Abstract
Inherited retinal dystrophies (IRDs) are a group of clinically and genetically heterogeneous degenerative disorders. To date, mutations have been associated with IRDs in over 270 disease genes, but molecular diagnosis still remains elusive in about a third of cases. The methodologic developments in genome sequencing techniques that we have witnessed in this last decade have represented a turning point not only in diagnosis and prognosis but, above all, in the identification of new therapeutic perspectives. The discovery of new disease genes and pathogenetic mechanisms underlying IRDs has laid the groundwork for gene therapy approaches. Several clinical trials are ongoing, and the recent approval of Luxturna, the first gene therapy product for Leber congenital amaurosis, marks the beginning of a new era. Due to its anatomical and functional characteristics, the retina is the organ of choice for gene therapy, although there are quite a few difficulties in the translational approaches from preclinical models to humans. In the first part of this review, an overview of the current knowledge on methodological issues and future perspectives of gene therapy applied to IRDs is discussed; in the second part, the state of the art of clinical trials on the gene therapy approach in IRDs is illustrated.
Highlights
The neuroretina is a light-sensitive membrane located in the back of the eye, with specialized sensory properties to enable the capture of light by photoreceptors, its conversion into electric signals through a phototransduction process, and further integration and processing of the electric impulses into an image at the central nervous system (CNS) level
For example mutations of the PROM1 gene have been shown to result in retinitis pigmentosa (RP) and in Stargardt disease; of interest, in addition, is the broad spectrum of diseases seen in patients with ABCA4 retinopathies, from Stargardt disease/fundus flavimaculatus, to cone–rod dystrophy to RP
In the mouse retinas of a humanized CEP290 mouse model that carried the Leber congenital amaurosis (LCA) mutation, the delivery of bare and associated virus (AAV)-mediated Antisense Oligonucleotides (AONs) reduced the amount of aberrant CEP290 transcripts, demonstrating that both AON delivery methods provide an excellent strategy for the treatment of LCA associated with CEP290 [143]
Summary
The neuroretina is a light-sensitive membrane located in the back of the eye, with specialized sensory properties to enable the capture of light by photoreceptors, its conversion into electric signals through a phototransduction process, and further integration and processing of the electric impulses into an image at the central nervous system (CNS) level. To meet the important need for genetic diagnosis and to amplify the detection rate of the causative mutation, new and fascinating diagnostic avenues have been explored, starting from single-gene DNA sequencing (using the Sanger technique), moving to sequencing of panels of genes (by next-generation sequencing (NGS)) of the whole exome (by whole exome sequencing (WES)) up to investigating the entire genome (by whole genome sequencing (WGS)) [11,12] The spread of such innovative technologies among genetic laboratories will certainly improve the diagnostic potential for IRDs. Due to the heterogeneous presentation of IRDs, the congruence of clinical and molecular diagnosis is a necessary goal to characterize the phenotype exactly and to increase the chance of therapeutically beneficial strategies. It may allow identification of phenotype-modulating genes through cohort studies of patients with mutations in the same gene but with different phenotype severities [12,13,14]
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