ABSTRACT
CNRS, Molecular Genetics, Department o f Hepato-Gastroenterology, Faculty o f Medicine, University o f Nice Sophia Antipolis, 06107 Nice, France
Table of Contents 1. From transient angiogenic gene therapy to regenerative stem cell/gene therapy 2. Safety and promises of transient angiogenic/vasculogenic gene therapy
a) Unintegrating gene vectors and safe therapeutic transient topical gene therapy b) From single angiogenic growth factors to pleiotropic factors and synergistic
combinations 3. From vasculogenic to regenerative stem cell therapy for cardiovascular disease
a) Vasculogenic angioblasts/EPCs and regenerative multipotent stem cells b) Pioneering clinical trials: topical transplantation of autologous bone marrow
cells and EPCs c) Toward multipotent/pluripotent stem cell therapy and co-delivery strategies
4. Stem cell gene therapy: toward therapeutic myocardium regeneration a) Transient ex vivo gene therapy as a stem cell amplification process b) Transient topical gene therapy as a booster for stem cell homing/regenerative
efficiency c) Regenerative stem cell gene therapy: synergistic combinations aimed at
myocardium regeneration
5. References 6. Summary
* E-mail: Roger.Bertolotti@unice.fr
1. FROM TRANSIENT ANGIOGENIC GENE THERAPY TO REGENERATIVE STEM CELL/GENE THERAPY
As shown in the previous chapters, pioneering angiogenic clinical trials of Isner and co-workers mediated by vascular endothelial growth factor (VEGF) minigene transfer (Isner et al., 1996; Baumgartner et al., 1998; Isner et al., 1998; Losordo et al., 1998; Symes et al., 1999) have been instrumental both in the establishment of gene therapy as an effective medical practice (see also Bertolotti, 2002a and 2002b) and in the emergence of transient transgene expression as a gene therapy breakthrough (Bertolotti, 1998 and 2000). In addition, these pioneering trials drove Isner and co workers 1) to the identification of circulating endothelial progenitor cells (EPCs) in peripheral blood and to the demonstration that neovascularization in adult ischemic tissue is not restricted to angiogenesis (sprouting of endothelial cells from preexisting vessels; Folkman, 1971) but also involves vasculogenesis (Asahara et al., 1997) where mobilization of bone marrow EPCs (Takahashi et al., 1999; Asahara et al., 1999a) is increased by VEGF gene therapy (Asahara et al., 1999b; Kalka et al., 2000a and 2000c) culminating in therapeutic EPC homing in the ischemic tissues (Asahara et al., 1997 and 1999b; Kalka et al., 2000a and 2000c), 2) to the subsequent development of vasculogenic stem cell therapy (Kalka et al., 2000b; Kawamoto et al., 2001), and 3) to the combination of both pioneering approaches where therapeutic homing and expansion/differentiation capabilities of EPCs are associated to transient ex vivo gene therapy (Iwaguro et al., 2002). Such a stem cell gene therapy approach dramatically increases the efficiency of experimental therapeutic angio/vasculogenesis (Iwaguro et al., 2002), thereby paving the way to effective myocardium regeneration (see Bertolotti, 2002a and 2002b). Importantly enough, in conjunction with the use of multipotent/pluripotent stem cells, stem cell gene therapy is expected to be a breakthrough both for tantalizing regenerative medicine and basic therapy for inherited disease (Bertolotti, 2001 and Introduction chapter).
