Gene-Based Therapeutics for Acquired Retinal Disease: Opportunities and Progress

Abstract

Acquired retinal diseases such as age-related macular degeneration and diabetic retinopathy rank among the leading causes of blindness and visual loss worldwide. Effective treatments for these conditions are available, but often have a high treatment burden, and poor compliance can lead to disappointing real-world outcomes. Development of new treatment strategies that provide more durable treatment effects could help to address some of these unmet needs. Gene-based therapeutics, pioneered for the treatment of monogenic inherited retinal disease, are being actively investigated as new treatments for acquired retinal disease. There are significant advantages to the application of gene-based therapeutics in acquired retinal disease, including the presence of established therapeutic targets and common pathophysiologic pathways between diseases, the lack of genotype-specificity required, and the larger potential treatment population per therapy. Different gene-based therapeutic strategies have been attempted, including gene augmentation therapy to induce in vivo expression of therapeutic molecules, and gene editing to knock down genes encoding specific mediators in disease pathways. We highlight the opportunities and unmet clinical needs in acquired retinal disease, review the progress made thus far with current therapeutic strategies and surgical delivery techniques, and discuss limitations and future directions in the field.

Challenges in Age-Related Macular Degeneration: From Risk Factors to Novel Diagnostics and Prevention Strategies

“…Efforts will be also needed for improving management of patients suffering from AMD Stage 4. Although gene therapies have potential and are promising, there are significant obstacles, such as safety, long-term efficacy, and cost, to these therapeutic options for AMD becoming mainstream ( 94 , 95 ).…”

Cell-cell interaction in the pathogenesis of inherited retinal diseases

“…Suprachoroidal delivery in the space between the sclera and the choroid has also been shown to be a safe approach in preclinical and clinical studies yet it poses risk to spread viral vectors into the systemic circulation and could lead to adverse physical and immune response ( Kansara et al, 2020 ; Naftali Ben Haim and Moisseiev, 2021 ; Tan et al, 2021 ).…”

AAV-Based Strategies for Treatment of Retinal and Choroidal Vascular Diseases: Advances in Age-Related Macular Degeneration and Diabetic Retinopathy Therapies

“…Hitherto, we have discussed therapies involving gene augmentation or addition, utilising AAV to deliver a therapeutic gene targeting specific aspects of the disease pathogenesis [ 27 ]. Nonetheless, gene-editing technology has evolved and has broadened the range of candidate therapies for AMD.…”

“…Current treatment of most of these chronic conditions is effective, albeit burdensome for patients and clinicians, particularly in the long-term. Thus, cost, low compliance and consequent therapeutic failure limit the efficacy of available therapies, emphasising the unmet need for safe and effective longer-acting alternatives with better regimens [ 27 ]. AAV-mediated expression of molecules targeting pathways involved in the pathogenesis of these diseases has emerged as a powerful strategy to overcome the outlined challenges.…”