Gene therapy for growth hormone deficiency mediated by minicircle DNA electrotransfer in dwarf mice

Abstract

Gene therapy is a promising treatment modality for inherited and acquired diseases by delivering genes into the target cells to restore or promote specific cellular functions. In spite of the gene therapy potency, the utility of this strategy is defined by the balance between safety and effectiveness. While virus-derived vectors have a high efficiency in the DNA deliver in comparison with the non-viral vectors, their use is limited because the undesirable immune responses to viral capsid proteins, regeneration of virulent viruses and others. In contrast, non-viral vectors are safer and easy to produce on a large scale. However, the duration of the protein expression using the non-viral vectors is transient, during only a few days, followed by a period of prolonged low level expression. The low level protein expression can be due to the difficulty of the exogenous DNA to transfer across the cell membrane up to the nucleus. A new generation of DNA vectors, called minicircle (MC), has reduced size due to the lack of the bacterial backbone sequence and is potentially safer than the plasmids currently used in gene therapy. Minicircle combined to physical methods, like electrotransfer, provides higher gene transfer efficiency compared with conventional non-viral vectors. MC constitutes a promising alternative to plasmid DNA for non-viral gene therapy in terms of biosafety, improved gene transfer and potential bioavailability, due to their minimal size. In this work we intend to construct minicircle plasmids expressing the human (hGH) or the mouse (mGH) growth hormone in order to electrotransfer them into dwarf mice and study this non-viral gene therapy approach for GH deficiency. (AU)