TRANSLATIONAL PERSPECTIVES — TRANSIENT EPIGENETIC GENE THERAPY: HAZARD-FREE CELL REPROGRAMMING APPROACH AND RISING ARM OF A UNIVERSAL STEM CELL GENE THERAPY PLATFORM

Abstract

Random integration of retroviral transgenes is a major oncogenic hazard that hampers both current clinical gene therapy trials and the genesis of clinical-grade induced pluripotent stem (iPS) cells. Noticeably, we have devised a universal stem cell gene therapy platform aimed at eliminating random integration of therapeutic DNA, at reversing inherited diseases including mitochondrial (mt)DNA ones by reestablishing wild-type genomic homeostasis, and at tackling both inherited and acquired/aging disorders through long-term or transient gene therapy protocols culminating in synergistic combinations. Our platform has a transient epigenetic arm directed at long-term transcriptional inactivation/activation of endogenous genes through the transient action of promoter-specific siRNAs or sense/antisense oligonucleotides, thereby opening an attractive avenue for hazard-free reprogramming of therapeutic iPS cells. Therefore, in addition to its obvious original applications such as long-term transcriptional silencing of autosomal-dominant mutant alleles, the transient epigenetic gene therapy arm could initiate the clinical iPS cell era whereby epigenetic reprogramming of patient somatic cells will not only drive regenerative medicine sensu stricto but also the other arms of our universal stem cell gene therapy platform. Both product and drive of our platform, such hazard-free iPS cells and their derivatives should accommodate all kinds of protocols including 1) long-term gene therapy mediated by endonuclease-boosted gene targeting (gene repair/alteration or targeted transgene integration) or cybridization (mtDNA transfer), and 2) transient regenerative gene therapy aimed at synergizing both regenerative cell therapy sensu stricto and long-term/epigenetic gene therapy through the magnification of the homing/regenerative/differentiative potential of therapeutic stem cells. Our approach is thus discussed 1) in light of emerging concurrent transgene-free reprogramming protocols that rely on protein transduction, small molecules or unintegrating vectors and 2) in terms of somatic cell genetic-like breakthrough in which somatic cells can be safely reprogrammed ex vivo into patient-specific pluripotent stem cells, amplified, engineered through standard/personalized protocols, subjected to potential clonal selections and lineage commitments, and then returned to the patient, thereby driving effective therapeutic repopulative/regenerative dynamics into relevant niches (long-term engraftment) and tissues (basic and regenerative cell turn-over).