Topical delivery of HIF-1 inhibitors for retinal and choroidal vascular diseases

PROJECT SUMMARY Injectable therapies for blocking vascular endothelial growth factor (VEGF) have provided impressive initial benefits to most patients with neovascular age-related macular degeneration (nAMD), though some have a suboptimal response. Other vasoactive proteins in addition to VEGF may contribute to the progression of nAMD. An alternative strategy would be to target hypoxia-inducible factor 1 (HIF-1), which is a master regulator of these other vasoactive proteins. We have demonstrated that intraocular delivery of HIF-1 inhibitors is effective in preventing retinal neovascularization (RNV) and choroidal neovascularization (CNV) in a variety of mouse models, where achieving therapeutically relevant drug levels without reaching toxic concentrations is both achievable and key in developing an effective treatment strategy. Another drawback of anti-VEGF therapies has been the disappointing long-term outcomes, as the injections do not eliminate CNV but rather temporarily stop vessel growth and leakage. Further, the short duration of action requires that injections be repeated every 1-2 months. When injections are missed, vessels continue to grow and leak, resulting in permanent retinal damage. One solution is to develop a non-invasive treatment that can be self-administered by patients so that treatment can continue even when patients are unable to return to their retina specialist. However, thus far, it has not been possible to deliver adequate amounts of drug to the retina in large animals (like humans) by topical eye drops. We have discovered an approach for effectively delivering drugs to the posterior segment in large animals, including rabbits and pigs, with once daily topical eye drops. Our unique eye drop-based drug delivery technology provides improved intraocular delivery of both water soluble and water insoluble drugs, including acriflavine. We hypothesize that a new hypotonic gelling eye drop formulation designed to maximize the residence time, intraocular penetration, and drug delivery to the posterior segment with minimal toxicity will be an important step toward the development of a new eye drop-based treatment for nAMD and other ocular diseases with neovascular sequelae. In Specific Aim 1, we will develop and fully characterize new polymer blends for optimal viscosity, shear thinning, gelation rate, and intraocular penetration of acriflavine. In Specific Aim 2, we will test gelling formulations optimized for various key properties versus standard liquid eye drops for maximum tolerated dose and efficacy in preventing CNV in a rat model. In Specific Aim 3, we will evaluate ocular pharmacokinetics and efficacy in rabbits, which are considered a relevant animal model to humans, particularly for characterizing delivery to the posterior segment with topical formulations. We will further evaluate ocular biocompatibility in rabbits, the most commonly used animal model to assess safety of ocular products due to the similarities in eye structure and the sensitivity of the eye to potential toxicity. If these preclinical studies progress as expected, we will be well-positioned for translation of a first-of-its-kind eye drop to the clinic.