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LCA, early-onset severe retinal dystrophy: current management and clinical trials

Malena Daich Varela, Thales Antonio Cabral de Guimaraes, Michalis Georgiou, Michel Michaelides | British Journal of Ophthalmology | Volume 6, Issue 4 | 12 March, 2021


Leber congenital amaurosis (LCA) is a severe congenital/early-onset retinal dystrophy. Given its monogenic nature and the immunological and anatomical privileges of the eye, LCA has been particularly targeted by cutting-edge research. In this review, we describe the current management of LCA, and highlight the clinical trials that are on-going and planned. RPE65-related LCA pivotal trials, which culminated in the first Food and Drug Administration-approved and European Medicines Agency-approved ocular gene therapy, have paved the way for a new era of genetic treatments in ophthalmology. At present, multiple clinical trials are available worldwide applying different techniques, aiming to achieve better outcomes and include more genes and variants. Genetic therapy is not only implementing gene supplementation by the use of adeno-associated viral vectors, but also clustered regularly interspaced short palindromic repeats (CRISPR)-mediated gene editing and post-transcriptional regulation through antisense oligonucleotides. Pharmacological approaches intending to decrease photoreceptor degeneration by supplementing 11-cis-retinal and cell therapy’s aim to replace the retinal pigment epithelium, providing a trophic and metabolic retinal structure, are also under investigation. Furthermore, optoelectric devices and optogenetics are also an option for patients with residual visual pathway. After more than 10 years since the first patient with LCA received gene therapy, we also discuss future challenges, such as the overlap between different techniques and the long-term durability of efficacy. The next 5 years are likely to be key to whether genetic therapies will achieve their full promise, and whether stem cell/cellular therapies will break through into clinical trial evaluation.


Leber congenital amaurosis (LCA) represents one of the severest diagnoses a family can receive regarding a child’s eyesight. It is characterized by early-onset visual impairment, nystagmus or roving eyes and severe photoreceptor dysfunction.1 LCA and early-onset severe retinal degeneration (EOSRD) belong to the same disease spectrum, with the latter being less severe; later onset of visual impairment, often better preserved visual acuity and decreased, but usually present electrophysiological responses.1 LCA/EOSRD affect approximately 1 in 80 000 children worldwide.2 Retinal examination can be unremarkable especially in the early stages or show mild signs such as retinal pigment epithelial mottling and vessel narrowing.3 Salt and pepper retinopathy, optic disc pallor and retinal pigment clumping (including nummular and bone spicule) usually appear in older individuals.

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