AMD, resulting in improved visual acuity and central foveal thickness on OCT [70]. A phase I study is underway, evaluating intravitreal infliximab for neovascular AMD, as well as for refractory diabetic macular edema [71].

Sirolimus

Sirolimus (Rapamycin, MacuSight, Inc., Union City, CA) was originally developed as a macrolide antifungal agent, but was found to possess potent immunosuppressive and antiproliferative properties. It is used to prevent rejection after organ transplantation, particularly after renal transplant. Sirolimus-eluting coronary stents are used for treatment of coronary artery disease.

Sirolimus inhibits the mammalian target of rapamycin, or mTOR, which effects cell growth and proliferation via the regulation of protein synthesis [72]. Sirolimus’s anti-angiogenic properties are linked to a decrease in VEGF production and to a markedly inhibited response of vascular endothelial cells to stimulation by VEGF [73]. Further, sirolimus downregulates hypoxiainducible factor-1a, a major upstream regulator of VEGF [74].

In a murine model, systemic sirolimus inhibited both choroidal and retinal neovascularization [75]. A phase I study [76] of 30 patients found intravitreal and subconjunctival sirolimus to be safe and well tolerated in all doses. A single administration of sirolimus was associated with improvement in visual acuity and retinal thickness. Preliminary findings suggested that subconjunctival administration was as effective, if not more so, that intravitreal sirolimus [77]. The phase II trial, known as EMERALD, is currently evaluating subconjunctival sirolimus in combination with intravitreal ranibizumab [78]. If proven effective, sirolimus’s subconjunctival delivery would be less invasive and potentially safer and better tolerated than intravitreal alternatives.

Gene Therapy

Gene therapy could possibly treat and prevent angiogenesis by blocking stimulatory proteins or increasing expression of endogenous inhibitors.

Ocular gene transfer is an appealing treatment approach because of its potential to provide a sustained therapeutic response within the eye with little systemic impact.

Pearl

Gene therapy could possibly treat and prevent angiogenesis by blocking stimulatory proteins or increasing expression of endogenous inhibitors. Ocular gene transfer is an appealing treatment approach because of its potential to provide a sustained therapeutic response within the eye with little systemic impact.

Successful gene therapy technology hinges on a detailed understanding of the molecular pathogenesis of retinal and subretinal neovascularization, along with a safe and effective vector for gene transfer. Adenoviral (Ad) vectors are relatively easy to produce, have good capacity, and can mediate good expression levels in many cells types with an appropriate promoter. One concern with adenoviral vectors is that they induce an inflammatory response, which could destroy transduced cells and prevent repeat injections. Adeno-associated viral (AAV) vectors are more difficult to produce than adenoviral vectors, with a capacity limited to less than 5 kb. However, adeno-associated viral vectors beget little to no immune response, mediating prolonged transgene expression with little toxicity [79].

AdPEDF.11

Pigment epithelial-derived growth factor (PEDF) has neurotrophic, neuroprotective, and antiangiogenic properties [80–82]. Researchers have shown that an adenoviral vector containing complementary DNA encoding human PEDF, known as AdPEDF.11 (GenVec, Inc., Gaithersburg, MD, USA) or AdGVPEDF.11D, inhibits ocular neovascularization in two murine models [82]. AdPEDF.11 induces apoptosis of endothelial cells in new blood vessels, but not in normal vasculature [82]. Intriguingly, subconjunctival