Gene Therapy in Retinal Dystrophies

Lucia Ziccardi, Viviana Cordeddu, Lucia Gaddini, Andrea Matteucci, Mariacristina Parravano, Fiorella Malchiodi-Albedi, Monica Varano, Lucia Ziccardi, Viviana Cordeddu, Lucia Gaddini, Andrea Matteucci, Mariacristina Parravano, Fiorella Malchiodi-Albedi, Monica Varano

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.

Keywords: animal models for retinal dystrophy; editing; hereditary retinal disease; human iPSC-derived retina and retinal pigment epithelium; optogenetics and splice modulation therapy; pre- and clinical gene therapy; retinal gene augmentation; retinal imaging; retinal pathology.

Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Retinal structure under light microscopy. The photographs highlight its histological complexity and evidence the connections between the different cell populations. (A) A section of rat retinal tissue, photographed using a differential interference contrast microscope, highlighting retinal layers. (B) Synaptophysin (Syn)-positive dots decorate the IPL, indicating the presence of synapses. In red, cellular retinaldehyde-binding protein (CRALBP)-positive Müller glia, spanning through all the retinal layers. (C) GABAergic neurons (GABA) in the inner layers of the retina. (D) A diagonal cross section reveals the rich connections between vimentin-positive Müller glia and GABAergic neuronal components. Nuclei are stained in blue with DAPI. PR OS = photoreceptors, outer segment; PR IS = photoreceptors, inner segment; GCL = ganglion cell layer; OPL = outer plexiform layer; ONL = outer nuclear layer; IPL = inner plexiform layer; INL = inner nuclear layer. Scale bar = 20 μm.

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