Gene Therapy in Corneal Transplantation

Abstract

Corneal transplantation is the most commonly performed organ transplantation. Immune privilege of the cornea is widely recognized, partly because of the relatively favorable outcome of corneal grafts. The first-time recipient of corneal allografts in an avascular, low-risk setting can expect a 90% success rate without systemic immunosuppressive agents and histocompatibility matching. However, immunologic rejection remains the major cause of graft failure, particularly in patients with a high risk for rejection. Corticosteroids remain the first-line therapy for the prevention and treatment of immune rejection. However, current pharmacological measures are limited in their side-effect profiles, repeated application, lack of targeted response, and short duration of action. Experimental ocular gene therapy may thus present new horizons in immunomodulation. From efficient viral vectors to sustainable alternative splicing, we discuss the progress of gene therapy in promoting graft survival and postulate further avenues for gene-mediated prevention of allogeneic graft rejection.

Variable Responses to Corneal Grafts: Insights from Immunology and Systems Biology

“…Together with findings from the CCTS regarding the role of minor histocompatibility complex antigens in corneal graft rejection [133], genomic SNP analyses of corneal rejection-associated hotspots hold promise in prognosticating corneal allograft rejection. Furthermore, full genomic analysis of donors and recipients that examines individual corneal functional capabilities and immunologic characteristics could open up the possibility of precision gene therapy, such as individualized anti-angiogenic and anti-apoptotic gene therapy, to target rejection-promotive genes that vary in every patient [134].…”

Treatment of ocular disorders by gene therapy

“…Although corneal allografts enjoy the privilege of being among the most successful solid organ transplants, their two-year graft survival rate of over 90% in ''low-risk'' avascular host beds significantly decreases over time [163]. Nevertheless, immunologic rejection remains a leading cause of graft failure.…”

“…Other strategies are the modulation of the immune response through the expression of pro-inflammatory cytokines that mediate graft rejection, or the inhibition of apoptotic pathways [163]. Ex vivo gene therapy of the donor cornea has been demonstrated to prolong corneal allograft survival in various animal models.…”

“…Nevertheless, immunologic rejection remains a leading cause of graft failure. The prevalence of graft rejection varies from 5% to 40%, depending upon vascularization of the recipient cornea and prior episodes of graft failure, with rejection rates approaching 70% in vascularized "high-risk" beds, even with maximal local and systemic immune suppression [163].…”

Controlled Release of rAAV Vectors from APMA-Functionalized Contact Lenses for Corneal Gene Therapy

“…Besides retina, cornea represents an attractive target for gene therapy because of its accessibility, immune privilege, stability in vivo, and transparency; factors that facilitate gene delivery and monitoring for corneal diseases (e.g., corneal haze, corneal neovascularization, herpetic stromal keratitis, mucopolysaccharidosis VII, corneal transplantation, and graft rejection, among others) [7][8][9][10]. Cornea is an avascular tissue that refracts the light (together with the lens) and acts as a first protective barrier due to the tight junctions of the epithelium and Bowman's membrane.…”