Abstract
BackgroundIn situ production of a secreted therapeutic protein is one of the major gene therapy applications. Nevertheless, the plasmatic secretion peak of transgenic protein may be deleterious in many gene therapy applications including Epo gene therapy. Epo gene transfer appears to be a promising alternative to recombinant Epo therapy for severe anaemia treatment despite polycythemia was reached in many previous studies. Therefore, an accurate level of transgene expression is required for Epo application safety. The aim of this study was to adapt posology and administration schedule of a chosen therapeutic gene to avoid this potentially toxic plasmatic peak and maintain treatment efficiency. The therapeutic potential of repeated muscular electrotransfer of light Epo-plasmid doses was evaluated for anaemia treatment in β-thalassemic mice.MethodsMuscular electrotransfer of 1 μg, 1.5 μg, 2 μg 4 μg or 6 μg of Epo-plasmid was performed in β-thalassemic mice. Electrotransfer was repeated first after 3.5 or 5 weeks first as a initiating dose and then according to hematocrit evolution.ResultsMuscular electrotransfer of the 1.5 μg Epo-plasmid dose repeated first after 5 weeks and then every 3 months was sufficient to restore a subnormal hematrocrit in β-thalassemic mice for more than 9 months.ConclusionThis strategy led to efficient, long-lasting and non-toxic treatment of β-thalassemic mouse anaemia avoiding the deleterious initial hematocrit peak and maintaining a normal hematocrit with small fluctuation amplitude. This repeat delivery protocol of light doses of therapeutic gene could be applied to a wide variety of candidate genes as it leads to therapeutic effect reiterations and increases safety by allowing careful therapeutic adjustments.
Highlights
In situ production of a secreted therapeutic protein is one of the major gene therapy applications
Erythropoietin (Epo) gene transfer appears to be a promising alternative for severe anaemia treatment since it requires less frequent treatment repeat and may allow sustained Epo secretion and constant patient coverage
Epo gene transfer has already been tested on normal animals and on anaemia animal models such as β-thalassemia and chronic renal failure models
Summary
In situ production of a secreted therapeutic protein is one of the major gene therapy applications. Epo gene transfer has already been tested on normal animals and on anaemia animal models such as β-thalassemia and chronic renal failure models To this end, various gene transfer strategies have been used such as ex-vivo strategies using engrafted transduced myoblasts or other cell types [2,3,4], viral strategies using adenovirus [5] adeno-associated virus [6,7], helper-dependent adenovirus [8], or nonviral strategies using naked DNA injection [9], poloxamer/ DNA formulations [10] or naked DNA injection associated to electrotransfer [9,11,12,13]. In the particular case of Epo, an accurate level of transgene expression is required for safety reasons
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