Antisense oligonucleotide corrects splice abnormality in hereditary myopathy with lactic acidosis

作者：Sanaker Petter Schandl; Toompuu Marina; McClorey Graham; Bindoff Laurence A^*

来源：Gene, 2012, 494(2): 231-236.

DOI：10.1016/j.gene.2011.11.021

• Metabolic myopathy
• Intronic mutation
• Cryptic exon
• Antisense oligonucleotide
• Intronic splicing silencer

Hereditary myopathy with lactic acidosis (HML) (OMIM #255125) presents in childhood with exercise intolerance and muscle pain on trivial exercise, lactic acidosis, dyspnoea, palpitations, and rhabdomyolysis which can be fatal. The disease is recessively inherited and caused by a deep intronic, single base transition in the iron-sulfur cluster scaffold, ISCU gene that causes retention of a pseudoexon and introduction of a premature termination codon. IscU protein deficiency causes secondary defects in several iron-sulfur dependant proteins, including enzymes involved in aerobic energy metabolism. We have shown in a previous study that the splice abnormality affects skeletal muscle more than other tissues, leading to the purely muscular phenotype. Antisense oligonucleotides (AOs) have been able to redirect mRNA splicing in a number of disease models, and show promise in clinical studies. We designed 2%26apos;O-methyl phosphorothioate AOs targeting either splice site of the detrimental HMI. pseudoexon. The acceptor site AO effectively redirected splicing towards the normal state in cultured muscle fibroblasts, whilst the donor site AO promoted pseudoexon inclusion in both patient and control cells. Our results show that AO therapy seems feasible in HML, but care must be taken to avoid adverse splicing effects.

• 出版日期2012-2-25