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. Stem cells and life-long therapeutic gene expression paradigm
a) Stem cell gene therapy for X-SCID patients: a paradigm trial b) Selective growth of gene-corrected cells: ADA-SCID case c) Potential universality of life-long stem cell gene therapy d) Random-insertional carcinogenesis as a booster for site-specific integration and
gene repair technologies 2. Stem cells as targets of transient gene therapy
a) Therapeutic angio/vasculogenesis as a transient gene therapy breakthrough and a key clinical step for regenerative gene therapy
b) Bone marrow(BM)-derived endothelial progenitor cells (EPCs) as key targets of therapeutic angio/vasculogenesis
c) Transient topical gene therapy as a basic tool for regenerative medicine 3. Autologous stem cell therapy as a breakthrough in cardiovascular regenerative medicine
a) Therapeutic homing of EPCs as the key to vasculogenic stem cell therapy b) Bone marrow multipotent stem cells for myocardium regeneration c) Pioneering stem cell therapy clinical trials for cardiovascular ischemia d) Peripheral blood as an attractive source for autologous stem cells
4. Stem cell gene therapy: combining ex vivo protocols with transient in vivo topical gene therapy
a) Amplification of the proliferative/regenerative potential of stem cells by transient or regulated ex vivo gene therapy
b) Transient topical gene therapy as a booster for the therapeutic homing/ regenerative potential of transplanted stem cells
* E-mail: Roger.Bertolotti@unice.fr
c) Combining ex vivo protocols with transient topical gene therapy 5. Conclusion: therapeutic stem cell homing and stem cell gene therapy 6. References 7. Summary
a) Stem cell gene therapy for X-SCID patients: a paradigm trial The first unequivocal success for gene therapy was reported in April
2000 (Cavazzana-Calvo et al,, 2000) for patients with X-linked severe combined immunodeficiency (X-SCID). This gene therapy trial for an inherited disease stands as the very paradigm of life-long therapeutic gene expression mediated by targeted autologous stem cells. Indeed, engrafment and selective repopulating ability of ex vivo gene-corrected hematopoietic stem cells (HSCs) have been instrumental in the success of this seminal clinical trial where efficient retroviral transduction of bone marrow HSCs is synergized by the homing ability of these transduced stem cells and the selective growth advantage of their lymphoid progenitor derivatives over mutant X-SCID cognates (Fig. 1). The self-renewing and differentiative capability of these stem cell targets provides thus for long-term transgenic lymphoid cell replacement (Hacein-Bey-Abina et al,, 2002; Fischer et al,, 2002) and is thus expected to result in life-long cure for this inherited disease.
