Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Stem Cells. Dec 26, 2015; 7(11): 1233-1250
Published online Dec 26, 2015. doi: 10.4252/wjsc.v7.i11.1233
Towards in vivo amplification: Overcoming hurdles in the use of hematopoietic stem cells in transplantation and gene therapy
Murtaza S Nagree, Lucía López-Vásquez, Jeffrey A Medin
Murtaza S Nagree, Department of Medical Biophysics, Faculty of Medicine, University of Toronto, Toronto, ON M5G 1L7, Canada
Lucía López-Vásquez, Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada
Jeffrey A Medin, University Health Network, Toronto, ON M5G 1L7, Canada
Author contributions: Nagree MS, López-Vásquez L and Medin JA wrote the manuscript.
Supported by Canadian Institutes of Health Research Grant to Medin JA, No. MOP-123528.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Jeffrey A Medin, PhD, University Health Network, 5R406 Max Bell Research Centre, 101 College Street, Toronto, ON M5G 1L7, Canada.
Telephone: +1-416-3404745
Received: August 8, 2015
Peer-review started: August 8, 2015
First decision: September 22, 2015
Revised: October 8, 2015
Accepted: November 23, 2015
Article in press: November 25, 2015
Published online: December 26, 2015

With the advent of safer and more efficient gene transfer methods, gene therapy has become a viable solution for many inherited and acquired disorders. Hematopoietic stem cells (HSCs) are a prime cell compartment for gene therapy aimed at correcting blood-based disorders, as well as those amenable to metabolic outcomes that can effect cross-correction. While some resounding clinical successes have recently been demonstrated, ample room remains to increase the therapeutic output from HSC-directed gene therapy. In vivo amplification of therapeutic cells is one avenue to achieve enhanced gene product delivery. To date, attempts have been made to provide HSCs with resistance to cytotoxic drugs, to include drug-inducible growth modules specific to HSCs, and to increase the engraftment potential of transduced HSCs. This review aims to summarize amplification strategies that have been developed and tested and to discuss their advantages along with barriers faced towards their clinical adaptation. In addition, next-generation strategies to circumvent current limitations of specific amplification schemas are discussed.

Keywords: Gene therapy, Hematopoietic stem cells, In vivo selection, Chemical Inducer of Dimerization, Chemo-selection, Lentivirus

Core tip: Though hematopoietic stem cell (HSC)-directed gene therapy is becoming a viable therapy for many disorders, optimization of clinical output needs improvement. One approach to circumvent lower efficiencies of gene transfer and/or engraftment is to apply in vivo amplification strategies. Here we review various modules that have been developed and tested to mediate amplification of HSCs after gene transfer.