Tia J. Kowal

Recent advances in optogenetics hold promise for vision restoration in degenerative eye diseases. Optogenetics refers to techniques that use light to control the cellular activity of targeted cells. Although optogenetics is a relatively new technology, multiple therapeutic options are already being explored in pre-clinical and phase I/II clinical trials with the aim of developing novel, safe, and effective treatments for major blinding eye diseases, such as glaucoma and retinitis pigmentosa. Optogenetic approaches to visual restoration are primarily aimed at replacing lost or dysfunctional photoreceptors by inserting light-sensitive proteins into downstream retinal neurons that have no intrinsic light sensitivity. Such approaches are attractive because they are agnostic to the genetic causes of retinal degeneration, which raises hopes that all forms of retinal dystrophic and degenerative diseases could become treatable. Optogenetic strategies can also have a far-reaching impact on translational research by serving as important tools to study the pathogenesis of retinal degeneration and to identify clinically relevant therapeutic targets. For example, the CRY-CIBN optogenetic system has been recently applied to animal models of glaucoma, suggesting a potential role of OCRL in the regulation of intraocular pressure in trabecular meshwork. As optogenetic strategies are being intensely investigated, it appears crucial to consider the opportunities and challenges such therapies may offer. Here, we review the more recent promising optogenetic molecules, vectors, and applications of optogenetics for the treatment of retinal degeneration and glaucoma. We also summarize the preliminary results of ongoing clinical trials for visual restoration.

Joubert syndrome is a group of rare disorders that stem from defects in a sensory organelle, the primary cilia. Affected patients often present with disorders involving multiple organ systems, including the brain, eyes, and kidneys. Common symptoms include breathing abnormalities, mental developmental delays, loss of voluntary muscle coordination, and abnormal eye movements, with a diagnostic “molar tooth” sign observed by magnetic resonance imaging (MRI) of the midbrain. We reviewed the ocular phenotypes that can be found in patients with Joubert syndrome. Ocular motor apraxia is the most frequent (80% of patients), followed by strabismus (74%) and nystagmus (72%). A minority of patients also present with ptosis (43%), chorioretinal coloboma (30%), and optic nerve atrophy (22%). Although mutations in 34 genes have been found to be associated with Joubert syndrome, retinal degeneration has been reported in only 38% of patients. Mutations in AHI1 and CEP290, genes critical to primary cilia function, have been linked to retinal degeneration. In conclusion, Joubert syndrome is a rare pleiotropic group of disorders with variable ocular presentations.