A5066870896- Muscle Physiology and Disorders
- RNA Research and Splicing
- Virus-based gene therapy research
- Genetic Neurodegenerative Diseases
- RNA Interference and Gene Delivery
- Neurogenetic and Muscular Disorders Research
- CRISPR and Genetic Engineering
- Cardiomyopathy and Myosin Studies
- Viral Infections and Immunology Research
- Advanced biosensing and bioanalysis techniques
- Viral Infectious Diseases and Gene Expression in Insects
- RNA modifications and cancer
- RNA regulation and disease
- MicroRNA in disease regulation
- Hereditary Neurological Disorders
- Biotin and Related Studies
- Extracellular vesicles in disease
- CAR-T cell therapy research
- Adipose Tissue and Metabolism
- Mitochondrial Function and Pathology
- IL-33, ST2, and ILC Pathways
- Exercise and Physiological Responses
- Genetics and Neurodevelopmental Disorders
- Nuclear Structure and Function
- Retinal Development and Disorders
Nationwide Children's Hospital
2016-2025
The Ohio State University
2015-2024
Instituto Nacional de Rehabilitación
2023
Massachusetts Eye and Ear Infirmary
2014
Harvard University
2014
University of Iowa
2003-2008
National Heart Lung and Blood Institute
2005
National Institutes of Health
2005
University of Washington
2002-2004
University of Missouri
2003
Huntington's disease (HD) is a fatal, dominant neurogenetic disorder. HD results from polyglutamine repeat expansion (CAG codon, Q) in exon 1 of , conferring toxic gain function on the protein huntingtin (htt). Currently, no preventative treatment exists for HD. RNA interference (RNAi) has emerged as potential therapeutic tool treating diseases by directly reducing gene expression. Here, we show that RNAi directed against mutant human htt reduced mRNA and expression cell culture mouse brain....
The transcription factor REST silences neuronal gene expression in non-neuronal cells. In neurons, the protein is sequestered cytoplasm part through binding to huntingtin. Polyglutamine expansions huntingtin, which causes Huntington's disease (HD), abrogates REST-huntingtin binding. Consequently, translocates nucleus, occupies RE1 repressor sequences and decreases expression. this work, we found that levels of several microRNAs (miRNAs) with upstream sites are decreased HD patient cortices...
Huntington's disease (HD) is a fatal, dominant neurodegenerative caused by polyglutamine repeat expansion in exon 1 of the HD gene, which encodes huntingtin protein. We and others have shown that RNAi candidate therapy for because expression inhibitory RNAs targeting mutant human transgenes improved neuropathology behavioral deficits mouse models. Here, we developed shRNAs conserved sequences homolog (HDh) mRNAs to initiate preclinical testing knockin model HD. screened 35 vitro subsequently...
Macrophages are essential for skeletal muscle homeostasis, but how their dysregulation contributes to the development of fibrosis in disease remains unclear. Here, we used single-cell transcriptomics determine molecular attributes dystrophic and healthy macrophages. We identified six clusters unexpectedly found that none corresponded traditional definitions M1 or M2 Rather, predominant macrophage signature was characterized by high expression fibrotic factors, galectin-3 (gal-3) osteopontin...
Vectors based on recombinant adeno-associated viruses (rAAV) have emerged as tools of choice for gene transfer to skeletal muscle. rAAV vectors demonstrate efficient, safe, and stable transduction. Multiple serotypes AAV exist, but serotype 2 (rAAV2) are the most thoroughly characterized frequently employed. Here, we characterize transduction musculature using pseudotyped with 6 capsid proteins (rAAV6). We that rAAV6 can efficiently transduce mice at levels >500-fold higher than is...
Facioscapulohumeral muscular dystrophy (FSHD) is associated with D4Z4 repeat contraction on human chromosome 4q35. This genetic lesion does not result in complete loss or mutation of any gene. Consequently, the pathogenic mechanisms underlying FSHD have been difficult to discern. In leading pathogenesis models, contractions are proposed cause epigenetic changes, which ultimately increase expression genes myopathic potential. Although no gene has conclusively linked development, recent...
Huntington's disease (HD) and other polyglutamine (polyQ) neurodegenerative diseases are characterized by neuronal accumulation of the protein, suggesting that cellular ability to handle abnormal proteins is compromised. As both a cochaperone ubiquitin ligase, C-terminal Hsp70 (heat shock protein 70)-interacting (CHIP) links two major arms quality control, molecular chaperones, ubiquitin-proteasome system. Here, we demonstrate CHIP suppresses polyQ aggregation toxicity in transfected cell...
Duchenne muscular dystrophy (DMD) is the most common inherited lethal muscle degenerative disease. Currently there no cure. Highly abbreviated microdystrophin cDNAs were developed recently for adeno-associated virus (AAV)-mediated DMD gene therapy. Among these, a C-terminal-truncated DeltaR4-R23/DeltaC microgene (DeltaR4/DeltaC) has been considered as very promising therapeutic candidate gene. In this study, we packaged CMV.DeltaR4/DeltaC cassette in AAV-5 and evaluated transduction...
No treatment exists for facioscapulohumeral muscular dystrophy (FSHD), one of the most common inherited muscle diseases. Although FSHD can be debilitating, little effort has been made to develop targeted therapies. This lack focus on therapy perpetuated because genes and pathways involved in disorder were not understood. Now, more than 2 decades after efforts decipher root cause began, this barrier translation is finally lowering. Specifically, several recent studies support an pathogenesis...
Background— More than 90% of Duchenne muscular dystrophy (DMD) patients develop cardiomyopathy, and many die cardiac failure. Despite tremendous progress in skeletal muscle gene therapy, few attempts have been made to treat cardiomyopathy. Microdystrophin genes are shown correct pathological lesions the mdx mouse model for DMD. Here, we tested therapeutic potential adeno-associated virus (AAV)–mediated microdystrophin therapy heart. Methods Results— AAV was delivered newborn cavity. The...
Gene therapy approaches are being deployed to treat recessive genetic disorders by restoring the expression of mutated genes. However, feasibility these for dominantly inherited diseases — where treatment may require reduction in a toxic mutant protein resulting from gain-of-function allele is unclear. Here we show efficacy allele-specific RNAi as potential Charcot-Marie-Tooth disease type 2D (CMT2D), caused dominant mutations glycyl-tRNA synthetase (GARS). A de novo mutation GARS was...
FacioScapuloHumeral muscular Dystrophy (FSHD) is one of the most prevalent hereditary myopathies and generally characterized by progressive muscle atrophy affecting face, scapular fixators; upper arms distal lower legs. The FSHD locus maps to a macrosatellite D4Z4 repeat array on chromosome 4q35. Each unit contains DUX4 gene; which flanked polyadenylation site FSHD-permissive alleles, allows for production stable mRNAs. In addition, an open chromatin structure required gene transcription....
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant or digenic disorder linked to derepression of the toxic DUX4 gene in muscle. There currently no pharmacological treatment. The emergence enabled development cell and animal models that could be used for basic translational research. Since toxic, model has been challenging, but progress made, revealing tight regulation expression critical creating viable animals develop myopathy. Here, we report such a —...
Despite the well-accepted view that chronic inflammation contributes to pathogenesis of Duchenne muscular dystrophy (DMD), function and regulation eosinophils remain an unclear facet type II innate immunity in dystrophic muscle. We report observation group 2 lymphoid cells (ILC2s) are present skeletal muscle principal regulators during dystrophy. Eosinophils were elevated DMD patients mice along with interleukin (IL)-5, a major eosinophil survival factor was predominantly expressed by ILC2s....
Charcot-Marie-Tooth disease type 1A (CMT1A), the most common inherited demyelinating peripheral neuropathy, is caused by PMP22 gene duplication. Overexpression of WT in Schwann cells destabilizes myelin sheath, leading to demyelination and ultimately secondary axonal loss disability. No treatments currently exist that modify course. The direct route CMT1A therapy will involve reducing normal levels. To accomplish this, we developed a strategy reduce using artificial miRNAs targeting human...
RNAi emerged as a prospective molecular therapy nearly 15 years ago. Since then, two major platforms have been under development: oligonucleotides and gene therapy. Oligonucleotide-based approaches seen more advancement, with some promising therapies that may soon reach market. In contrast, vector-based for remained largely in the pre-clinical realm, limited clinical safety efficacy data to date. We are developing approach treat autosomal-dominant disorder facioscapulohumeral muscular...
D4Z4 repeats are present in at least 11 different mammalian species, including humans and mice. Each repeat contains an open reading frame encoding a double homeodomain (DUX) family transcription factor. Aberrant expression of the ORF called DUX4 is associated with pathogenesis Facioscapulohumeral muscular dystrophy (FSHD). toxic to numerous cell types over-expression caused dysmorphism developmental arrest frogs zebrafish, embryonic lethality transgenic mice, lesions mouse muscle. Because...
Sarcolipin (SLN) is a regulator of sarco/endo plasmic reticulum Ca 2+ -ATPase (SERCA) pump and has been shown to be involved in muscle nonshivering thermogenesis (NST) energy metabolism. Interestingly, SLN expression significantly upregulated both during development several disease states. However, the significance altered patho-physiology not completely understood. We have previously that transgenic over-expression skeletal detrimental, can promote oxidative metabolism exercise capacity. In...
Effective gene therapy for gain-of-function or dominant-negative disease mutations may require eliminating expression of the mutant copy together with wild-type replacement. We evaluated such a knockdown-replace strategy in mouse model DNM1 disease, debilitating and intractable neurodevelopmental epilepsy. To challenge approach robustly, we expressed patient-based variant GABAergic neurons-which resulted growth delay lethal seizures evident by postnatal week three-and delivered to newborn...
Facioscapulohumeral muscular dystrophy (FSHD) is a potentially devastating muscle disease caused by de-repression of the toxic DUX4 gene in skeletal muscle. FSHD patients may benefit from inhibition therapies, and although several experimental strategies to reduce levels are being developed, no approved modifying therapies currently exist. We developed CRISPR-Cas13b system that cleaves mRNA reduces protein level, protects cells DUX4-mediated death, FSHD-associated biomarkers vitro . In vivo...
Abstract Facioscapulohumeral muscular dystrophy (FSHD) is a potentially devastating myopathy caused by de-repression of the DUX4 gene in skeletal muscles. Effective therapies will likely involve inhibition. RNA interference (RNAi) one powerful approach to inhibit , and we previously described RNAi therapy achieve silencing FSHD cells mice using engineered microRNAs. Here report strategy direct against natural microRNA miR-675 which derived from lncRNA H19 . Human inhibits expression...