title: Use of antisense oligonucleotides to correct the splicing error in ISCU myopathy patient cell lines.
abstract: ISCU myopathy is an inherited disease that primarily affects individuals of northern Swedish descent who share a single point mutation in the fourth intron of the ISCU gene. The current study shows correction of specific phenotypes associated with disease following treatment with an antisense oligonucleotide (ASO) targeted to the site of the mutation. We have shown that ASO treatment diminished aberrant splicing and increased ISCU protein levels in both patient fibroblasts and patient myotubes in a concentration dependent fashion. Upon ASO treatment, levels of SDHB in patient myotubular cell lines increased to levels observed in control myotubular cell lines. Additionally, we have shown that both patient fibroblast and myotubular cell lines displayed an increase in complex II activity with a concomitant decrease in succinate levels in patient myotubular cell lines after ASO treatment. Mitochondrial and cytosolic aconitase activities increased significantly following ASO treatment in patient myotubes. The current study suggests that ASO treatment may serve as a viable approach to correcting ISCU myopathy in patients.
authors.affiliation: Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Holmes-Hampton
authors.affiliation: Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Crooks
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA, Neuromuscular Center, Institute for Exercise and Environmental Medicine, Texas Health Presbyterian Hospital Dallas, Dallas, TX 75231, USA.
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Haller
authors.affiliation: Department of Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Shuling
authors.initials: S
authors.lastname: Guo
authors.affiliation: Department of Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Freier
authors.affiliation: Department of Antisense Drug Discovery, Ionis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Brett P
authors.initials: BP
authors.lastname: Monia
authors.affiliation: Molecular Medicine Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA.
authors.forename: Tracey A
authors.initials: TA
authors.lastname: Rouault
mesh_terms: D000140:Acidosis, Lactic / Q000151:congenital* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D005260:Female; D006801:Humans; D007438:Introns / Q000235:genetics; D007506:Iron-Sulfur Proteins / Q000235:genetics*; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology; D009135:Muscular Diseases / Q000151:congenital* / Q000235:genetics / Q000473:pathology / Q000628:therapy; D016376:Oligonucleotides, Antisense / Q000235:genetics* / Q000627:therapeutic use; D010641:Phenotype; D017354:Point Mutation; D012326:RNA Splicing / Q000187:drug effects / Q000235:genetics; D013385:Succinate Dehydrogenase / Q000096:biosynthesis / Q000235:genetics*
chemical_list: C506160:ISCU protein, human; D007506:Iron-Sulfur Proteins; D016376:Oligonucleotides, Antisense; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase