Gene and cell therapy for prion diseases.

Prion diseases are neurodegenerative disorders characterized by the accumulation of an abnormal prion protein named PrP(Sc). PrP(Sc) results from the post-translational conformational modification of the host-encoded protein PrP(C). To date there is no treatment for this inexorably fatal disease. Hence, a major focus of research consists in the identification of new molecules that could interfere with in vivo prion propagation. Promising therapeutic approaches to block the production of PrP(Sc) are based on PrP RNA interference, passive or active immunization, dominant negative inhibition of PrP(Sc) formation, as well as inhibition of interactions between PrP(Sc) and other cofactors. Although these anti-prion molecules can be directly administered in vivo, the process to produce and purify them in high quantity is often challenging and expensive. An alternative strategy consists in the development of gene therapy systems of delivery. Importantly, the diagnosis of prion disease in humans remains difficult and often leaves a short therapeutic window after the appearance of the first clinical signs. As serious damages to the brain generally occur before clinical symptoms manifest, an ideal therapeutic strategy must target not only the formation of toxic aggregates, but also the brain destruction already incurred. This could be achieved by combining gene therapy with cell therapy. In this review we have chosen to highlight the multiple targets and potential gene or cell replacement therapeutic approaches. This review also presents the evidence for the transplantation of stem cells as well as the combination of cell and gene therapy as promising strategies against prion diseases.