Stem cell gene therapy the risks of insertional m

Authors: Chuanfeng Wu Cynthia E Dunbar

Publish Date: 2011/12/27

Volume: 5, Issue: 4, Pages: 356-371

PDF Link

Abstract

Virusbased vectors are widely used in hematopoietic stem cell HSC gene therapy and have the ability to integrate permanently into genomic DNA thus driving longterm expression of corrective genes in all hematopoietic lineages To date HSC gene therapy has been successfully employed in the clinic for improving clinical outcomes in small numbers of patients with Xlinked severe combined immunodeficiency SCIDX1 adenosine deaminase deficiency ADASCID adrenoleukodystrophy ALD thalassemia chronic granulomatous disease CGD and WiskottAldrich syndrome WAS However adverse events were observed during some of these HSC gene therapy clinical trials linked to insertional activation of protooncogenes by integrated proviral vectors leading to clonal expansion and eventual development of leukemia Numerous studies have been performed to understand the molecular basis of vectormediated genotoxicity with the aim of developing safer vectors and lowerrisk gene therapy protocols This review will summarize current information on the mechanisms of insertional mutagenesis in hematopoietic stem and progenitor cells due to integrating gene transfer vectors discuss the available assays for predicting genotoxicity and mapping vector integration sites and introduce newlydeveloped approaches for minimizing genotoxicity as a way to further move HSC gene therapy forward into broader clinical application

Keywords: