Retroviral integration and human gene therapy

Abstract

Long-term correction of genetic diseases requires permanent integration of therapeutic genes into chromosomes of affected cells. Retroviral vectors are the most widely used delivery vehicles because of their efficiency and precision of integration. However, retroviral integration can take place at a variety of chromosomal sites, and examples have been reported of integration of therapeutic vectors activating oncogenes and causing cancer in patients. This issue of the JCI presents three articles that update successful human gene therapy trials and furthermore evaluate the sites of integration in cells from treated patients, including samples from individuals experiencing serious adverse events following therapy (see the related articles beginning on pages 2225, 2233, and 2241).

Figure 1. Gene correction using retroviral vectors, and monitoring the placement of integration sites after evolution in patients.

A population of cells is removed from the patient (i) and transduced ex vivo with a retroviral vector carrying the corrected gene (ii–iii). The gene-corrected cells are subsequently reinfused into the patient (iv). The population of vector integration sites is diverse prior to transplantation, with each cell harboring integrated proviral copies at different locations in the genome. Examination years later of the population of gene-corrected cells reveals that the population of provirus has changed because of evolution of cells in vivo (v). In some cases this can include proliferation of cells where integrated proviruses activated oncogenes, leading to an adverse event.