A5038457477- Muscle Physiology and Disorders
- RNA Research and Splicing
- RNA modifications and cancer
- RNA Interference and Gene Delivery
- Virus-based gene therapy research
- CRISPR and Genetic Engineering
- RNA regulation and disease
- Tissue Engineering and Regenerative Medicine
- Neurogenetic and Muscular Disorders Research
- RNA and protein synthesis mechanisms
- Adipose Tissue and Metabolism
- Extracellular vesicles in disease
- Cardiomyopathy and Myosin Studies
- Advanced biosensing and bioanalysis techniques
- Viral Infections and Immunology Research
- Genetic Neurodegenerative Diseases
- GDF15 and Related Biomarkers
- Pluripotent Stem Cells Research
- Biotin and Related Studies
- Mesenchymal stem cell research
- Nutrition and Health in Aging
- Genetics and Neurodevelopmental Disorders
- Signaling Pathways in Disease
- Congenital heart defects research
- Peptidase Inhibition and Analysis
Nationwide Children's Hospital
2015-2024
The Ohio State University
2014-2023
University of Utah
2021
The Ohio State University Wexner Medical Center
2020-2021
Aix-Marseille Université
2011-2015
Inserm
2007-2015
Génétique Médicale & Génomique Fonctionelle
2009-2013
Hôpital de la Timone
2013
Institut de Neurobiologie de la Méditerranée
2009-2010
Health First
2009
DMD pathogenic variants for Duchenne and Becker muscular dystrophy are detectable with high sensitivity by standard clinical exome analyses of genomic DNA. However, up to 7% mutations deep intronic analysis muscle-derived RNA is an important diagnostic step patients who have negative testing but abnormal dystrophin expression in muscle. In this study, muscle biopsies were evaluated from 19 features a dystrophinopathy, mutation analysis. Reverse transcription-polymerase chain reaction or...
Mutations in DYSF encoding dysferlin cause primary dysferlinopathies, autosomal recessive diseases that mainly present clinically as Limb Girdle Muscular Dystrophy type 2B and Miyoshi myopathy. More than 350 different sequence variants have been reported DYSF. Like dystrophin, the size of mRNA is above limited packaging AAV vectors. Alternative strategies to gene transfer muscle cells must then be addressed for patients. A therapy approach Duchenne muscular dystrophy was recently developed,...
A naturally occurring miniversion of the dysferlin protein found in a patient shows that gene therapy by minigene transfer may be possible dysferlinopathies.
Therapeutic exon skipping as a treatment for Duchenne muscular dystrophy (DMD) has largely concentrated on the delivery of antisense oligomers to treat out-of-frame deletions. Here we report preclinical development an adeno-associated virus (AAV)-encapsidated viral vector containing four copies noncoding U7 small nuclear RNA (U7snRNA), each targeted either splice donor or acceptor sites DMD 2. We have previously shown that this (scAAV9.U7.ACCA) Dup2 mouse model results in expression...
Exon-skipping therapies aim to convert Duchenne muscular dystrophy (DMD) into less severe Becker (BMD) by altering pre-mRNA splicing restore an open reading frame, allowing translation of internally deleted and partially functional dystrophin protein. The most common single exon deletion-exon 45 (Δ45)-may theoretically be treated skipping either flanking (44 or 46). We sought predict the impact these assessing clinical severity in dystrophinopathy patients.Phenotypic data including...
Mutations in the dysferlin gene (DYSF) lead to a complete or partial absence of protein skeletal muscles and are at origin dysferlinopathies, heterogeneous group rare autosomal recessive inherited neuromuscular disorders. As step towards better understanding DYSF mutational spectrum, possible inclusion patients future therapeutic clinical trials, we set up Universal Mutation Database for Dysferlin (UMD-DYSF), Locus-Specific developed with UMD® software. The main objective UMD-DYSF is provide...
Dysferlinopathies are a family of disabling muscular dystrophies with LGMD2B and Miyoshi myopathy as the main phenotypes.They associated molecular defects in DYSF, which encodes dysferlin, key player sarcolemmal homeostasis.Previous investigations have suggested that exon skipping may be promising therapy for subset patients dysferlinopathies.Such an approach aims to rescue functional proteins when targeting modular specific tissues.We sought evaluate dysferlin recovery following 32 cells...
Duchenne muscular dystrophy (DMD) is an X-linked progressive disease characterized by loss of dystrophin protein that typically results from truncating mutations in the DMD gene. Current exon-skipping therapies have sought to treat deletion abolish open reading frame (ORF) skipping adjacent exon, order restore ORF allows translation internally deleted yet partially functional protein, as seen with many patients milder Becker (BMD) phenotype. In contrast approach, one copy a duplicated exon...
Duchenne muscular dystrophy (DMD) is a devastating X-linked recessive genetic myopathy. DMD physiopathology still not fully understood and prenatal onset suspected but difficult to address. The bone morphogenetic protein 4 (BMP4) critical signaling molecule involved in mesoderm commitment. Human induced pluripotent stem cells (hiPSCs) from healthy individuals human embryonic (hESCs) treated with BMP4 allowed us model the early steps of myogenesis normal contexts. Unexpectedly, 72h following...
Exon skipping strategies in Duchenne muscular dystrophy (DMD) have largely been directed toward altering splicing of exons flanking out-of-frame deletions, with the goal restoring an open mRNA reading frame that leads to production internally deleted but partially functional dystrophin protein.We sought apply exon duplication mutations, assuming inherently limited efficiency antisense oligonucleotide-induced would more frequently skip a single copy duplicated exon, rather than both and...
Facioscapulohumeral muscular dystrophy (FSHD) arises from epigenetic changes that de-repress the DUX4 gene in muscle. The full-length protein causes cell death and muscle toxicity, therefore we hypothesize FSHD therapies should center on inhibiting expression. In this study, developed a strategy to accomplish inhibition using U7-small nuclear RNA (snRNA) antisense expression cassettes (called U7-asDUX4). These non-coding RNAs were designed inhibit production or maturation of pre-mRNA by...
The AAV9 gene therapy vector presented in this study is safe mice and non-human primates highly efficacious without causing overexpression toxicity, a major challenge for clinical translation of Rett syndrome vectors to date. Our team designed new truncated methyl-CpG-binding protein 2 (MECP2) promoter allowing widespread expression MECP2 after single injection into the cerebrospinal fluid symptoms up 18 months injection. Additionally, at lower doses compared with previous constructs as...
Duchenne muscular dystrophy (DMD) is associated with the loss of dystrophin, which plays an important role in myofiber integrity via interactions β-dystroglycan and other members transmembrane dystrophin-associated protein complex. The ZZ domain, a cysteine-rich zinc-finger domain near dystrophin C-terminus, implicated forming stable interaction between β-dystroglycan, but mechanism pathogenesis missense mutations has remained unclear because not all such have been shown to alter binding...
Exon skipping therapies for Duchenne muscular dystrophy that restore an open reading frame can be induced by the use of noncoding U7 small nuclear RNA (U7snRNA) modified antisense exon-targeting sequence delivered adeno-associated virus (AAV) vector. We have developed AAV vector (AAV9.U7-ACCA) containing four U7snRNAs targeting splice donor and acceptor sites dystrophin exon 2, resulting in highly efficient exclusion DMD 2. assessed specificity variation AAV9.U7-ACCA delivery Dmd 2...
Duchenne muscular dystrophy (DMD) is a progressive X-linked disease caused by mutations in the DMD gene that prevent expression of functional dystrophin protein. Exon duplications represent 6%-11% mutations, and exon 2 (Dup2) are most common (∼11%) duplication mutations. An exon-skipping strategy for Dup2 presents large therapeutic window. Skipping one copy results full-length expression, whereas skipping both copies (Del2) activates an internal ribosomal entry site (IRES) 5, inducing highly...