Leber congenital amaurosis/early-onset severe retinal dystrophy: current management and clinical trials

Abstract

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.

The Role of Inflammation in Retinal Neurodegeneration and Degenerative Diseases

“…Leber congenital amaurosis (LCA) presents a spectrum of hereditary retinal disorders and is a severe congenital/early-onset retinal dystrophy (EORD). Globally, LCA affects around 1 in 8000 children [ 122 ]. LCA is reported based on symptoms of severe visual damage at birth or within a few months of the infant’s life and is often presented with roving eye movements or nystagmus.…”

Structural evaluation in inherited retinal diseases

“…7 The huge disease burden caused by IRD 8 and the advancements in retinal genetics, imaging and molecular biology, have led to the development of clinical trials of novel therapeutics. [9][10][11] Gene supplementation, gene editing through clustered regularly interspaced short palindromic repeats (CRISPR) technology, antisense oligonucleotides, optogenetics and stem cell-based therapies are some of the techniques currently being tested to improve eyesight and/or reduce the rate of disease progression. 1-5 10 12 The multiple on-going and upcoming trials emphasise the need for reliable and repeatable measurements, for both patient stratification and endpoint assessment.…”

Leber’s Congenital Amaurosis: Current Concepts of Genotype-Phenotype Correlations

“…Animal studies have been conducted on commonly involved genes, including GUCY2D, RPE65, AIPL1, RPGRIP1, LCA5, CEP290, and RDH12, mostly by using adeno-associated virus (AAV) vector-mediated or lentiviral-vector-mediated gene augmentation therapy [15]. Moreover, clinical trials focusing on GUCY2D, RPE65, and CEP290 are ongoing [109]. To date, the most advanced progress has been made in the treatment of RPE65 mutations [110][111][112][113].…”