Approximately one half of blind people suffer from untreatable conditions. These are degenerations of the nervous part of the eye, especially the retina, which generates electrical current from light stimulation and the optic nerve, which transmits the current to the brain where the image is interpreted. Retinal and optic nerve degenerations are at the frontiers of medicine. Indeed, neuron replacement still remains a challenge and it is impossible to re-connect a severed optic nerve, which prevents the graft of an eye. These very severe conditions lead to visual loss, generally in a progressive manner but sometimes already from birth, and in most cases are irreversible. We therefore need to design and validate new treatments, which will prevent the progression of the disease towards vision loss. One also must try to repair lesions to restore vision.
Most monogenic forms of inherited retinopathies are associated with genes expressed in photoreceptors (PR) or retinal pigment epithelium (RPE) where they encode proteins that are critical for PR structure, function and survival. Specific cellular processes and biochemical pathways implicated in retinal dystrophies include: PR development, morphogenesis, phototransduction, visual cycle, cellular metabolism, protein folding, among others.
The vision and survival of rod and cone require continuous renewal of the visual chromophore, the 11-cis retinal, which forms together with the opsin proteins, the rhodopsin and cone visual pigments.
Inherited retinal pathologies include dystrophies of the retina and the optic nerve.
Hereditary retinal dystrophies are neurodegenerations of the retina with a prevalence of 1/3000 in industrialized countries. These are progressive Mendelian genetic diseases that cause dysfunction and cell death, including photoreceptors and retinal pigment epithelial cells. The progressive degeneration of photoreceptor cells causes the accumulation of intra-retinal pigment deposits, generally located in the retinal periphery, thus constituting the majority subgroup of retinitis pigmentosa (RP). Less common, lesions of various appearance affect the macula, the central region of the retina, represent the subgroup of macular dystrophies (MD) including Stargard disease and Best disease. Hereditary optic neuropathies (prevalence 1/20 000 to 1/30 000) are also important causes of blindness, characterized by the degeneration of retinal ganglion cells (RGCs), and their axons transducing visual information from the retina to the brain.
Inherited retinal dystrophies and hereditary optic neuropathies gradually lead to a more or less complete blindness without any current therapeutic possibility.
The retina is particularly amenable to gene therapy because it is accessible via relatively non-invasive routes, it is small and enclosed allowing the use of small vector doses, and it is immuno-privileged due to sequestration from the systemic circulation by the blood-retina barrier. Moreover, inherited retinal dystrophies (IRDs) are favourable candidates for gene therapy because they are often monogenic, have characteristic clinical signs allowing an early diagnosis, and progress slowly to blindness allowing a large therapeutic window.