariates, frequency of use explained over 70% of the variability in change scores. Family feedback was overwhelmingly positive., Conclusion: Use of in-home BWSS is a safe, feasible and useful option to increase exercise dosage after treatment in SMA and may help optimize motor abilities., Trial Registration: Study registered with: Clinicaltrials.gov Clinicaltrials.gov identifier: NCT05715749., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Iammarino et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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.

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 SGCB transgene. Patients aged 4-15 years with confirmed SGCB mutations at both alleles received one intravenous infusion of either 1.85 × 10 13 vector genome copies kg - 1 (Cohort 1, n = 3) or 7.41 × 10 13 vector 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 ., (© 2024. The Author(s).)

Introduction/aims: Delandistrogene moxeparvovec is indicated in the United States for the treatment of ambulatory pediatric patients aged 4 through 5 years with Duchenne muscular dystrophy (DMD) with a confirmed mutation in the DMD gene. Long-term delandistrogene moxeparvovec microdystrophin protein (a shortened dystrophin that retains key functional domains of the wild-type protein) expression may positively alter disease progression in patients with DMD. We evaluated long-term safety and functional outcomes of delandistrogene moxeparvovec in patients with DMD., Methods: An open-label, phase 1/2a, nonrandomized controlled trial (Study 101; NCT03375164) enrolled ambulatory males, ≥4 to <8 years old, with DMD. Patients received a single intravenous infusion (2.0 × 10 14 vg/kg by supercoiled quantitative polymerase chain reaction) of delandistrogene moxeparvovec and prednisone (1 mg/kg/day) 1 day before to 30 days after treatment. The primary endpoint was safety. Functional outcomes were change from baseline in North Star Ambulatory Assessment (NSAA) and timed function tests., Results: Four patients (mean age, 5.1 years) were enrolled. There were 18 treatment-related adverse events; all occurred within 70 days posttreatment and resolved. Mean NSAA total score increased from 20.5 to 27.5, baseline to year 4, with a mean (standard deviation) change of +7.0 (2.9). Post hoc analysis demonstrated a statistically significant and clinically meaningful 9-point difference in NSAA score, relative to a propensity-score-weighted external control cohort (least-squares mean [standard error] = 9.4 [3.4]; P = .0125)., Discussion: Gene transfer therapy with delandistrogene moxeparvovec treatment is well tolerated, with a favorable safety profile. Functional improvements are sustained through 4 years, suggesting delandistrogene moxeparvovec may positively alter disease progression., (© 2023 Sarepta Therapeutics Inc and The Authors. Muscle & Nerve published by Wiley Periodicals LLC.)

Introduction: Delandistrogene moxeparvovec (SRP-9001) is an investigational gene transfer therapy designed for targeted expression of SRP-9001 dystrophin protein, a shortened dystrophin retaining key functional domains of the wild-type protein. Methods: This Phase 2, double-blind, two-part (48 weeks per part) crossover study (SRP-9001-102 [Study 102]; NCT03769116) evaluated delandistrogene moxeparvovec in patients, aged ≥4 to <8 years with Duchenne muscular dystrophy. Primary endpoints (Part 1) were change from baseline (CFBL) in SRP-9001 dystrophin expression (Week 12), by Western blot, and in North Star Ambulatory Assessment (NSAA) score (Week 48). Safety assessments included treatment-related adverse events (TRAEs). Patients were randomized and stratified by age to placebo (n = 21) or delandistrogene moxeparvovec (n = 20) and crossed over for Part 2. Results: SRP-9001 dystrophin expression was achieved in all patients: mean CFBL to Week 12 was 23.82% and 39.64% normal in Parts 1 and 2, respectively. In Part 1, CFBL to Week 48 in NSAA score (least-squares mean, LSM [standard error]) was +1.7 (0.6) with treatment versus +0.9 (0.6) for placebo; p = 0.37. Disparity in baseline motor function between groups likely confounded these results. In 4- to 5-year-olds with matched baseline motor function, CFBL to Week 48 in NSAA scores was significantly different (+2.5 points; p = 0.0172), but not significantly different in 6-to-7-year-olds with imbalanced baseline motor function (-0.7 points; p = 0.5384). For patients treated with delandistrogene moxeparvovec in Part 2, CFBL to Week 48 in NSAA score was +1.3 (2.7), whereas for those treated in Part 1, NSAA scores were maintained. As all patients in Part 2 were exposed to treatment, results were compared with a propensity-score-weighted external control (EC) cohort. The LSM difference in NSAA score between the Part 2 treated group and EC cohort was statistically significant (+2.0 points; p = 0.0009). The most common TRAEs were vomiting, decreased appetite, and nausea. Most occurred within the first 90 days and all resolved. Discussion: Results indicate robust expression of SRP-9001 dystrophin and overall stabilization in NSAA up to 2 years post-treatment. Differences in NSAA between groups in Part 1 were not significant for the overall population, likely because cohorts were stratified only by age, and other critical prognostic factors were not well matched at baseline., Competing Interests: DG, SL, SW, RP, TS, LRR-K are empolyed by Sarepta Therapeutics Inc. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mendell, Shieh, McDonald, Sahenk, Lehman, Lowes, Reash, Iammarino, Alfano, Sabo, Woods, Skura, Mao, Staudt, Griffin, Lewis, Wang, Potter, Singh and Rodino-Klapac.)

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 rs(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., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Physical Therapy Association.)

Introduction/aims: Dysferlinopathy demonstrates heterogeneity in muscle weakness between patients, which can progress at different rates over time. Changing muscle strength due to disease progression or from an investigational product is associated with changing functional ability. The purpose of this study was to compare three methods of strength testing used in the Clinical Outcome Study (COS) for dysferlinopathy to understand which method and which muscle groups were most sensitive to change over time., Methods: Patients were evaluated at each study visit using functional scales, manual muscle testing, and handheld dynamometry (HHD) at all 15 sites. A fixed-frame system (Fixed) was used at a subset of seven sites. Screening and baseline visits were evaluated for reliability. Data over a 1-year period were analyzed to determine sensitivity to change among strength modalities and individual muscle groups., Results: HHD and Fixed captured significant change across 1 year in summed muscle strength score of four muscle groups (P < .01). Strength summed scores were significantly correlated with functional scales (rho = 0.68-0.92, P < .001). Individual muscle groups, however, showed high levels of variability between visits., Discussion: Although both HHD and Fixed demonstrate change over 12 months, HHD is a less expensive option that provides data on a continuous scale and may be easier to implement. Due to variability in strength measures, researchers should carefully consider use of strength testing as an outcome and may wish to select functional measures with less variability as clinical trial endpoints., (© 2022 Wiley Periodicals LLC.)

Background: Approved treatments in spinal muscular atrophy (SMA) have resulted in unprecedented gains for many individuals. Use of available outcomes, typically developed for a specific type of SMA, do not cover the range of progression, often resulting in a battery of functional testing being completed at visits. Our objective was to validate the Neuromuscular Gross Motor Outcome (GRO) as a tool to quantify function in SMA across the span of abilities., Methods: Patients with genetically confirmed SMA completed functional testing at each visit including the Neuromuscular GRO and other appropriate gross motor outcomes., Results: We enrolled 91 patients with SMA types 1 to 3 between 8 days and 32.1 years. The GRO utilizes a 0- to 2-point scale with scores in our cohort ranging from 1 to 95 points with no floor or ceiling effect. GRO scores were significantly different across functional categories (P < 0.001) and treatment status (P = 0.01) and correlated to other functional assessments (P ≤ 0.001). All patients were measured using the GRO, whereas traditional outcomes were only appropriate on 36% to 59% of our cohort., Conclusion: The Neuromuscular GRO quantifies function across the span of age and abilities included in our cohort, allowing for continuous longitudinal monitoring on one scale to reduce the burden of testing in our heterogeneous clinic population., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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.

Introduction: Clinical trials targeting younger cohorts of boys with Duchenne muscular dystrophy are necessary as earlier intervention may maximize treatment effect. Boys with Duchenne muscular dystrophy often have gross motor delays very early in life, and although they gain skills, they are on a lower trajectory than typical peers. Quantifying the natural rate of motor maturation in Duchenne muscular dystrophy from an early age permits identification of deviations from the expected trajectory related to treatment effects., Methods: The purpose of our study was to define the natural history in boys aged from ≥3 to <8 years using the North Star Ambulatory Assessment (NSAA), 100-meter timed test (100m), 10-meter walk/run (10m), time to rise (Rise), and 4-stair climb (4SC). Assessments were completed as standard of care during regularly scheduled clinic visits., Results: One hundred sixty-two boys with DMD aged 3.1 to 7.9 years on glucocorticoids were evaluated using one or more of the following tests as appropriate for age: NSAA (N = 158; 3.1-7.9 years), 100m (N = 131; 3.4-7.9 years), 10m (N = 162; 3.1-7.9 years), Rise (N = 160; 3.1-7.9 years), and 4SC (N = 153; 3.1-7.9 years). Longitudinal data are presented by age in a subcohort (N = 64)., Conclusions: Our study documents the baseline function of boys with DMD who are being treated with corticosteroids. These data will be useful to compare ongoing and future therapeutic intervention(s) for DMD., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background and Objectives: Historically, autosomal recessive 5q-linked spinal muscular atrophy (SMA) has been the leading inherited cause of infant death. SMA is caused by the absence of the SMN1 gene, and SMN1 gene replacement therapy, onasemnogene abeparvovec-xioi, was Food and Drug Administration approved in May 2019. Approval included all children with SMA age <2 years without end-stage weakness. However, gene transfer with onasemnogene abeparvovec-xioi has been only studied in children age ≤8 months., Methods: In this article, we report key safety and early outcome data from the first 21 children (age 1-23 months) treated in the state of Ohio., Results: In children ≤6 months, gene transfer was well tolerated. In this young group, serum transaminase (aspartate aminotransferase and alanine aminotransferase) elevations were modest and not associated with γ glutamyl transpeptidase elevations. Initial prednisolone administration matched that given in the clinical trials. In older children, elevations in aspartate aminotransferase, alanine aminotransferase and γ glutamyl transpeptidase were more common and required a higher dose of prednisolone, but all were without clinical symptoms. Nineteen of 21 (90%) children experienced an asymptomatic drop in platelets in the first week after treatment that recovered without intervention. Of the 19 children with repeated outcome assessments, 11% ( n = 2) experienced stabilization and 89% ( n = 17) experienced improvement in motor function., Conclusions: In this population, with thorough screening and careful post-gene transfer management, replacement therapy with onasemnogene abeparvovec-xioi is safe and shows promise for early efficacy., Competing Interests: POTENTIAL CONFLICT OF INTEREST: Dr Waldrop has served on advisory boards for Sarepta Therapeutics and Avexis Inc. Dr Storey has served on advisory boards for Avexis Inc and Sarepta Therapeutics. Dr Mosher has served on advisory boards for Sarepta and PTC Therapeutics. Drs Goldstein and Bass have served on speaker and advisory boards for Biogen. Dr Alfano has served on advisory boards for Genentech-Roche, Acceleron Pharma, and Audentes Therapeutics. Dr Mendell has received personal fees from Sarepta Therapeutics, Avexis Inc, and Vertex Pharmaceuticals. Dr Connolly has served on advisory boards for Sarepta Therapeutics, Avexis, and Genentech-Roche and serves on the DMSB for Catabasis; the other authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2020 by the American Academy of Pediatrics.)

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.

Aim: To evaluate the utility of Ability Captured Through Interactive Video Evaluation (ACTIVE) scaled scores to quantify meaningful change in individuals with spinal muscular atrophy (SMA) types 2 or 3 due to disease progression or treatment., Method: ACTIVE is a custom-designed video game that measures workspace volume (WSV). Participants included 62 individuals with SMA (mean age [SD] 10y 9mo [5y], range 2y 9mo-24y) and 362 frequency-matched controls (mean age [SD] 10y 9mo [3y 6mo], range 3y 2mo-24y 9mo). Participants completed ACTIVE, other traditional assessments, and patient-reported outcomes. Responsiveness to change was evaluated by comparing longitudinal data on untreated participants to those receiving Spinraza., Results: ACTIVE was significantly correlated to the Hammersmith Functional Motor Scales Expanded and Revised Upper Limb Module (ρ=0.85 and ρ=0.92 respectively; p<0.001). Relevance to patients and families was established by strong correlations to the Patient Reported Outcomes Measurement Information System self- and parent proxy-measures of upper extremity ability (ρ=0.63 and ρ=0.70 respectively; p<0.001). Responsiveness to change was demonstrated by significant change in scaled scores after treatment (median 15.9 points, Wilcoxon signed-rank test p<0.01). A preliminary minimum clinically important difference is presented., Interpretation: These results suggest that ACTIVE WSV scores are a meaningful assessment with which to quantify change over time in individuals with SMA types 2 and 3., What This Paper Adds: Ability Captured Through Interactive Video Evaluation (ACTIVE) quantifies upper extremity function in spinal muscular atrophy. ACTIVE's scaled workspace volume strongly correlates to self- and parent-report of function. ACTIVE quantifies meaningful change after treatment., (© 2019 Mac Keith Press.)