Anti-VEGF aptamer (pegaptanib) therapy for ocular vascular diseases.

Vascular endothelial growth factor (VEGF) is a central regulator of both physiological and pathological angiogenesis. Pegaptanib, a 28-nucleotide RNA aptamer specific for the VEGF(165) isoform, binds to it in the extracellular space, leaving other isoforms unaffected, and inhibits such key VEGF actions as promotion of endothelial cell proliferation and survival, and vascular permeability. Pegaptanib already has been examined as a treatment for two diseases associated with ocular neovascularization, age-related macular degeneration (AMD) and diabetic macular edema (DME). Preclinical studies have shown that VEGF(165) alone mediates pathological ocular neovascularization and that its inactivation by pegaptanib inhibits the choroidal neovascularization observed in patients with neovascular AMD. In contrast, physiological vascularization, which is supported by the VEGF(121) isoform, is unaffected by this inactivation of VEGF(165). In addition, animal model studies have shown that intravitreous injection of pegaptanib can inhibit the breakdown of the blood-retinal barrier characteristic of diabetes and even can reverse this damage to some degree. These preclinical findings formed the basis for randomized controlled trials examining the efficacy of pegaptanib as a therapy for AMD and DME. The VEGF Inhibition Study in Ocular Neovascularization (VISION) trial comprising two replicate, pivotal phase 3 studies, demonstrated that intravitreous injection of pegaptanib resulted in significant clinical benefit, compared with sham injection, for all prespecified clinical end points, irrespective of patient demographics or angiographic subtype, and led to pegaptanib's approval as a treatment for AMD. A phase 2 trial has provided support for the efficacy of intravitreous pegaptanib in the treatment of DME.

Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular disease.

Aptamers are oligonucleotide ligands that are selected for high-affinity binding to molecular targets. Pegaptanib sodium (Macugen; Eyetech Pharmaceuticals/Pfizer) is an RNA aptamer directed against vascular endothelial growth factor (VEGF)-165, the VEGF isoform primarily responsible for pathological ocular neovascularization and vascular permeability. After nearly a decade of preclinical development to optimize and characterize its biological effects, pegaptanib was shown in clinical trials to be effective in treating choroidal neovascularization associated with age-related macular degeneration. Pegaptanib therefore has the notable distinction of being the first aptamer therapeutic approved for use in humans, paving the way for future aptamer applications.

Targeting angiogenesis, the underlying disorder in neovascular age-related macular degeneration.

Angiogenesis has a causal role in many diseases, including neovascular age-related macular degeneration (AMD). Identification of key regulators of angiogenesis, including vascular endothelial growth factor (VEGF), fibroblast growth factor 2, pigment epithelium-derived growth factor, angiopoietins and extracellular matrix molecules, has facilitated the development of novel therapeutic agents that target the underlying pathological angiogenic process. Among these, VEGF serves as a "master switch" for many ocular neovascular conditions through its promotion of endothelial cell proliferation and survival, vascular permeability and ocular inflammation. Two anti-VEGF agents are now clinically available: bevacizumab, an antibody for metastatic colorectal cancer, and pegaptanib sodium, an aptamer for neovascular AMD. Unlike bevacizumab, which binds all VEGF isoforms, pegaptanib targets only VEGF165, the isoform responsible for pathological ocular neovascularization and thus an ideal target for treatment of AMD. Although other therapies targeting angiogenesis in AMD are in clinical development, to date, pegaptanib is the only therapy approved by the Food and Drug Administration of the United States for the treatment of all neovascular AMD and represents a valuable addition to the hitherto limited options available for patients.

Macular translocation in patients with recurrent subfoveal choroidal neovascularization after laser photocoagulation for nonsubfoveal choroidal neovascularization.

PURPOSE: To report visual outcomes and to examine surgical factors affecting outcomes in patients undergoing macular translocation for recurrent subfoveal choroidal neovascularization after laser photocoagulation for nonsubfoveal choroidal neovascularization. DESIGN: Retrospective, noncomparative, interventional case series. PARTICIPANTS: A consecutive series of 31 eyes of 29 patients who underwent macular translocation for recurrent subfoveal choroidal neovascularization after laser photocoagulation for nonsubfoveal choroidal neovascularization. INTERVENTION: Inferior macular translocation with punctate retinotomy performed by a single surgeon. OUTCOME MEASURES: Surgical and visual outcomes at 3 and 6 months after surgery and complications data are reported. Associations between surgical factors and visual outcomes were analyzed statistically. RESULTS: Effective translocation was achieved in 77.4% of eyes. At 6 months, 54% of eyes achieved visual acuity (VA) better than 20/100, and 46% of eyes gained the equivalent of > or =2 Early Treatment Diabetic Retinopathy Study lines of vision. No association between size of recurrent choroidal neovascularization and visual outcome was identified. Eyes with a larger scar size experienced lower VA at 3 and 6 months, but scar size was not associated with change in VA at 3 and 6 months. Subretinal dissection during surgery to detach the macula was required in 8 of 31 eyes and was associated with a significantly increased incidence of peripheral retinal breaks. However, there was no difference in either VA or change in VA in eyes with and without subretinal dissection. Retinal detachment (RD) occurred in 6 of 31 eyes. No significant difference in the RD rate was observed between groups with or without subretinal dissection (P = 0.30). CONCLUSION: Our pilot data suggest that macular translocation can result in favorable surgical outcomes in patients with recurrent subfoveal choroidal neovascularization after laser photocoagulation for nonsubfoveal choroidal neovascularization. Use of subretinal dissection intraoperatively in these patients does not seem to affect visual outcome adversely, but may be associated with increased risk of peripheral retinal breaks.

Ocular toxicity of intravitreal trovafloxacin in the pigmented rabbit.

PURPOSE: Trovafloxacin is an expanded spectrum, newer-generation fluoroquinolone antibiotic with improved Gram-positive and anaerobic activity compared with existing quinolones, while maintaining Gram-negative activity comparable to ciprofloxacin. Given its broad spectrum of activity, trovafloxacin may have potential use for treatment of acute bacterial endophthalmitis. This study examined the toxicity of intravitreally administered trovafloxacin in the pigmented rabbit eye. METHODS: Doses of trovafloxacin ranging from 12.5 microg to 1000 microg were injected into the mid-vitreous of Dutch Belted rabbit eyes. Clinical examination was performed at 1, 3, and 14 days following injection. Animals were sacrificed and eyes were enucleated 14 days following injection. Light microscopy (LM) and transmission electron microscopy (TEM) studies of the optic nerve head, medullary ray, and inferior retina were performed to determine toxicity. RESULTS: At intravitreal doses of 500 microg and less, no toxicity was observed at the ophthalmoscopic or light microscopic level. By TEM, a dose-dependent increase in injury to retinal pigment epithelium, photoreceptors, and nerve fibers in the optic nerve head and medullary ray was observed from 50 microg to 500 microg. No toxicity was noted at doses of 12.5 microg and 25 microg. At doses of 750 microg and above, edema of the medullary ray was noted on ophthalmoscopy. Swelling of the peripapillary medullary ray and necrosis of the inferior retina were evident on LM. CONCLUSION: Intravitreal trovafloxacin doses of 50 microg and higher in the pigmented rabbit eye cause retinal and nerve fiber injury. Intravitreal doses 25 microg and lower appear to be safe, with no evidence of ocular toxicity.

Iatrogenic choroidal neovascularization occurring in patients undergoing macular surgery.

PURPOSE: To report three cases of choroidal neovascularization (CNV) that occurred following surgical disruption of Bruch membrane during macular surgery. METHODS: A retrospective case series was compiled. Macular translocation surgery with punctate retinotomy was performed in two patients for subfoveal CNV, and pars plana vitrectomy with epiretinal membrane (ERM) peeling was performed in one patient for idiopathic ERM. RESULTS: CNV developed at a site of subretinal cannulation in two cases of macular translocation, and at a site of inadvertent injury to Bruch membrane with a vitreoretinal pick in the one case that underwent ERM peeling. CONCLUSIONS: These cases underscore the need to monitor breaks in Bruch membrane for CNV following macular surgery.

Contribution of pneumolysin and autolysin to the pathogenesis of experimental pneumococcal endophthalmitis.

PURPOSE: To determine the contribution of pneumolysin and autolysin, two putative pneumococcal virulence proteins, to the pathogenesis of Streptococcus pneumoniae endophthalmitis. METHODS: Endophthalmitis was established in Lewis rats by intravitreal injection of pneumococcal strains at an inoculum of 10 organisms. The virulence of three closely related type 2 S. pneumoniae strains were compared: a pneumolysin-deficient derivative (PLN-A), an autolysin-deficient derivative (AL-6), and their isogenic wild-type parent (D 39). Clinical and histologic inflammation scores were compared 24 hours and 48 hours after inoculation. RESULTS: Eyes infected with PLN-A and AL-6 strains showed less anterior segment inflammation clinically at 24 hours than did eyes infected with the wild-type strain. Histologic examination at 24 hours showed significantly less corneal infiltration and vitritis and more relative preservation of retinal tissue in eyes infected with PLN-A and AL-6 strains than in eyes infected with the wild-type strain. At 48 hours, no observable differences between PLN-A and wild-type strains were present clinically or histologically. Histologically, however, the AL-6 strain caused less retinal damage than did the wild-type strain. CONCLUSIONS: Intraocular infection with pneumolysin-deficient S. pneumoniae results in less severe tissue damage in the first 24 hours of disease compared with infection with pneumolysin-producing S. pneumoniae. Autolysin-deficient S. pneumoniae shows a similar degree of attenuated virulence. Pneumolysin and autolysin may contribute to the early pathogenesis of pneumococcal endophthalmitis.