Evaluating the Efficacy and Safety of CRISPR-Cas9-Mediated Gene Editing for the Treatment of Inherited Retinal Dystrophies in Preclinical Large-Animal Models

Dr. Vikram Menon, Dr. Priya Nair

Department of Biotechnology, Indian Institute of Science, Bengaluru, India

Abstract

Inherited retinal dystrophies (IRDs) encompass a diverse array of genetic degenerative conditions marked by the gradual malfunction of photoreceptors and subsequent vision impairment. Although gene therapy has progressed, treatment options are still constrained by the wide range of mutations found in over 300 genes. The CRISPR-Cas9 genome editing system has become a groundbreaking therapeutic approach, allowing for the precise rectification of harmful mutations at the genomic level. Large-animal models, such as those involving dogs, cats, sheep, and non-human primates, provide crucial translational insights due to their anatomical and physiological similarities to the human retina. This detailed research article assesses the effectiveness and safety of CRISPR-Cas9-mediated gene editing in treating IRDs using preclinical large-animal models. It compiles current research on gene editing techniques, delivery mechanisms, mutation-specific targeting, and functional outcomes like photoreceptor preservation, restoration of retinal sensitivity, and structural recovery. The article places particular emphasis on safety issues, including off-target effects, immune reactions, genotoxicity, and the long-term integrity of the retina. Methodological approaches covering in vivo genome editing, both viral and non-viral delivery systems, electrophysiological assessments, and histopathological evaluations are explored. Findings from preclinical studies suggest that CRISPR-Cas9 can successfully restore gene expression and reduce retinal degeneration in various IRD models, particularly in monogenic disorders such as retinitis pigmentosa and Leber congenital amaurosis. Nonetheless, concerns about unintended genomic changes and immune-related toxicity require thorough assessment before moving to clinical applications. Comparative studies highlight the essential role of large-animal models in predicting therapeutic outcomes and potential side effects due to their close resemblance to human eye structure. In summary, the evidence indicates that CRISPR-Cas9-mediated gene editing offers significant potential as a long-lasting therapeutic option for IRDs, contingent upon the refinement of delivery techniques, editing accuracy, and long-term safety measures. The article concludes by discussing future research directions and the challenges of translating CRISPR-based retinal therapies into clinical practice.

Keywords

CRISPR-Cas9; Genetic Editing; Inherited Retinal Disorders; Large-Animal Models; Retinitis Pigmentosa; Leber Congenital Amaurosis; Genome Engineering; Photoreceptor Degeneration; AAV Vectors; Preclinical Safety