Biomaterial Inhibitor of HIF-1 for Prolonged Anti-Angiogenesis in Eye

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 DESCRIPTION: Age-related macular degeneration (AMD) and proliferative diabetic retinopathy (PDR) are major causes of blindness and visual impairment. Vascular endothelial growth factor (VEGF) plays a critical role in the development and progression of neovascular AMD and the current standard of care is monthly intraocular injections of ranibizumab (Lucentis(r)), an antibody fragment that specifically blocks VEGF; two other VEGF binding proteins, bevacizumab (Avastin(r)) and VEGF Trap-eye (Eylea(r)), provide similar benefits. Frequent office visits and injections are necessary to suppress disease progression, however, they also create significant burden on elderly patients, their families, and the health care system, and the risk of severe vision loss from endophthalmitis increases with increased number of injections. Moreover, attempts to reduce visit and injection frequency leave uncovered periods, increasing the chance of subretinal fibrosis and/or hemorrhage and reduced visual outcomes. Therefore, new sustained delivery treatments that provide constant protection are needed. To address this unmet need, we are developing a polymer-drug conjugate technology. In preliminary studies, we have demonstrated that doxorubicin (DXR), an inhibitor of hypoxia-inducible factor-1 (HIF-1), strongly suppresses and causes regression of ocular neovascularization (NV), but has a short duration of action and narrow therapeutic window. In contrast, our pilot data shows that microparticles of a novel DXR- polymer conjugate (DXR-PSA-PEG3) prolong anti-angiogenic activity at very low DXR doses. Particles that are 0.65 µm in diameter suppressed ocular NV in rho/VEGF transgenic mice, in which the rhodopsin promoter drives expression of VEGF in photoreceptors, for 5 weeks, more than twice as long in the same animal model as a 10 µg/µL intraocular injection of ranibizumab, the same concentration used in humans. No toxicity was observed using sensitive methods, even at 100-times the effective dose. Our pilot data also shows that the polymer particles cause down-regulation of multiple HIF-1 controlled pro-angiogenesis factors, leading to regression of NV (current therapies only reduce leaking from NV). We hypothesize that modifications of the DXR-polymer and microparticle size will allow suppression of ocular NV after a single intraocular injection for several months without causing toxicity, an important step in the development of a new treatment for neovascular AMD and ischemic retinopathies such as diabetic retinopathy. In Specific Aim 1, we will develop and fully characterize new polymers and microsphere formulations that release DXR- monomer conjugates continuously in vitro over much longer periods of time than previously achieved. In Specific Aim 2, we will determine the maximum tolerated dose (MTD) and perform pharmacokinetic (PK) and safety studies in rodents on promising formulations from Aim 1. In Specific Aim 3, we will test the efficacy, including the duration of efficacy, of lead formulations from Specific Aim 2 in animal models of ocular NV. If these pre-clinical studies proceed as expected, we are well-positioned for translation into the clinic.