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 × 1014 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.

Objective: To evaluate long-term safety and functional outcomes 4 years post-treatment with delandistrogene moxeparvovec (SRP-9001) in Study 101 (NCT03375164): a Phase 1/2a, single-dose, open-label clinical trial. Background: Delandistrogene moxeparvovec is an investigational gene transfer therapy developed to address the root cause of Duchenne muscular dystrophy (DMD) through targeted skeletal and cardiac muscle expression of SRP-9001 dystrophin protein, which contains key functional domains of dystrophin. Design/Methods: Four ambulatory patients with DMD (≥4 to <8 years old) were enrolled. Patients received an intravenous infusion of delandistrogene moxeparvovec (2.0×1014 vg/kg) and prednisone (1 mg/kg/day), 1-day pre- to 30-days post-treatment. The primary outcome was safety. Secondary outcomes included SRP-9001 dystrophin expression. Key efficacy outcomes included change from baseline in North Star Ambulatory Assessment (NSAA) and timed function tests. Results: A total of 72 adverse events were reported, the majority of which occurred in the first 70-days post-treatment and 18 (25.0%) of which were treatment-related. At 4 years post-treatment, no new safety events were reported. There was an improvement in function, with a change from baseline in mean (SD) NSAA at 90 days and 1 year of 5.3 (1.0) and 5.5 (2.7) points, respectively. Delandistrogene moxeparvovec demonstrated sustained stabilization of function 4 years post-treatment, with a mean 7-point (2.9) increase from baseline in NSAA. Similar trends were observed for timed function tests, including Time to Rise, 4-stair Climb, and 10- and 100-meter Walk/Run. In a post-hoc analysis, delandistrogene moxeparvovec showed a statistically significant difference >9 points in mean change from baseline NSAA at 4 years versus a propensity-score-weighted external control cohort (Δ=9.4, SE=3.4; P=0.0125), far exceeding the threshold for a clinically meaningful difference. Conclusions: Delandistrogene moxeparvovec was well tolerated with no new safety signals 4-years post-treatment. Functional assessments demonstrated long-term, sustained, clinically meaningful improvement in motor function at ages where functional decline would be expected based on natural history. Disclosure: Dr. Mendell has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Vertex. Dr. Mendell has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Novartis. Dr. Mendell has received research support from Sarepta. Dr. Sahenk has nothing to disclose. Ms. Lehman has nothing to disclose. The institution of Ms. Lowes has received research support from Sarepta Therapeutics. Dr. Reash has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ATOM International. Dr. Reash has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Casimir, LLC. The institution of Dr. Reash has received research support from Sarepta. Dr. Reash has received intellectual property interests from a discovery or technology relating to health care. Dr. Reash has received intellectual property interests from a discovery or technology relating to health care. Dr. Iammarino has received personal compensation in the range of $0-$499 for serving as a Consultant for Genentech. Ms. Alfano has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for ATOM International, Ltd (Amicus Therapeutics, Catabasis, Genethon, Italfarmaco, NS Pharma, Pfizer, PTC Therapeutics). Ms. Alfano has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sarepta Therapeutics. The institution of Ms. Alfano has received research support from Novartis Gene Therapies. The institution of Ms. Alfano has received research support from Sarepta Therapeutics. The institution of Ms. Alfano has received research support from Audentes Therapeutics/Astellas Gene Therapies. Ms. Alfano has received intellectual property interests from a discovery or technology relating to health care. Sarah Lewis has received stock or an ownership interest from Sarepta. Kathleen Church has nothing to disclose. Richard Shell has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Avexis. Richard Shell has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Rachael Potter has received stock or an ownership interest from Sarepta Therapeutics. Ms. Griffin has stock in Sarepta Therapeutics. Ms. Griffin has received intellectual property interests from a discovery or technology relating to health care. Mark Hogan has nothing to disclose. Shufang Wang has received personal compensation for serving as an employee of Sarepta Therapeutics INC. Shufang Wang has received stock or an ownership interest from Sarepta Therapeutics INC. Dr. Mason has received personal compensation for serving as an employee of Sarepta. Dr. Mason has stock in Sarepta. An immediate family member of Dr. Mason has stock in Sarepta. The institution of an immediate family member of Dr. Mason has received research support from Biogen. The institution of Dr. Mason has received research support from NIH. The institution of Dr. Mason has received research support from Chest Foundation. Dr. Darton has received personal compensation for serving as an employee of Sarepta Therapeutics. Dr. Darton has stock in Sarepta Therapeutics. Ms. Rodino-Klapac has received personal compensation for serving as an employee of Sarepta Therapeutics, Inc.. Ms. Rodino-Klapac has received stock or an ownership interest from Sarepta Therapeutics. Ms. Rodino-Klapac has received intellectual property interests from a discovery or technology relating to health care.

Tuesday, April 5May 3, 2022Free AccessPhase 1/2a Trial of SRP-9001 in Patients with Duchenne Muscular Dystrophy: 3-Year Safety and Functional Outcomes (S23.004)Jerry R. Mendell, Zarife Sahenk, Kelly J. Lehman, Carrie Nease, Linda P. Lowes, Natalie F. Reash, Megan A. Iammarino, … Show All … , Lindsay N. Alfano, Jordan Vaiea, Sarah Lewis, Kathleen Church, Richard Shell, Rachael A. Potter, Danielle A. Griffin, Eric R. Pozsgai, Mark Hogan, Larry Hu, Kathryn Giblin, and Louise R. Rodino-Klapac Show FewerAuthors Info & AffiliationsMay 3, 2022 issue98 (18_supplement)https://doi.org/10.1212/WNL.98.18_supplement.2568 Letters to the Editor

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 x 10(14)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 gamma-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.

Introduction: Cloacal malformations, a confluence of the urinary tract, vagina and rectum into a single common channel, has a broad and complex anatomic spectrum requiring an imaging tool for visualization, measurement, and surgical planning for the reconstruction of these structures. We evaluated the role of 3-D fluoroscopy for this purpose, as it offers a combination of spatial correlation with precise anatomic measurements. Methods: We examined our imaging protocol for patients with a cloaca! malformation and report our experience with rotational fluoroscopy and 3-D reconstruction in 16 consecutive patients referred for cloacal reconstruction. The length of the common channel (CC), the length of the urethra from the bladder neck to the common channal, and the height (and existence or absence) of a vagina or vaginas were determinants of the surgical procedures used for the repair. Results: We performed 16 consecutive 3-D cloacagrams (age range 4 months to 9 years) using a new protocol (Figure 1) that provided the following data which helped with surgical planning: Gynecologic: 3 cases with a single vagina, 5 cases with a duplicated Mullerian system (3 of which were asymmetric) and 2 cases with high vaginas requiting vaginal replacement. Colorectal: Four had a high rectum requiring an abdominal approach, and 6 had a rectum reachable via a posterior sagittal approach. Urologic: Two ectopic ureters requiting reimplantation, 3 patients had vesicoureteral reflux (1 bilateral, 2 unilateral), 1 patient had no bladder, and 7 had a normal sized bladder. Common channel length and urethral length were demonstrated in all cases and used to decide between a total urogenital mobilization or a separation of vagina(s) from the common channel, urogenital separation. Conclusion: The 3-D cloacagram can help predict the surgical plan for urologic, gynecologic, and colorectal components of the cloacal repair. It can predict the CC length as well as the length of the urethra. It helps with predicting the need for vaginal replacement and whether an abdominal approach is needed for the rectum. Its effectiveness is based on the ability to adequately distend structures and see their distal most extent, an advantage over other modalities such as MRI. Added benefits (particularly from the 3D view) include a better spatial understanding of the defect and the diagnosis of concomitant urological abnormalities such as vesicoureteral reflux and ectopic ureters. Disadvantages to this procedure include the need for general anesthesia and a higher exposure to radiation. (C) 2019 Elsevier Inc. All rights reserved.

Chemical injuries from household products cause significant morbidity and mortality annually in pediatric patients. We present a rare case of a 21-month-old male with significant esophageal and cutaneous chemical burns secondary to non-accidental trauma. Given the unique challenges associated with multiple burn types we describe this case and provide a current review of the literature on the management of these potentially devastating injuries.

Purpose: To analyze technique, outcomes, and complications of a large series of pediatric percutaneous nephrostomy (PCN) procedures performed at 4 tertiary pediatric centers. Materials and Methods: Retrospective multicenter study of PCNs performed during an 11-year period. Six hundred seventy-five PCNs were performed on 441 patients (median age: 4 y, range: 1 d-18 y, median weight: 17 kg, range: 0.7112 kg); 31% were younger than 1 year. The most frequent indications for PCN procedures included hydronephrosis (57%), calculus (14%), and infection (12%). Forty-five percent of patients had severe and 32% had moderate hydronephrosis. Results: Technical success was 99% (n = 668); 7 failures occurred from lost access, during tract dilatation (n = 5) and during staghorn calculi without dilatation (n = 2). General anesthesia was used in 73% of procedures. Combined ultrasound and fluoroscopy was used in 98% of procedures. Of the 668 procedures, 561 (84%) were primary nephrostomy insertions, and 107 (16%) were a variety of exchanges (secondary catheter insertions). Twenty-four of 675 (4%) were transplanted kidneys. Access sites included lower (47%), mid (28%), and upper (12%) poles and pelvis (11%). Catheters were predominantly 7-8 French (n = 352). The mean catheter dwell time was 25 days (0-220 d). Total primary catheter days were 14,482, with an additional 2,241 days after secondary procedures. Follow-up in 653/668 (98%) procedures documented elective removal (79%) and salvage procedures (21%), which included wire exchange (8.7%), nephroureteral stent/catheter conversion (8.8%), and tube upsizing (3.5%). Periprocedural complications occurred in 30/668 (4.5%) procedures: 1 major (0.1%) self-limiting hematuria requiring transfusion and 29 (4.4%) minor complications. Conclusions: PCN is safe and successful in children of all ages, with few major complications. PCN in children is associated with specific technical challenges and requires ongoing management tailored to the very young to achieve good outcomes.

Background: Sclerotherapy has been described as a treatment option for nonparasitic pediatric splenic cysts; however, there are limited data on its long-term effectiveness. Methods: We performed a retrospective review and prospective follow-up imaging study of children treated for nonparasitic splenic cysts at our institution during 2006-2015. Included patients had International Classification of Disease, Ninth Revision, Clinical Modification diagnosis code 289.59 or 759.0 and underwent either sclerotherapy or a partial splenic operation (partial splenectomy, cyst excision, or marsupialization). Charts were reviewed for demographics, imaging, treatments, and complications. Identified patients were contacted and asked to return for splenic ultrasonography. Results: Six surgical patients and 19 sclerotherapy patients were identified. Sclerotherapy patients underwent a median of four treatments with a decrease in the size of the cyst or complete ablation in 89.5% (17/19). Of the two patients who underwent unsuccessful sclerotherapy, one patient had sclerotherapy with sotradecol and ethanol for eight treatments, developed infection, and underwent total splenectomy. The other patient did not improve with sclerotherapy and underwent partial splenectomy. Nine patients (eight patients treated with sclerotherapy and one patient treated with partial splenectomy) were successfully contacted and underwent follow-up imaging at a median follow-up of 2.4 y since last treatment. Of the eight patients treated with sclerotherapy, four patients remained cystfree, three had small residual asymptomatic cysts stable in size, and one developed a recurrent small asymptomatic cyst; the patient treated with surgery had no recurrence. Conclusions: Sclerotherapy appears to be an effective and durable alternative treatment for children with splenic cysts. (C) 2017 Elsevier Inc. All rights reserved.

Treatment of sIBM poses many challenges. The cause of this disease is enigmatic, and although considered to be an inflammatory myopathy, there is resistance to anti-inflammatory and immunosuppressive agents. sIBM muscle biopsies show vacuolated muscle fibers, widespread inflammation, and intracellular amyloid deposits. Follistatin is a potent inhibitor of the myostatin pathway and its potential as a therapeutic vehicle is enhanced by a pathway independent of the activin IIB receptor. We have demonstrated both safety and efficacy following direct intramuscular injection of follistatin in the quadriceps muscle in a previously reported gene therapy trial in Becker muscular dystrophy (Mendell JR, et al Mol Ther 2015). No off target effects were encountered attributed to the use of an alternatively spliced follistatin isoform, FS344, also used in the current sIBM gene therapy trial. Enrollment in the current gene therapy trial included 6 subjects with either definite or possible sIBM (Griggs RC, et al. Ann Neurol 1995). Pretreatment MRI's were obtained to determine areas of relative muscle sparing/lack of fibrosis. The intramuscular injections of AAV1.CMV.FS344 to 12 to 14 sites in the quadriceps muscle delivered 1.2X1012 vg/kg. Injections were performed with direct ultrasound guidance to target the most normal appearing muscle bundles, and intramuscular position was confirmed with simultaneous EMG. A three-patient, single limb, safety trial preceded the Phase I/IIA trial reported here. During the ongoing gene therapy trial, a control sIBM group (n=20) was prospectively studied by performance of the 6MWT with follow up from 9-28 months. The 6MWT was the primary functional outcome (See table below). sIBM patients treated with AAV1.CMV.FS344 increased the 6MWT distance by 46.5m (457 to 503.5, p =0.001). Untreated sIBM controls lost 38.5m over a similar time period resulting in net difference of 85.0m between groups (p=0.0007). To validate findings and confirm the lack of selection bias we compared a subgroup of untreated sIBM controls (n=8), matched for age, gender, and 6MWD at baseline. Matched controls lost 39m (p=0.0036) in the 6MWD, a virtually identical loss to the larger control group. The results of this study demonstrate that sIBM can benefit from follistatin gene therapy based on improvement in distance walked in the 6MWT. We did find a hierarchy of response based on muscle preservation and avoiding gene delivery to areas of fibrosis. In this study, gene delivery was limited to the quadriceps muscle, but in future trials more widespread delivery could potentially be more effective. Tabled 1Six Minute Walk Distance Pre- and Post-Treatment* [median values (interquartile ranges provided)]GroupBaseline (m)Final Compared to Baseline (m)Change from Baseline (m)Change per Month (m)sIBM Gene Therapy Pts (n =6)457 (431,475)Improved to 503.5 (443, 573)+46.5 (2,117)+3.09 (0.39, 8.9)Untreated sIBM Controls (n =20)393 (356.5,.451.5)Declined to 354.5 (303.5,410.5)−38.5 (−73,−22) p =0.0007−2.3 (−4,−1. 1) P =0.0032Matched sIBM Controls for age, gender, and 6MWD (n = 8)459 (439.5,469)Declined to 420 (388.5,447.5)−39.0 (−77,−8) p = 0.0036−2.2 (−4.8. −0.7) P=0.0118 Open table in a new tab Data analysis used SAS 9.3 (SAS Institute, Cary NC) with two-sided p-values.

Objective To describe a single-center, 10-year experience with the use of antegrade enemas.Study design Retrospective analysis of 99 patients treated with antegrade enemas at Nationwide Children's Hospital.Results Study subjects (median age 8 years) were followed for a mean time of 46 months (range 2-125 months) after cecostomy placement. Seventy-one patients had the cecostomy placed percutaneously and 28 by surgery. Thirty-five patients had functional constipation and 64 patients an organic disease (spinal abnormalities, cerebral palsy, imperforate anus, Hirschsprung's disease). While using antegrade enemas, 71% became symptom-free, in 20 subjects symptoms improved, in 2 subjects symptoms did not change, and in 7 subjects symptoms worsened. Poor outcome was associated with surgical placement of the cecostomy (P < .001), younger age (P = .02), shorter duration of symptoms (P = .01), history of Hirschsprung's disease (P = .05), cerebral palsy (P = .03), previous abdominal surgery (P = .001), and abnormal colonic manometry (P = .004). In 88%, successful irrigation solution included use of a stimulant laxative, and subjects who used a stimulant did significantly better (P < .001) than subjects who started without a stimulant. In 13 patients, the cecostomy was removed 49.7 months after placement without recurrence of symptoms. Major complications occurred in 12 patients and minor complications in 47.Conclusions Antegrade enemas represent a successful and relatively safe therapeutic option in children with severe defecatory disorders. Prognostic factors are identified. (J Pediatr 2012;161:700-4).