Antisense oligonucleotide therapeutics for iron-sulphur cluster deficiency myopathy.
Iron-sulphur cluster deficiency myopathy is caused by a deep intronic mutation in ISCU resulting in inclusion of a cryptic exon in the mature mRNA. ISCU encodes the iron-sulphur cluster assembly protein IscU. Iron-sulphur clusters are essential for most basic redox transformations including the respiratory-chain function. Most patients are homozygous for the mutation with a phenotype characterized by a non-progressive myopathy with childhood onset of early fatigue, dyspnoea and palpitation on trivial exercise. A more severe phenotype with early onset of a slowly progressive severe muscle weakness, severe exercise intolerance and cardiomyopathy is caused by a missense mutation in compound with the intronic mutation. Treatment of cultured fibroblasts derived from three homozygous patients with an antisense phosphorodiamidate morpholino oligonucleotide for 48 h resulted in 100% restoration of the normal splicing pattern. The restoration was stable and after 21 days the correctly spliced mRNA still was the dominating RNA species.
Kollberg
Gittan
G
Department of Clinical Chemistry, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. gittan.kollberg@gu.se
Holme
Elisabeth
E
D001483:Base Sequence; D002478:Cells, Cultured; D005347:Fibroblasts / Q000502:physiology; D006801:Humans; D007506:Iron-Sulfur Proteins / Q000172:deficiency* / Q000235:genetics*; D008969:Molecular Sequence Data; D009025:Morpholines / Q000627:therapeutic use; D060172:Morpholinos; D009135:Muscular Diseases / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy*; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000627:therapeutic use*; D012326:RNA Splicing / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D012867:Skin / Q000166:cytology; D013997:Time Factors
C506160:ISCU protein, human; D007506:Iron-Sulfur Proteins; D009025:Morpholines; D060172:Morpholinos; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger