Exp Hematol. 2016 Apr 19. pii: S0301-472X(16)30079-0. doi: 10.1016/j.exphem.2016.04.007. [Epub ahead of print]

Optimizing autologous cell grafts to improve stem cell gene therapy.

Psatha N¹, Karponi G², Yannaki E³.

Abstract

Over the past decade, stem cell gene therapy has achieved unprecedented curative outcomes for several genetic disorders. Despite the unequivocal success, clinical gene therapy still faces challenges. Genetically-engineered hematopoietic stem cells (HSCs) are particularly vulnerable to attenuation of their repopulating capacity once exposed to culture conditions, ultimately leading to low engraftment levels post-transplant. This becomes of particular importance when transduction rates are low or/and competitive transplant conditions are generated by a reduced intensity conditioning in the absence of a selective advantage of the transduced over the unmodified cells. These limitations could partially be overcome by introducing mega-doses of genetically-modified CD34+cells into conditioned patients or by transplanting HSCs with high engrafting and repopulating potential. In the present review, based on the lessons gained from the cord blood transplantation, we summarize the most promising approaches to date of increasing either the numbers of HSCs for transplantation or/and their engraftability, as a platform towards the optimization of engineered stem cell grafts.