Abstract
Inherited retinal degenerations (IRDs) are a diverse group of conditions that are often characterized by the loss of photoreceptors and blindness. Recent innovations in molecular biology and genomics have allowed us to identify the causative defects behind these dystrophies and to design therapeutics that target specific mechanisms of retinal disease. Recently, the FDA approved the first in vivo gene therapy for one of these hereditary blinding conditions. Current clinical trials are exploring new therapies that could provide treatment for a growing number of retinal dystrophies. While the field has had early success with gene augmentation strategies for treating retinal disease based on loss-of-function mutations, many novel approaches hold the promise of offering therapies that span the full spectrum of causative mutations and mechanisms. Here, we provide a comprehensive review of the approaches currently in development including a discussion of retinal neuroprotection, gene therapies (gene augmentation, gene editing, RNA modification, optogenetics), and regenerative stem or precursor cell-based therapies. Our review focuses on technologies that are being developed for clinical translation or are in active clinical trials and discusses the advantages and limitations for each approach.
Highlights
Inherited retinal degenerations (IRDs) are a genetically and clinically heterogeneous group of disorders that are often characterized by severe loss of vision
Many therapies currently in development are designed to treat IRDs associated with a specific genotype; the field is increasingly focused on generalizable treatment strategies that can be applicable to a broad range of retinal dystrophies and degenerations
Advancements in molecular biology and a detailed understanding of the pathophysiology of retinal disease allowed for the development of the first FDA-approved gene therapy for biallelic RPE65-associated Leber congenital amaurosis (LCA), voretigene neparvovecrzyl (LUXTURNA)
Summary
Inherited retinal degenerations (IRDs) are a genetically and clinically heterogeneous group of disorders that are often characterized by severe loss of vision While these disorders have long been considered untreatable, recent advances in molecular biology have led to the first FDA-approved gene therapy for a retinal dystrophy, voretigene neparvovec-rzyl (LUXTURNA) for RPE65-associated Leber congenital amaurosis (LCA). Vision science researchers have been at the forefront of innovations in gene therapy and regenerative medicine This is not a coincidence, given that the eye offers many advantages for the study and development of these technologies. Much of the progress in clinical therapies would have been impossible without the existence of a variety of preclinical animal models for inherited retinal degenerations, which have fueled the rapid growth in our understanding of the pathobiology of vision loss. These models have allowed for the generation of innovative experimental therapies and proof-of-principle experiments that demonstrated their therapeutic benefit in slowing down retinal degeneration and even restoring vision
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