A5039313795- Muscle Physiology and Disorders
- RNA Research and Splicing
- RNA Interference and Gene Delivery
- RNA modifications and cancer
- Virus-based gene therapy research
- CRISPR and Genetic Engineering
- Neurogenetic and Muscular Disorders Research
- Adipose Tissue and Metabolism
- Advanced biosensing and bioanalysis techniques
- Biochemical and Molecular Research
- Telomeres, Telomerase, and Senescence
- Biliary and Gastrointestinal Fistulas
- Autism Spectrum Disorder Research
- Cardiomyopathy and Myosin Studies
- Language Development and Disorders
- Metabolism and Genetic Disorders
- Amoebic Infections and Treatments
- Kawasaki Disease and Coronary Complications
- RNA regulation and disease
- Lysosomal Storage Disorders Research
- Coronary Artery Anomalies
- RNA and protein synthesis mechanisms
- Genetics and Neurodevelopmental Disorders
- Chromatin Remodeling and Cancer
- Retinal Development and Disorders
Nationwide Children's Hospital
2014-2023
The Ohio State University Wexner Medical Center
2020-2021
The Ohio State University
2015-2016
Battelle
2010
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...
In a phase 1/2, open-label dose escalation trial, we delivered rAAVrh74.MCK.GALGT2 (also B4GALNT2) bilaterally to the legs of two boys with Duchenne muscular dystrophy using intravascular limb infusion. Subject 1 (age 8.9 years at dosing) received 2.5 × 1013 vector genome (vg)/kg per leg (5 vg/kg total) and subject 2 6.9 5 (1 1014 total). No serious adverse events were observed. Muscle biopsy evaluated 3 or 4 months post treatment versus baseline showed evidence GALGT2 gene expression...
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 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...
While advances in network and pathway analysis have flourished the era of genome-wide association analysis, understanding genetic mechanism individual loci on phenotypes is still readily accomplished using modeling approaches. Here, we demonstrate two novel genotype-phenotype models implemented a flexible platform. The examples come from families with specific language impairment (SLI), failure to develop normal without explanatory factors such as low IQ or inadequate environment. In...
Duchenne muscular dystrophy (DMD) is a devastating muscle-wasting disease that arises due to the loss of dystrophin expression, leading progressive motor and cardiorespiratory function. Four exon-skipping approaches using antisense phosphorodiamidate morpholino oligomers (PMOs) have been approved by FDA restore DMD open reading frame, resulting in expression functional but internally deleted protein, patients with single-exon duplications, exon skipping has potential full-length expression....
To date, exon-skipping therapies for Duchenne muscular dystrophy (DMD) patients have focused on with out-of-frame exon deletions, in whom treatment results larger but in-frame internal deletions which lead to translation of an internally truncated partially functional dystrophin protein. We are developing duplication mutations, accounting around 6% all the intent induce production wild-type transcripts and As a model most common single duplication, we developed new mouse 2 (the Dup2 mouse)...
Abstract Although the major determinant of disease severity in patients with severe Duchenne muscular dystrophy (DMD) or milder Becker (BMD) is whether their dystrophin gene ( DMD ) mutation disrupts mRNA reading frame allows expression a partially functional protein, other genes have been proposed demonstrated to modify progression. In companion paper this one, we describe our novel approaches genome-wide association study (GWAS) loss ambulation (LOA) largest search date for loci...
Abstract The major determinant of disease severity in patients with severe Duchenne muscular dystrophy (DMD) or milder Becker (BMD) is whether their dystrophin gene ( DMD ) mutation disrupts the mRNA reading frame allows expression a partially functional protein. However, even complete absence dystrophin, variability observed, and candidate studies have implicated several genes as possible modifiers. Our previous genome-wide association study (GWAS) for age at loss ambulation (LOA) provided...
We recently identified an internal ribosome entry site (IRES) within exon 5 of the DMD gene. Mutations that truncate reading frame 5' this can result in use IRES for alternate translational initiation beginning 6 results expression N-truncated isoform. Despite lacking calponin homology domain 1 (CH1) actin binding (ABD1), isoform is highly functional, as demonstrated by minimal symptoms patients who express it. Consistent with genotype-phenotype correlations patients, not active presence 2...
Most mutations that truncate the reading frame of DMD gene result in loss dystrophin expression and lead severe Duchenne muscular dystrophy. However, frame-truncating within first five exons mild dystrophinopathy with a N-truncated dystrophin. We have recently shown this is due to activation an internal ribosome entry site (IRES) exon 5 resulting translation from 6 AUG codon. demonstrated IRES active patients expressing dystrophin, raising possibility therapeutic use isoform. To explore we...
Currently, exon skipping therapies for Duchenne muscular dystrophy (DMD) have been developed patients with out-of-frame deletions where treatment will lead translation of an internally truncated but partially functional dystrophin protein. In contrast, we are focusing on treating duplications mutations, accounting around 6% all resulting in wild-type transcript and a full-length Modeling the most common single duplication first mouse containing duplicated 2. We performed proof-of-principle...