Investigative Ophthalmology & Visual Science | 2019
Leber Congenital Amaurosis (LCA): Potential for Improvement of Vision
Abstract
Leber congenital amaurosis (LCA) is a group of monogenic inherited retinal degenerations that typically show early onset and severe visual dysfunction. In addition, there is a natural history of progressive loss of photoreceptors and associated further loss of vision. The therapeutic goal of slowing the natural history of degenerative disease has a long history of effort and deserves our attention, but it is imperative to have realistic timelines and careful protocols that define how efficacy will be measured over many years. The therapeutic goal of improving vision is easier to detect over a shorter period of observation. However, modern techniques of noninvasive examination in LCA have demonstrated that only a subset of patients can be predicted to have potential for improvement of vision, given safe and effective therapies. Discussed herein are two LCA subtypes, the ciliopathy of CEP290-LCA and the phototransduction defect of GUCY2D-LCA, that show a common potential for improvement of vision despite differences in molecular mechanism. Mutations in several hundred genes are now known to cause inherited retinal diseases (IRDs). IRDs represent a highly heterogeneous group of disorders that have one common element: abnormal visual function originating at the level of retinal photoreceptors. A subset of IRDs comprises syndromic diseases, whereas the majority are nonsyndromic and affect only the retina even when the gene is expressed ubiquitously. The source of photoreceptor dysfunction can be due to maldevelopment of cells, a defect in the neighboring retinal pigment epithelium (RPE) cells, progressive loss of cells to neurodegeneration, a variety of other pathophysiological mechanisms, or a combination thereof. Until a decade ago, IRDs were treated mainly with nutrient supplements aimed to slow the disease. Then, converging information from molecular and retinal biology, animal models, human phenotyping, and therapeutic tools reached a critical mass, and led to the first successful proof of concept of a gene-based treatment of an IRD caused by RPE65 mutations. Extensive research followed to describe the extent and the source of improvement of visual function, durability of the treatment, and the effects on the rate of photoreceptor degeneration. Recent approval of this gene therapy approach for marketing in the United States and Europe has generated greater interest in the development of treatments for other IRDs. There is no one-size-fits-all approach to gene-based treatments for IRDs. Therapeutic directions for different IRDs need to be aligned with the underlying molecular pathophysiology, with the tools available for their delivery, and with consideration of the recipient retinal cells expected to be retained at the time of the intervention. For example, larger genes cannot be packaged into some viral vectors, or rod photoreceptor-based treatments would not be appropriate for adult patients with Class A rhodopsin mutations who have only cones remaining. Outcome measures also need to be optimized to the expected magnitude and timing of the efficacy signal. For example, evidence for successful slowing of disease progression may take years to detect but improvements in vision may occur in days to weeks. Among the more severe IRDs are those clinically classified as LCA. LCA manifests vision loss that usually occurs congenitally or in early infancy. There is nystagmus (involuntary eye movements), and a deceptively benign fundus appearance at early stages, but the disease expression tends to be indistinguishable from that of other IRDs at later stages. Abnormal electroretinograms localize the vision defect to the outer retina, at the photoreceptors. The attraction of some forms of LCA as a target for therapy rests not only in the severity of the vision loss but also in the key fact that improvement of visual function is potentially achievable because there is evidence of dissociation of function and structure. The first form of LCA with sufficient proof of concept research, understanding of molecular mechanism, and detailed pretreatment human disease characterization indicating structural preservation but severe functional losses was the RPE disease with a defective retinoid cycle: RPE65LCA. The improved vision in RPE65-LCA patients post therapy in three clinical trials conducted independently but almost simultaneously, is in contrast to the results in another RPE-based severe and early-onset IRD caused by mutations in MERTK. Despite longstanding rodent proof of concept research and understanding of mechanism, there was limited characterization of the human disease and no published demonstration of structure–function dissociation. A clinical trial protocol mimicking that of the RPE65-LCA trials in MERTK patients failed to achieve the efficacy results of RPE65-LCA. Two photoreceptor diseases within the clinical category of LCA, CEP290-LCA and GUCY2D-LCA, have been shown to have a dissociation of structure and function in affected humans and thus are good candidates for appropriate vision improving therapies.