The Next Generation of Molecular and Cellular Therapeutics for Inherited Retinal Disease

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.

A Description of the Yield of Genetic Reinvestigation in Patients with Inherited Retinal Dystrophies and Previous Inconclusive Genetic Testing

“…Since gene-based treatments like gene augmentation/replacement [8,9,[23][24][25][26][27][28][29][30][31], gene silencing, AONs [32,33], and gene editing using the CRISPR/Cas9 system [3,[5][6][7] may be the future for patients with IRDs, confirmation of the genotype has become even more crucial during the last years. In our department, we have, since the 1990s, strived to both perform careful phenotyping and to verify the genotype in all our IRD patients.…”

“…Inherited retinal dystrophies (IRDs) are one of the most common causes of serious visual impairment in children and young adults in developed countries [1,2]. Until quite recently, IRDs have been untreatable, but during the last decades, extensive research concerning gene-based therapies [3][4][5][6][7] has evolved and the first gene augmentation therapy, Voretigene Neparvovec for treatment of RPE65-associated retinal dystrophies [8,9], was approved in USA in 2017 and in Europe 2018. Since the novel therapies such as gene…”

Cellular and molecular alterations in neurons and glial cells in inherited retinal degeneration

“…It is well known that RPE secretes an array of proteins and growth factors such as FGFs, TGF-β, insulin-like growth factor-I (IGF-I), CNTF, and platelet-derived growth factor (PDGF), which are essential for the development and maintenance of retinal health ( Strauss, 2005 ). The forced upregulation or exogenous administration of some of these factors has been tested as possible neuroprotective therapies for retinal dystrophies ( Dias et al, 2018 ; Martinez Velazquez and Ballios, 2021 ). In some cases, their release is dependent on the polarization state of the cells.…”

Autologous Adipose Tissue Stem Cell-Derived Terminally Differentiated Retinal Pigment Epithelium Monolayer on a Biocompatible Scaffold, to Restore Vision in Age-Related Macular Degeneration Patients

“…Cell replacement therapy is an attractive option for retinal diseases as the eye is an easily accessible and readily monitored human organ; additionally, the risk of cell transplant rejection is limited due to the autonomous and partially privileged immune structure [4]. Therefore, the development of advanced therapy medicinal products (ATMPs) has become a fast-growing field and presents an opportunity for preserving or restoring vision even in advanced stages of retinal degeneration, when photoreceptor degeneration has already occurred [5]. As there are currently almost no elective therapies available for AMD and other RPE disorders, RPE replacement, especially in later disease stages, has significantly accelerated progress in the field of RPE biology [2].…”