Adeno-Associated Virus Mediated Gene Therapy for Corneal Diseases

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.

Efficacious, safe, and stable inhibition of corneal neovascularization by AAV-vectored anti-VEGF therapeutics

“…Topical application, the easiest route of administration, has a relatively low transduction efficiency, and the transduction of non-target tissues when vector is spread through tears remains a potential adverse effect. 28 Subconjunctival injection is relative easy and simple, leading to the potential transduction of a wide range of ocular tissues. 29 Intrastromal injection, technically difficult for beginners, has demonstrated serotypedependent transduction of different anterior eye segments.…”

“…Currently, therapeutic agents targeting the cornea are mainly administered via topical instillation, subconjunctival injection, or intrastromal injection. Topical instillation of rAAV vectors without the removal of the superficial epithelium have demonstrated relatively low transduction efficiencies; 28 therefore, we primarily compared the biodistribution of rAAV vectors following subconjunctival and intrastromal injection routes. We injected mouse cornea with rAAV2 or rAAV8 packaged with the eGFP reporter transgene under a chicken b-actin ubiquitous promoter (rAAV2-eGFP or rAAV8-eGFP) at equal doses (1.6 Â 10 10 genome copies [GCs]/cornea), either via intrastromal or subconjunctival routes (Figure 1A).…”

Diabetic eye: associated diseases, drugs in clinic, and role of self-assembled carriers in topical treatment

“…Gene therapy of diabetic eye diseases is also an active field of research and clinical translation. The approval of Luxturna ® , a virus-based gene delivery system for inherited retinal dystrophy, paved the road for other developments [87][88][89]. There are currently 492 recruiting or active clinical trials on ocular gene therapy, most of which use adeno-associated viruses as carriers, according to ClinicalTrials.gov, clinicaltrialsregister.eu and rctportal.niph.go.jp.…”

Rapid Characterization of AAV gene therapy vectors by Mass Photometry

“…The first rAAV based therapy was approved by the US Food and Drug Administration in 2012, and five viral vector treatments are currently available [3]. There are also over 200 ongoing clinical trials for various rAAV based gene therapies [4]. The increasing demand for rAAVs for both laboratory [5,6] and clinical applications accelerated the development of new techniques for rAAV production and characterization.…”