RPE and Gene Therapy

The RPE represents one of the two major cell types in the retina that have been targeted by gene therapy, next to the photoreceptors. Following subretinal delivery, viral vectors, such as adeno-associated virus (AAV), lentivirus or adenovirus based vectors, or nanoparticles deliver genetic material into this cell type, allowing robust and long term transgene expression as the basis for the gene addition therapy approach. Due to this characteristic of the RPE cell layer, several RPE based inherited retinal dystrophies, such as RPE65 or MERTK deficiency and choroideremia, have been addressed by gene therapeutic approaches that have reached clinical stage with more than 100 patients treated cumulatively around the world. Usually, RPE defects result in loss of photoreceptor function, and the clinical benefit is mainly measured at the photoreceptor level, with varying degree of improvement. Treatment approaches for other disorders are at the preclinical level, including gene addition as well as the newly developed genome editing approach, which relies on the cell’s own capacity to repair an artificially induced DNA double strand break near the target site. Gene therapeutic approaches have also been developed for age-related acquired retinal disorders, in which the disease-causing factors that are often associated with neovascular changes to the retina or chronic stimulation of the immune system, are targeted either by gene addition or genome editing.