From Gene Editing to Artificial Retinas: A Roadmap for Multifaceted Therapeutic Platforms to Overcome Retinal Degeneration
Background
The Silent Shadow of Impending Blindness
Inherited Retinal Degenerations (IRD), a group of genetic disorders causing vision loss due to problems in the light-receiving retina, has long been classified as a representative intractable disease with no cure. This group of diseases, in which photoreceptor cells in the inner eye are destroyed, exhibits very high genetic diversity. More than 250 causative genes have been identified to date, resulting in significant differences in the onset mechanism and progression of symptoms among patients. In the past, the only treatment available was limited conservative therapy, such as vitamin supplementation, to partially delay disease progression. Patients had to helplessly watch as their visual field narrowed from the periphery, leading to complete vision loss. As a result, attention has been focused on the collaboration between basic science and clinical medicine to accurately analyze genetic information and biologically and physically restore damaged retinal tissue.
Key Findings
From Gene Editing to Microchip Implantation: Four Major Therapeutic Pathways
The recently published retinal disease analysis summarizes the systematic classification of IRD according to the type of photoreceptor cell damage and outlines four therapeutic platforms used in the latest clinical trials. First, gene therapy delivers normal genes to patients with specific, identified causative gene defects. Voretigene neparvovec, a therapeutic agent, has been approved for the treatment of Leber Congenital Amaurosis (LCA), caused by a defect in the RPE65 gene of the Retinal Pigment Epithelium (RPE). It uses Adeno-Associated Virus (AAV) as a vector to inject genes into the subretinal space, restoring visual function. Second, cell therapy involves transplanting RPE or photoreceptor cells differentiated from induced Pluripotent Stem Cells (iPSC). This approach is known to be easily applicable to a wide range of patients because it directly replaces the lost physical retinal structure, regardless of the type of gene mutation. Third, optogenetic therapy, which targets patients in the late stages with complete photoreceptor cell destruction, has garnered attention. This involves injecting the gene for channelrhodopsin, a light-sensitive protein, into the remaining bipolar or ganglion cells in the retina, inducing the cells to directly perceive light. Finally, artificial retina technology involves implanting a microelectrode chip into the retina to stimulate the optic nerve. This is significant in that it uses a mechanical device to convert external visual information into electrical signals and transmit them to the brain, even when the nerves are damaged to the point that biological treatment is impossible.
Significance and Prospects
A Path Towards Personalized Precision Medicine
Various technological advancements offer hope to visually impaired patients, but there are still many challenges to be overcome before they can be widely used in clinical practice. A precise genetic diagnostic infrastructure to identify individual patient mutations must be established first, in order to design personalized treatment methods. Ensuring safety is also a long-term challenge. The immune rejection response caused by the AAV vector must be minimized, and the long-term engraftment of transplanted stem cell-derived cells in the retina must be confirmed through long-term follow-up observation, so that the procedure can be performed with confidence. In the case of optogenetics and artificial retina devices, research is urgently needed to improve visual resolution so that patients can fully identify everyday objects. Following this, national discussions are needed to reduce the high treatment costs to an affordable level and establish a public insurance support system, so that patients can receive tangible benefits. Nevertheless, the combination of advanced biotechnology and precision medicine is leading to the development of treatments for inherited retinal degeneration. As multifaceted research combining the advantages and disadvantages of each treatment method continues, the era of personalized vision rehabilitation is gradually approaching.
Inherited retinal degenerations are a diverse group of genetic disorders that result in progressive vision loss. Advances in genetic testing have revealed pathogenic variants in hundreds of genes, reflecting the remarkable heterogeneity of these conditions and pointing to the complexity of the developmental and homoeostatic processes needed for a lifetime of good vision. This Review summarises the clinical presentation of inherited retinal degenerations, outlines broad disease categories based on the primary type of retinal cell affected, and highlights novel treatment approaches including gene, cell, optogenetic, and implantable chip therapies.
This study has played a significant role in clinical practice as a compass for establishing personalized precision medicine diagnostic and treatment pathways for patients. For example, an ophthalmologist can, instead of simply recommending conservative treatment to a patient with a retinal disease, use Next Generation Sequencing (NGS) to identify the causative mutation. For early-stage patients diagnosed with LCA, a plan can be established to rapidly administer AAV-based gene therapy to prevent photoreceptor cell death. For late-stage patients with most photoreceptor cells lost, a long-term plan can be developed to restore vision through stem cell-derived RPE transplantation or optogenetic technology. From a bio-industrial perspective, this will lead to the growth of the market for complex therapeutic agents that combine gene editing and stem cell technology. In the field of visual rehabilitation equipment, it has provided a new milestone in the development of high-resolution artificial retina chips using ultra-fine electrodes.