Careful adjustment of Epo non-viral gene therapy for β-thalassemic anaemia treatment

Emmanuelle E Fabre¹^,2^,3^,4 , Pascal Bigey¹^,2^,3^,4 , Yves Beuzard⁵ , Daniel Scherman¹^,2^,3^,4 and Emmanuel Payen⁵

¹Unité de Pharmacologie Chimique et Génétique, INSERM U640, Faculté de Pharmacie, 4 avenue de l'observatoire, 75006 Paris, France

²Unité de Pharmacologie Chimique et Génétique, CNRS UMR 8151, Faculté de Pharmacie, 4 avenue de l'observatoire, 75006 Paris, France

³Unité de Pharmacologie Chimique et Génétique, Université Paris Descartes, Faculté de Pharmacie, 4 avenue de l'observatoire, 75006 Paris, France

⁴Unité de Pharmacologie Chimique et Génétique, Ecole Nationale Supérieure de Chimie de Paris, 11 rue Pierre et Marie Curie, 75005 Paris, France

⁵Laboratoire de Thérapie Génique Hématopoïétique, Institut d'Hématologie (IUH), INSERM U733, Hôpital Saint-Louis, 75011 Paris, France

author email corresponding author email

Genetic Vaccines and Therapy 2008, 6:10doi:10.1186/1479-0556-6-10


Published:	11 March 2008

Abstract

Background

In 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.

Methods

Muscular 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.

Results

Muscular 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.

Conclusion

This 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.