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.
1.1. Retinal dystrophies and the visual cycle in the retinal pigment epithelium
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, photo transduction, visual cycle, cellular metabolism, protein folding, among others.
1.2. Inherited Optic Neuropathies and Mitochondrial Disorders
The non-syndromic hereditary optic neuropathies, including primarily the Dominant Optic Atrophy (DOA, prevalence 1/20 000) and the Leber Hereditary Optic Neuropathy (LHON, prevalence 1/30 000) are leading causes of hereditary blindness in Western countries. They are characterized by a degenerative process of the retinal ganglion cells (RGCs), with consequently a loss of the optic nerve fibers leading to the impairment of the visual transduction from the retina to the brain. Today, there is no treatment to prevent the progress of the degenerative process.
1.3. Genetics of retinitis pigmentosa
Inherited retinal dystrophies, prevalence 1/3000 in developed countries, belong to the vast group of neurodegenerations. They are Mendelian genetic conditions leading to the dysfunction and cell death of various retinal cell types, thus causing a loss in vision. Most of these diseases are due to death of photoreceptors and of their supporting tissue, the retinal pigment epithelium. When the initial lesions are located in the peripheral regions of the retina, they are defined as pigmentary retinopathies, including the retinitis pigmentosa (RP); when they are located in the central macula, they are named macular dystrophies (MD), including Stargardt disease and Best disease.
1.4. Gene therapy of retinal dystrophies
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, retinal dystrophies 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. However, there are a growing number of retinal diseases that lack an appropriate animal model, which compromises their chances of one day reaching the stage of a clinical therapeutic trial.