The transplantation of progenitor muscle cells in striated skeletal muscle of mdx mice, a model of dystrophin deficiency, is well known to induce the formation of mosaic fibres expressing dystrophin near the site of injection. We tried to determine if the number of injected cells is related to the number of dystrophin-positive fibres. The grafted cells provided by 5 day-old C57Bl10 mice are syngenic to mdx mice and were cultured to select undifferentiated progenitors. Dystrophin-positive fibres distinct to 'revertant' fibres were detectable 10 days following the graft of as few as 10(3) cells. The number of dystrophin-positive fibres increases logarithmically with the number of grafted cells. The data indicate that the number of dystrophin-positive fibres plateaus above 5x10(5)-10(6) grafted cells and that a greater number of progenitor cells is not required to obtain a better result.
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http://dx.doi.org/10.1016/j.neulet.2003.08.024 | DOI Listing |
J Neuromuscul Dis
May 2024
Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, USA.
Single exon duplications account for disease in a minority of Duchenne muscular dystrophy patients. Exon skipping in these patients has the potential to be highly therapeutic through restoration of full-length dystrophin expression. We conducted a 48-week open label study of casimersen and golodirsen in 3 subjects with an exon 45 or 53 duplication.
View Article and Find Full Text PDFPharmaceutics
June 2023
Department of Drug Delivery and Molecular Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo 192-0392, Japan.
Strategies for gene and nucleic acid delivery to skeletal muscles have been extensively explored to treat Duchenne muscular dystrophy (DMD) and other neuromuscular diseases. Of these, effective intravascular delivery of naked plasmid DNA (pDNA) and nucleic acids into muscles is an attractive approach, given the high capillary density in close contact with myofibers. We developed lipid-based nanobubbles (NBs) using polyethylene-glycol-modified liposomes and an echo-contrast gas and found that these NBs could improve tissue permeability by ultrasound (US)-induced cavitation.
View Article and Find Full Text PDFInt J Mol Sci
May 2023
Institute of Cytology, Russian Academy of Sciences, 194064 Saint-Petersburg, Russia.
Duchenne muscular dystrophy (DMD) is a severe muscular disorder caused by mutations in the dystrophin gene. It leads to respiratory and cardiac failure and premature death at a young age. Although recent studies have greatly deepened the understanding of the primary and secondary pathogenetic mechanisms of DMD, an effective treatment remains elusive.
View Article and Find Full Text PDFMol Ther Nucleic Acids
December 2022
The Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, USA.
Duchenne muscular dystrophy (DMD) is a devastating muscle-wasting disease that arises due to the loss of dystrophin expression, leading to progressive loss of motor and cardiorespiratory function. Four exon-skipping approaches using antisense phosphorodiamidate morpholino oligomers (PMOs) have been approved by the FDA to restore a open reading frame, resulting in expression of a functional but internally deleted dystrophin protein, but in patients with single-exon duplications, exon skipping has the potential to restore full-length dystrophin expression. Cell-penetrating peptide-conjugated PMOs (PPMOs) have demonstrated enhanced cellular uptake and more efficient dystrophin restoration than unconjugated PMOs.
View Article and Find Full Text PDFMol Ther Methods Clin Dev
September 2022
Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH 43205, USA.
Duchenne muscular dystrophy (DMD) is typically caused by mutations that disrupt the reading frame, but nonsense mutations in the 5' part of the gene induce utilization of an internal ribosomal entry site (IRES) in exon 5, driving expression of a highly functional N-truncated dystrophin. We have developed an AAV9 vector expressing U7 small nuclear RNAs targeting exon 2 and have tested it in a mouse containing a duplication of exon 2, in which skipping of both exon 2 copies induces IRES-driven expression, and skipping of one copy leads to wild-type dystrophin expression. One-time intravascular injection either at postnatal days 0-1 or at 2 months results in efficient exon skipping and dystrophin expression, and significant protection from functional and pathologic deficits.
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