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.
Department of Clinical Chemistry, Sahlgrenska University Hospital, SE-413 45 Göteborg, Sweden. gittan.kollberg@gu.se
Gittan
G
Kollberg
Elisabeth
E
Holme
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