Choroidal neovascularization (CNV) represents the most common cause of severe vision loss in patients with age-related macular degeneration (AMD). It is also the most common cause of legal blindness in the United States in patients over the age of 60. Therefore, the study of the diagnosis, prevention and treatment of this condition would have a major impact on the public health.? The laboratory is heavily involved in drug development for the treatment of neovascular AMD. These efforts are within the realm of drug delivery and drug formulation development. Within drug delivery, the laboratory is focusing on the use of sustained implant technology. One important aspect of this work is focusing on the ability of drugs to cross the scleral and allow for extraocular placement of these devices. Published work has reported on our observations that physiologic rather than physical barriers appear to limit drug penetration into the eye. Using a gadolinium implant, work in both alive and dead rabbits showed a dramatic difference in ocular drug penetration highlighting the importance of these physiologic barriers. In a further extension of this work in rabbits, various techniques to alter these physiologic barriers including cryotherapy to reduce choroidal blood flow and removal of conjunctival tissue to alter choroidal vascular and lymphatic elimination routes demonstrated the importance of these physiologic barriers. Further work using MRI imaging has established the importance of this technique is assessing ocular drug distribution especially within the realm of the real time in-vivo situation. Given the dramatic changes seen in the post-mortem experiments, confirmation of in-vivo correlates are essential. Several on-going projects of extraocular drug delivery are focusing on the use of implants releasing carboxyamido-triazole (CAI), 2-methoxyestradiol (2-ME2) and cyclosporine. In particular, implantation of cyclosporine implants in horses has reiterated the importance of the exact barriers to ocular drug penetration. For example, in this work, cyclosporine implants when placed in the surprachoroidal space of horses resulted in dramatic reductions in the clinical appearace of ocular inflammation while identical implants when placed into the subconjunctival space demonstrated no efficacy. In anticipation of an ocular clinical trial with this type of implant, work in rabbits on a subconjunctival implant releasing cyclosporine demonstrated the safety of this implant as well as the substantial increases in tissue distribution and levels of drug as compared with topical administration. This results has now been translated to an on-going clinical trial being performed at the Intramural program of the National Eye Institute entitled """"""""A Phase I Clinical Trial to Study the Safety of a Sustained-Release Subconjunctival Cyclosporine Implant for Ocular Graft-Vs-Host Disease (GVHD1) """""""". ? Focusing on the need for improvements in anti-angiogenic agents and modes of delivery, work is continuing on the sustained drug delivery of two integrin antagonists, EMD 0587 and a short peptide, C16Y, both of which have been shown in the laboratory to have anti-angiogenic effects in a laser-induced model of CNV. Additionally work is continuing on studying the pharmacokinetics of intravitreal antibody injections and the development of a novel formulation of triamcinolone acetonide for intravitreal and subconjunctival use.
