Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we will assume that you are happy to receive all cookies and you will not see this message again. Click 'Find out more' for information on how to change your cookie settings.

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'O-methyl phosphorothioate AOs targeting either splice site of the detrimental HML 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. © 2011.

Original publication

DOI

10.1016/j.gene.2011.11.021

Type

Journal article

Journal

Gene

Publication Date

25/02/2012

Volume

494

Pages

231 - 236