A5016629548- Muscle Physiology and Disorders
- Hereditary Neurological Disorders
- Peripheral Neuropathies and Disorders
- Virus-based gene therapy research
- Nerve injury and regeneration
- Neurogenetic and Muscular Disorders Research
- Botulinum Toxin and Related Neurological Disorders
- Genetic Neurodegenerative Diseases
- Cardiomyopathy and Myosin Studies
- Biotin and Related Studies
- Pain Mechanisms and Treatments
- CAR-T cell therapy research
- Inflammatory Myopathies and Dermatomyositis
- RNA Research and Splicing
- RNA Interference and Gene Delivery
- Tissue Engineering and Regenerative Medicine
- Neurological diseases and metabolism
- Adipose Tissue and Metabolism
- Mitochondrial Function and Pathology
- Cancer Treatment and Pharmacology
- RNA regulation and disease
- Cellular transport and secretion
- Skin and Cellular Biology Research
- Viral Infections and Immunology Research
- Muscle and Compartmental Disorders
Nationwide Children's Hospital
2016-2025
The Ohio State University
2014-2024
Centre for Life
2023
Newcastle University
2023
Johns Hopkins University
2023
Sarepta Therapeutics (United States)
2015-2017
Pediatrics and Genetics
2013
The Ohio State University Wexner Medical Center
2012
John D. Dingell VA Medical Center
2008
University of Michigan–Ann Arbor
2008
In prior open-label studies, eteplirsen, a phosphorodiamidate morpholino oligomer, enabled dystrophin production in Duchenne muscular dystrophy (DMD) with genetic mutations amenable to skipping exon 51. The present study used double-blind placebo-controlled protocol test eteplirsen's ability induce and improve distance walked on the 6-minute walk (6MWT).DMD boys aged 7 13 years, confirmed deletions correctable by 51 200 400 m 6 MWT, were randomized weekly intravenous infusions of 30 or 50...
We report on delivery of a functional dystrophin transgene to skeletal muscle in six patients with Duchenne's muscular dystrophy. Dystrophin-specific T cells were detected after treatment, providing evidence expression even when the protein was not visualized muscle. Circulating dystrophin-specific unexpectedly two before vector treatment. Revertant fibers, which expressed functional, truncated from deleted endogenous gene spontaneous in-frame splicing, contained epitopes targeted by...
Myoblast transfer has been proposed as a technique to replace dystrophin, the skeletal-muscle protein that is deficient in Duchenne's muscular dystrophy. Donor myoblasts injected into muscles of affected patients can fuse with host muscle fibers, thus contributing their nuclei, which are potentially capable replacing gene products. Previous controlled trials involving single have unsuccessful.
Duchenne muscular dystrophy (DMD) is a lethal X-linked disorder associated with dystrophin deficiency that results in chronic inflammation and severe skeletal muscle degeneration. In DMD mouse models patients, we find IkappaB kinase/NF-kappaB (IKK/NF-kappaB) signaling persistently elevated immune cells regenerative fibers. Ablation of 1 allele the p65 subunit NF-kappaB was sufficient to improve pathology mdx mice, model DMD. addition, conditional deletion IKKbeta mice elucidated functions...
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 cardiac muscle-specific promoter enhanced expression (MHCK7).To identify the 1-year safety tolerability of intravenous rAAVrh74.MHCK7.micro-dystrophin in DMD.This open-label, phase 1/2a nonrandomized controlled trial was conducted at Nationwide Children's...
The objective of this study was to establish the feasibility long-term gentamicin dosing achieve stop codon readthrough and produce full-length dystrophin. Mutation suppression codons, successfully achieved in mdx mouse using gentamicin, represents an important evolving treatment strategy Duchenne muscular dystrophy (DMD).Two DMD cohorts received 14-day (7.5mg/kg/day): Cohort 1 (n = 10) patients 2 8) frameshift controls. Two additional were treated (7.5mg/kg) for 6 months: 3 12) dosed weekly...
Becker muscular dystrophy (BMD) is a variant of dystrophin deficiency resulting from DMD gene mutations. Phenotype variable with loss ambulation in late teenage or mid-life years. There currently no treatment for this condition. In BMD proof-of-principle clinical trial, potent myostatin antagonist, follistatin (FS), was used to inhibit the pathway. Extensive preclinical studies, using adeno-associated virus (AAV) deliver follistatin, demonstrated an increase strength. For we alternatively...
To describe the quantification of novel dystrophin production in patients with Duchenne muscular dystrophy (DMD) after long-term treatment eteplirsen.Clinical study 202 was an observational, open-label extension randomized, controlled 201 assessing safety and efficacy eteplirsen DMD a confirmed mutation gene amenable to correction by skipping exon 51. Patients received once-weekly IV doses 30 or 50 mg/kg. Upper extremity muscle biopsy samples were collected at combined week 180, blinded,...
Introduction: Delandistrogene moxeparvovec (SRP-9001) is an investigational gene transfer therapy designed for targeted expression of SRP-9001 dystrophin protein, a shortened retaining key functional domains 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 in patients, aged ≥4 to <8 years with Duchenne muscular dystrophy. Primary endpoints (Part 1) were change from...
<b><i>Objective:</i></b> In patients presenting with painful, burning feet minimal signs of neuropathy, the following questions were addressed: 1) How many these have a peripheral neuropathy? 2) What is role skin biopsy in establishing diagnosis 3) conditions are associated and 4) laboratory studies useful this patient population? <b><i>Methods:</i></b> A total 117 consecutive referred for evaluation prospectively studied. All underwent nerve conduction (NCS) battery blood tests, including...
Increasing the size and strength of muscles represents a promising therapeutic strategy for musculoskeletal disorders, interest has focused on myostatin, negative regulator muscle growth. Various myostatin inhibitor approaches have been identified tested in models disease with varying efficacies, depending age at which inhibition occurs. Here, we describe one-time gene administration myostatin-inhibitor-proteins to enhance mass normal dystrophic mouse >2 years, even when delivered aged...
Abstract Objective: The aim of this study was to attain long‐lasting alpha‐sarcoglycan gene expression in limb‐girdle muscular dystrophy, type 2D (LGMD2D) subjects mediated by adeno‐associated virus (AAV) transfer under control a muscle specific promoter (tMCK). Methods: rAAV1.tMCK.hSGCA (3.25 × 10 11 vector genomes) delivered the extensor digitorum brevis 3 with documented SGCA mutations via double‐blind, randomized, placebo controlled trial. Control sides received saline. blind not broken...
Abstract Objective α‐Sarcoglycan deficiency results in a severe form of muscular dystrophy (limb‐girdle type 2D [LGMD2D]) without treatment. Gene replacement represents strategy for correcting the underlying defect. Questions related to this approach were addressed clinical trial, particularly need immunotherapy and persistence gene expression. Methods A double‐blind, randomized controlled trial using rAAV1.tMCK.hSGCA injected into extensor digitorum brevis muscle was conducted. Control...
A 1-month-old boy was admitted because of failure to thrive. He floppy and had bilateral ptosis, diminished reflexes, poor suck. aspiration pneumonia, developed seizures, died at age 3 1/2 months. Laboratory data showed lactic acidosis, proteinuria, glycosuria generalized aminoaciduria. an only child, family history negative. Muscle biopsy large clumps granules positive with oxidative enzyme stains increased lipid droplets. Ultrastructural studies aggregates mitochondria, many which were...
<b>Background: </b> Xenografts from patients with Charcot–Marie–Tooth type 1A (CMT1A) have shown delayed myelination and impaired regeneration of nude mice axons passing through the grafted segments. Neurotrophin-3 (NT-3), an important component Schwann cell (SC) autocrine survival loop, could correct these deficiencies. <b>Objective: To assess efficacy NT-3 treatment in preclinical studies using animal models CMT1A to conduct a double-blind, placebo-controlled, randomized, pilot clinical...
Abstract Attentionl has recently been directed toward patients having a polyneuropathy IgM anti‐Myelin‐associated glycoprotein (anti‐MAG) antibody. The possibility of pathogenetic role for the anti‐MAG antibody in evolution and development central nervous system signs, including tremor ataxia, remains unresolved. In 5 with this syndrome whose clinical courses were followed closely, 1 whom complete postmortem examination was performed, we made folowing obsercvations: (1) did not localize to...
A vector delivered into muscles of monkeys generates a natural regulatory molecule, which increases muscle size and strength may be useful therapeutically.
Duchenne muscular dystrophy is a monogenic disease potentially treatable by gene replacement. Use of recombinant adeno-associated virus (AAV) will ultimately require vascular approach to broadly transduce muscle cells. We tested the impact preexisting AAV antibodies on microdystrophin expression following delivery nonhuman primates. Rhesus macaques were treated isolated limb perfusion using fluoroscopically guided catheter. In addition serostatus stratification, animals placed into one three...
Recessive Charcot-Marie-Tooth disease type-4J (CMT4J) and its animal model, the pale tremor mouse (plt), are caused by mutations of FIG4 gene encoding a PI(3,5)P(2) 5-phosphatase. We describe 9-year clinical course CMT4J, including asymmetric, rapidly progressive paralysis, in two siblings. Sensory symptoms were absent despite reduced numbers sensory axons. Thus, phenotypic presentation CMT4J clinically resembles motor neuron disease. Time-lapse imaging fibroblasts from patients demonstrates...
Limb-girdle muscular dystrophies are a genetically diverse group of diseases characterized by chronic muscle wasting and weakness. Recessive mutations in ANO5 (TMEM16E) have been directly linked to several clinical phenotypes including limb-girdle dystrophy type 2L Miyoshi myopathy 3, although the pathogenic mechanism has remained elusive. is member Anoctamin/TMEM16 superfamily that encodes both ion channels regulators membrane phospholipid scrambling. The phenotypic overlap myopathies with...
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 include weakness the quadriceps, finger flexors, ankle dorsiflexors, and dysphagia. distribution is similar to Becker muscular dystrophy, where we previously reported improvement following intramuscular injection an isoform follistatin (FS344) by AAV1. For this clinical trial,...
Abstract This analysis aims to describe the outcomes of two nonambulatory patients with Duchenne muscular dystrophy (DMD) who participated in clinical studies. The consecutive trials eteplirsen (studies 201 and 202) were conducted DMD (N = 12) confirmed genetic mutations amenable exon 51 skipping. In study 201, 12 randomized receive once-weekly, double-blind intravenous infusions 30 or 50 mg/kg placebo for 24 weeks; then received open-label during weeks 25 through 28. All continued onto...