Gene Vector Integration Profiling in Eye and Brain

Nerve cells, or neurons, and the sensory cells of the eye, located in the retina, represent preferred targets for therapeutic gene delivery. Neurons and retinal cells are very enduring and stably integrated into the complex cellular networks that enable the sensory, cognitive and effector functions of the nervous system. The low tissue turnover implies that the cells mostly do not undergo division (mitosis) and, thus, maintain a membrane around their nuclei that represents a major hurdle to gene delivery.

Lentiviruses are complex retroviruses which have evolved with the ability to transfer their genomes into the nucleus of non-dividing cells. Furthermore, lentiviral gene vectors are most efficient in pasting the therapeutic sequences into the cellular chromosomes, which are long strands of DNA containing the cellular genes arranged like beads on a string. However, the exact position at which the therapeutic sequences are introduced into the chromosomes cannot be predicted, as the integration process is untargeted. To prevent the random activation of genes controlling cell growth by this type of untargeted transgene insertion, it is important to understand the mechanisms of gene vector integration.

In the April 2011 issue of Molecular Therapy, Dr. Cynthia Bartholomae and colleagues report that the spectrum of integration events in eye and brain cells is different from that observed in the more frequently investigated blood-forming cells. Their careful analysis reveals that a cellular factor, known to be associated with the lentiviral integration machinery, is present at low levels in eye and brain cells, thus, providing a potential explanation for their data. The relatively neutral integration spectrum and the low cell turnover in these tissues suggest that carcinogenic side effects of therapeutic gene transfer might be rare.