Cocaine abuse vaccine TA-CD(ImmuLogic Pharmaceutical)

Inflammation and neovascularization are key pathological events in human age-related macular degeneration (AMD). Activated microglia/macrophages (mi/ma) and retinal pigmented epithelium (RPE) play an active role in every stage of disease progression. Systemic therapies that can target these cells and address both inflammation and neovascularization will broaden the impact of existing therapies and potentially open new avenues for early AMD where there are no viable therapies. Utilizing a clinically relevant rat model of AMD that mirrors many aspects that of human AMD pathological events, we show that systemic hydroxyl-terminated polyamidoamine dendrimer-triamcinolone acetonide conjugate (D-TA) is selectively taken up by the injured mi/ma and RPE (without the need for targeting ligands). D-TA suppresses choroidal neovascularization significantly (by >80%, >50-fold better than free drug), attenuates inflammation in the choroid and retina, by limiting macrophage infiltration in the pathological area, significantly suppressing pro-inflammatory cytokines and pro-angiogenic factors, with minimal side effects to healthy ocular tissue and other organs. In ex vivo studies on human postmortem diabetic eyes, the dendrimer is also taken up into choroidal macrophages. These results suggest that the systemic hydroxyl dendrimer-drugs can offer new avenues for therapies in treating early/dry AMD and late/neovascular AMD alone, or in combination with current anti-VEGF therapies. This hydroxyl dendrimer platform but conjugated to a different drug is undergoing clinical trials for severe COVID-19, potentially paving the way for faster clinical translation of similar compounds for ocular and retinal disorders.

Diabetic retinopathy (DR) is the leading cause of blindness in working‐age adults. Severe visual loss in DR is primarily due to proliferative diabetic retinopathy, characterized by pathologic preretinal angiogenesis driven by retinal ischemia. Microglia, the resident immune cells of the retina, have emerged as a potentially important regulator of pathologic retinal angiogenesis. Corticosteroids including triamcinolone acetonide (TA), known for their antiangiogenic effects, are used in treating retinal diseases, but their use is significantly limited by side effects including cataracts and glaucoma. Generation‐4 hydroxyl polyamidoamine dendrimer nanoparticles are utilized to deliver TA to activated microglia in the ischemic retina in a mouse model of oxygen‐induced retinopathy (OIR). Following intravitreal injection, dendrimer‐conjugated TA (D‐TA) exhibits selective localization and sustained retention in activated microglia in disease‐associated areas of the retina. D‐TA, but not free TA, suppresses inflammatory cytokine production, microglial activation, and preretinal neovascularization in OIR. In addition, D‐TA, but not free TA, ameliorates OIR‐induced neuroretinal and visual dysfunction. These results indicate that activated microglia are a promising therapeutic target for retinal angiogenesis and neuroprotection in ischemic retinal diseases. Furthermore, dendrimer‐based targeted therapy and specifically D‐TA constitute a promising treatment approach for DR, offering increased and sustained drug efficacy with reduced side effects.