Abstract
According to the World Health Organization, corneal diseases are the fourth leading cause of blindness worldwide accounting for 5.1% of all ocular deficiencies. Current therapies for corneal diseases, which include eye drops, oral medications, corrective surgeries, and corneal transplantation are largely inadequate, have undesirable side effects including blindness, and can require life-long applications. Adeno-associated virus (AAV) mediated gene therapy is an optimistic strategy that involves the delivery of genetic material to target human diseases through gene augmentation, gene deletion, and/or gene editing. With two therapies already approved by the United States Food and Drug Administration and 200 ongoing clinical trials, recombinant AAV (rAAV) has emerged as the in vivo viral vector-of-choice to deliver genetic material to target human diseases. Likewise, the relative ease of applications through targeted delivery and its compartmental nature makes the cornea an enticing tissue for AAV mediated gene therapy applications. This current review seeks to summarize the development of AAV gene therapy, highlight preclinical efficacy studies, and discuss potential applications and challenges of this technology for targeting corneal diseases.
Highlights
Acquired or inherited variations in genomic DNA can lead to suboptimal, malfunctioning, or nonfunctional proteins, resulting in reduced cellular fitness and disease [1]
This review provides a brief overview of associated virus (AAV)-based gene therapy while highlighting potential AAV gene therapy approaches and challenges towards developing novel therapies for corneal diseases
Advances in detection tools, anti-inflammatory therapies, pain-management therapies, and corneal surgery including corneal transplantations, have improved clinical outcomes; with improved understanding of disease pathology, future studies should be focused on developing better therapies
Summary
Acquired or inherited variations in genomic DNA can lead to suboptimal, malfunctioning, or nonfunctional proteins, resulting in reduced cellular fitness and disease [1]. Integration is preferred in dividing cells, and this process is mediated through the interaction between the Rep68/78 proteins and ITRs at the AAVS1 locus, which harbors sequence similarity with the ITRs. Upon coinfection of cells with helper viruses, AAV enters the lytic stage where AAV genome replication gets initiated through transcriptional activation via the alleviation of the Rep mediated repression at the p5 promoter region. The AAV particle harbors a relatively small yet remarkably complex genome, and through coinfection of helper viruses into the host cells, AAV is capable of expressing its genes, persisting, and/or integrating into the host genome, replicating, and packaging its genome to infecting additional cells
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