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Gene therapy trials in the ovine model of McArdle's disease
Journal article   Peer reviewed

Gene therapy trials in the ovine model of McArdle's disease

J.Mc.C. Howell, G. Pari, S. Wilton, S. Fletcher, L. Davies, F. Lloyd, J. Nalbantoglu, T. Collins, S. Di Mauro, B. Kakulas, …
Brain Pathology, Vol.10(4), pp.544-544
2000
DOI: https://doi.org/10.1111/j.1750-3639.2000.tb00297.x
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Abstract

USA McArdle’s disease is an autosomal, recessive disease in which muscle glycogen phosphorylase is deficient. The disease has recently been found in sheep. This paper gives results of trials with a first generation adenoviral vector, expressing (a) human muscle phosphorylase gene with a Rous Sarcoma virus promoter (ADV myophos) or (b) Lac Z reporter gene with a cyto- megalovirus promoter (ADV Lac Z) injected into semi- tendinosus muscles of 12 affected lambs at sites with or without prior injection of notexin. Biopsies were taken 10, 30 and 60 days after ADV injection. Frozen sections were stained with H and E and for phosphorylase, b galactosidase and glycogen. Glycogen phosphorylase activity was assayed biochemically. Biopsies 10 days after ADV myophos alone showed an approximately 10 fold increase in average glycogen phosphorylase activity compared to levels from uninjected muscle. Similar results were seen at 30 days with a slight decrease at 60 days. Combining notexin and ADV myophos resulted in 40 times the average glycogen phosphorylase activity compared to uninjected muscle at 10 days, but results at 30 and 60 days were similar to those obtained for ADV myophos alone. When either notexin or ADV LacZ only was injected average glycogen phosphorylase activity was comparable to that from ADV myophos only sites. Glycogen phosphorylase activity doubled when notexin and ADV LacZ were injected compared with ADV LacZ only. In frozen sections b galactosidase expression was similar irrespective of whether ADV LacZ was injected alone or with notexin, with 90% of muscle blocks strongly positive. The expression of b galactosidase activity was greater than that of phosphorylase. This may be due to the different promoters used. Phosphorylase was not seen in the uninjected muscle but was seen at sites injected with notexin only. This may be upregulation of the ovine form rather than expression of the human form. These aspects are currently being investigated.

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