Treatment of Proliferative Vitreoretinopathy using Aerosolized Methotrexate

Project Summary Proliferative vitreoretinopathy (PVR) is a major complication of retinal detachments and is responsible for most of the failures in retinal reattachment surgeries. About 10% of retinal detachment patients suffer from PVR. These patients often have poor visual outcome despite multiple surgeries. Our previous work on inhibition of PVR has focused on pharmacological intervention concurrent with the retinal reattachment surgery. We have developed an autologous porcine PVR model (APPM) that provides a PVR-affected model eye with anatomical features comparable to human eye. Further, we ensure that the model is based on retinal injury and dispersion of retinal pigment epithelial (RPE) cells and not exogenous cells or proteolytic intervention as used in prior research. Our model is closest in pathophysiology to the human disease. For drug delivery, we have developed a novel intraocular aerosol generator (IAG), which generates a fine mist of drug solution at the tip of a needle. IAG allows dispersing microgram quantities of therapeutic agents on the retina in a gas-filled vitrectomized eye, which is often the post-operative state of the eye in retinal reattachment surgeries. In recent years, methotrexate has emerged as a promising agent for the treatment of PVR due to its potential to block several PVR mechanisms simultaneously including inflammation, fibrosis and neoplastic cell proliferation. However, it has not been accepted in the clinical practice due to the lack of an effective delivery method. The present proposal is aimed at developing aerosolized methotrexate delivery as a treatment for PVR utilizing IAG in APPM for preclinical evaluation. In this Phase I project, we will conduct in-vitro evaluations followed by a pilot in-vivo study to examine the therapeutic effect of one, two and three weekly treatments with methotrexate. This work will also spur development of a general-purpose aerosolized intraocular drug delivery platform, which would be available for treating various eye conditions.PROJECT NARRATIVE This proposed project is relevant to public health as it addresses an important need in ocular health, i.e. inhibition of scar tissue growth in retinal detachment, which results in failures of retinal reattachment surgeries. Using a novel device and state-of-the-art animal model, this work would enable delivery of a scar-inhibiting drug, so as to improve the visual outcome for the patients prone to retinal scar tissue growth. Further, this project will introduce a novel and practicable intraocular drug delivery modality for the treatment of various eye diseases, including macular degeneration.