Furthermore, we have identified compounds with activity against DLK and LZK that potently promote survival of mouse and human RGCs, including the FDA-approved multi-kinase inhibitor sunitinib. We previously developed a primary cell-based method to perform high-throughput, functional genomic screening and we and others identified dual leucine zipper kinase (DLK MAP3K12) and leucine zipper kinase (LZK MAP3K13) as key mediators of RGC cell death in response in axonal injury. However, maintaining lower pressure can be challenging in some patients, and in others, even if significant pressure lowering is achieved, RGC loss continues. All of the current standard-of-care treatments for glaucoma are aimed at lowering intraocular pressure (IOP). Glaucoma is a neurodegenerative disease that causes irreversible vision loss due to the death of retinal ganglion cells (RGCs). Due to the rapid increase in the aging population, the number is expected to rise to 111 million by 2040. Glaucoma is the leading cause of irreversible blindness, impacting 80 million people worldwide. For a chronic disease such as glaucoma, a formulation that provides sustained therapeutic effects to complement IOP lowering therapies could provide improved disease management and promote patient quality of life. Importantly, therapeutically relevant retina drug concentrations were achieved with subconjunctival injection of SPC microcrystals in pigs. Furthermore, subconjunctival injection of SPC microcrystals also led to therapeutic effects in a rat model of corneal neovascularization. A single subconjunctival injection of sunitinib-pamoate complex (SPC) microcrystals provided 20 weeks of sustained retina drug levels, leading to neuroprotection in a rat model of optic nerve injury. Here, we describe an ion complexation approach for formulating microcrystals containing ~50% loading of a protein kinase inhibitor, sunitinib, to enhance survival of RGCs with subconjunctival injection. A complementary strategy to IOP reduction is the use of neuroprotective agents that interrupt the process of cell death by mechanisms independent of IOP. However, degeneration of retinal ganglion cells (RGCs) may continue to progress despite extensive lowering of IOP. Elevated intraocular pressure (IOP) is one of the major risk factors for glaucoma onset and progression, and available pharmaceutical interventions are exclusively targeted at IOP lowering. Glaucoma is the leading cause of irreversible blindness worldwide.
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