Therapeutic Applications of Adeno-Associated Virus (AAV) Gene Transfer of HLA-G in the Eye

Abstract

The purpose of this paper is to review human leukocyte antigen G (HLA-G) in the eye, its role in immune tolerance, and the potential therapeutic use of AAV gene transfer and expression of HLA-G in various ocular tissues. Several studies are reviewed that demonstrate efficacy in animal models of disease, including intracorneal delivery of AAV-HLA-G to treat corneal inflammation and prevent corneal graft rejection, subconjunctival injection of AAV-HLA-G for ocular graft vs. host disease and potentially dry eye disease, and intravitreal injection of AAV-HLA-G to inhibit uveitis. Furthermore, due to the anti-vascular function of HLA-G, AAV-HLA-G may be an effective therapy for posterior ocular diseases, such as neovascular age-related macular degeneration, diabetic retinopathy, and choroidal neovascularization. Therefore, AAV-mediated gene transfer of HLA-G may be an effective treatment for common immune-mediated, inflammatory, and neovascular diseases of the eye.

AAV-mediated gene therapies for glaucoma and uveitis: are we there yet?

“…HLA-G is involved in maintaining the ocular immune privilege and has shown beneficial effects in models of dry eye, corneal inflammation and neovascularisation (Ref. 18 ). An intravitreal injection containing equal amounts of HLA-G1 and HLA-G5 packaged into scAAV8 was given to rats before EAU induction by IRBP.…”

“…Extensive research has been conducted to improve understanding of underlying mechanisms driving these chronic, difficult to treat ophthalmic conditions, and several novel therapeutic approaches have been explored. These strategies include novel agents, nanocarriers, extended-release devices and gene- and cell-based therapies, each with unique advantages and relevance to the field, which have been reviewed elsewhere (Refs 4 , 10 , 11 , 12 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ).…”

Recent advances in ocular graft-versus-host disease

“…Several other promising novel treatments for ocular GVHD have demonstrated efficacy in reducing inflammation and halting disease progression. In a preclinical mouse model, a vascular adhesion protein-1 inhibitor ( 119 ), a secondary lymphoid-tissue chemokine (CCR ligand 21) antagonist ( 120 ), and subconjunctival injection of AAV-HLA-G (a therapy of adeno-associated virus (AAV) gene transfer of HLA-G) ( 121 ) served as effective and safe therapeutic agents to reduce inflammation and ameliorate clinical signs of ocular GVHD. However, these need to be registered for clinical use.…”

Corneal Regeneration Using Gene Therapy Approaches

“…The treated group did not exhibit edema and neovascularization for more than 2.5 months upon allotransplantation. Furthermore, xenotransplantation (human donor to rabbit recipient) showed a delayed rejection time from 18 days to 29 days [121]. Delivery of IL-10 and IL-12 with adenoviral vectors to ovine corneas exhibited higher rates of graft survival [55,144,145,185].…”