Table-2.
Therapeutic genes, vectors and delivery techniques used in gene therapy for ocular surface disorders and diseases
| Corneal Graft Rejection | ||||
|---|---|---|---|---|
| Gene | Vector | Model/Delivery | Species | Outcome |
| Bcl-xL | Lentivirus | Ex vivo | Mice | 90% survival rate after gene therapy versus 30% in controls |
| Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) | Adenovirus | Ex vivo, IV | Rat |
Ex vivo: Marginal prolongation in graft survival (1 day). i.v. Prolongation in graft survival by 9 days |
| Inducible T cell co-stimulator (ICOS) | Adenovirus | Ex vivo, IP | Rat | No significant prolongation in graft survival |
| IL-10 | Adenovirus | Ex vivo, IP | Rat | Ex vivo: No prolongation in graft survival i.p.: Marginal prolongation in graft survival (4 days) |
| IL-10 | Adenovirus | Ex vivo | Sheep | Remarkable prolongation in graft survival (35 days) |
| IL-12p40 gene | Adenovirus | Ex vivo, IP | Rat | No detectable change in graft survival |
| IL-12p40 gene | Adenovirus | Ex vivo | Sheep | Prolongation in graft survival from 18 days to 45 days |
| IL-4 | Adenovirus | Ex vivo | Rat | Rejection rate 85% in treated corneas and 63% in controls |
| IL-4 + CTLA4-Ig | MIDGE | Gene gun | Rat | Remarkable prolongation in graft survival |
| NGF | Adenovirus | Ex vivo and IP | Rat | Ex vivo: Median 3 days increase in graft survival No notable prolongation in graft survival |
| Corneal Wound Healing and Corneal Scarring / Haze | ||||
| Soluble TGFβR2 | Adenovirus. AAV, Nanoparticles |
IM, Topical application In vitro | Mice Rabbit Human |
Reduction in corneal edema, angiogenesis, inflammatory cell infiltration and deposition of extra-cellular matrix myofibroblast reduction |
| Tissue plasminogen activator | Plasmid | Intracameral electroporation | Rat | Decrease in fibrin deposition and opacity |
| Decorin | AAV | Topical | Rabbit Mice |
Decreased myofibroblasts, abnormal healing and opacity |
| Thymidine kinase | Retrovirus | Topical | Rabbit | Remarkable decrease in corneal haze in treated corneas |
| CyclinG1 | Retrovirus | Topical | Rabbit | Reduction in haze, a dramatic reduction in abnormal extracellular matrix production |
| Decorin | AAV | Topical, In vitro | Rabbit Human |
Remarkable reduction in corneal haze |
| Smad7 | Nanoparticles AAV |
Topical, In vitro | Rabbit | Reduction in corneal haze |
| BMP7 | Nanoparticles | Topical | Rabbit | Reduction in corneal haze |
| Alkali Burn Injury | ||||
| Smad7 | Adenovirus | Topical | Mice | Suppression of MCP-1, TGF-beta1, TGF-beta2, VEGF, MMP -9 and prevention of myofibroblast formation |
| BMP7 | Adenovirus, AAV | Topical, In vitro | Mice | Decrease in inflammatory cytokines, cell infiltration and myofibroblast formation. No reduction in neovascularization |
| PPARγ | Adenovirus | Topical | Mice | Inhibition of growth factors, MMP upregulation, monocytes/macrophages infiltration and myofibroblasts formation |
| Corneal Neovascularization | ||||
| sFlt-1 | Plasmid | Intrastromal | Mice | Complete inhibition of VEGF induced neovascularization |
| sFlt-1 | Adenovirus | Intracameral | Rat | 18% treated animals showed neovascularization compared to 82% controls |
| sFlt-1 | Adeno-associated virus | Intracameral | Mice Monkey |
Long term (8 months) regression of neovascularization in 85% of treated eyes |
| Flt23K, Flt24K | Plasmid, albumin polyplexes | Intrastromal | Mice | Intrastromal delivery of plasmid Flt23K suppressed VEGF (40%), leukocytes (49%) and neovascularization (66%). Flt24K suppressed VEGF expression (30%), leukocytes (25%) and neovascularization (49%) |
| Kringle 5 domain of plasminogen | Plasmid | Electroporation | Rat | Corneal neovascularization was significantly suppressed by K5 gene transfer in rats’ eyes |
| Endostatin- Kringle 5 | Lentivirus | Ex vivo | Rabbit | None of the 10 treated corneas developed neovascularization |
| IL10, IL12 | Plasmid | Topical | Mice | Significant suppression of neovascularization |
| Decorin | AAV | Rabbit | Significant suppression of neovascularization | |
| PEDF | AAV, GNP | Rabbit, Human cornea in vitro | Significant suppression of neovascularization | |
| Angiostatin | AAV | Subconjunctival injection | Rat, Organ culture | 50% reduction in area of neovascularization in treated animals |
| Vasohibin-1 | Adenovirus | Subconjunctival injection | Mice | 20% reduction in area of neovascularization in treated animals |
| Corneal Dystrophies | ||||
| β-glucuronidase | Adenovirus | Intrastromal, Intracameral | Mice | Correction of mucopolysaccharidosis phenotype |
| Herpes simplex Virus (HSV) Keratitis | ||||
| HSV glycoproteins (gB, gC, gD, gE, gI) | Plasmid | Multipe (IP, IM, sub-conjunctival) | Mice, Rabbit | Subconjunctival: Prevention of stromal keratitis IP, IM: Prevention of stromal as well as epithelial keratitis |
| Cytokines (IL-2 IL-10, TNFα, IFNα1) | Plasmid | Topical | Mice | Limited beneficial effect |
| Hepatocyte growth factor c-met | Adenovirus | In vitro | Human | Improved HGF signaling and restoration of normal protein patterns |
| Lacrimal gland, Dry Eye, Sjogren syndrome | ||||
| TNFα inhibitor | Adenovirus | Lacrimal gland injection | Rabbit | Enhanced tear production and suppression of immunohistopathology |
| IL-10 | Adenovirus | Lacrimal gland injection | Rabbit | Partially suppressed appearance of Sjögren-syndrome- features of reduced tear production, accelerated tear breakup, ocular surface disease and immunopathologic features |
| Conjunctival Scarring | ||||
| Smad7 | Adenovirus | Topical | Mice | Suppression of alpha-smooth muscle actin and VEGF in fibroblasts and invasion of macrophages |
| PPARγ | Adenovirus | Topical | Mice | Inhibition of monocyte/macrophage invasion, generation of myofibroblasts, and mRNA upregulation of cytokines/growth factors and collagen I alpha2 chain in healing conjunctiva. |
| Dominant negative p38MAPkinase | Adenovirus | Topical | Mice | Reduction of myofibroblast generation and suppression of mRNA expression of connective tissue growth factor and MCP-1 |
IM: Intra muscular, IP: Intra peritoneal, BMP: Bone morphogenic protein, CTLA-4 Ig: Cytotoxic T-lymphocyte-associated antigen-4 conjugated to human IgG heavy chain, Flt-1: A soluble form of the VEGF receptors, ICOS: Inducible co-stimulatory receptor expressed by activated T cells, IFN-γ: Interferon-gamma, IL: Interleukin, MCP-1: Macrophage chemoattractant protein-1, MMP: Matrix metalloproteinase, NGF: Nerve growth factor, PPARγ: Peroxisome proliferator-activated receptor-gamma, TGFβ: Transforming growth factor beta, TNFα: Tumor necrosis factor, VEGF: Vascular endothelium derived growth factor, GNP: Gold Nanoparticles