Emerging gene therapies for retinal degenerations.

Introduction Our most cherished sense, vision, begins with the process of phototransduction, a process performed by the highly specialized photoreceptor cells of the retina: the rods and cones (Rodieck, 1998). Rod photoreceptor cells are needed for night vision, as they are able to respond to very few photons, while cones are active under bright light conditions and are responsible for color vision. Many people are born with impaired vision, and many others experience loss of vision later in life. For example, age-related macular degeneration (AMD) occurs in 5% of people 80 years old in the U.S. (Rudnicka et al., 2012), while mutations in 200 genes can lead to loss of vision in younger individuals (RetNet; www.sph.uth.tmc.edu/Retnet). This review is focused on emerging strategies that employ gene therapy to combat vision loss, primarily due to mutations that affect photoreceptor cells. Exciting early results from the use of Adeno-associated virus (AAV) vectors in humans to combat Leber’s congenital amaurosis (LCA) (Bainbridge et al., 2008; Maguire et al., 2008), a relatively rare form of congenital blindness, has inspired several groups to employ AAV in a number of ways to combat other genetic diseases. Here, the efforts aimed toward one particular disease, retinitis pigmentosa (RP) (Hartong et al., 2006), will be covered, as there are excellent animal models (Rivas and Vecino, 2009; Fletcher et al., 2011) and it offers some straightforward possibilities to save photoreceptor function and/or photoreceptor cells themselves. Ironically, one of the possibilities is to use optogenetics, rather than gene replacement or knock-down, for restoration of vision (Busskamp and Roska, 2011). It is hoped that we can apply the lessons learned from RP to other diseases that also result in loss of photoreceptor cells, including AMD. Individuals with RP are typically born night-blind, due to rod dysfunction, but initially have full-field, high-acuity color vision. This is in keeping with the expression of many RP disease genes only in rods (www.sph.uth.tmc.edu/Retnet). For reasons that are still unclear (see Overview of therapeutic approaches to RP, below), loss of color vision then follows, and can occur as early as 5 years of age, or much later, in the fifth or sixth decade of life (Hartong et al., 2006; Berson, 2008). The progression of cone dysfunction and death eventually leads to total loss of vision, with the final loss in the center, due to loss of macular vision. The macula comprises only cones in its very center, and is the area of our highest acuity color vision. Invasion of retinal pigmented epithelial cells into the retina leads to the occurrence of black clumps within the retina, and hence the name of the disease. Attenuated retinal blood vessels and optic disc pallor are other hallmarks of the disease (Milam et al., 1998; Berson, 2008). There is no cure for RP, but there are several lines of therapeutic approaches that hold promise, including gene therapy.