Pharmacological modulation of ion currents for treatment of exfoliation glaucoma

The overall objective of the proposed study is identification of the potent and selective maxi-K+ channel agonist that can be developed as a topical drug for the treatment of exfoliation glaucoma. Open-angle glaucoma is a multifactorial optic neuropathy characterized by degeneration of retinal ganglion cells and atrophy of the optic nerve. High intraocular pressure (IOP) is a causative risk factor contributing to the glaucomatous optic neuropathy. While the majority of glaucoma patients can be effectively managed using current IOP-lowering medications, the treatment of exfoliation glaucoma (XFG), which accounts for 25% of glaucoma cases, remains to be a significant challenge. XFG is an aggressive form of the disease which is refractory to current glaucoma therapies. XFG has large diurnal IOP fluctuations and tends to progress more rapidly carrying worse prognosis and a higher risk of blindness. Developing a topical drug therapy (eye drops) for the effective diurnal control of IOP in exfoliation glaucoma addresses a highly significant unmet medical need in ophthalmology. XFG is caused by the accumulation of extracellular protein aggregates called exfoliation material (XFM) in ocular tissues. XFM blocks the fluid outflow through the trabecular meshwork, elevating IOP. Based on experimental evidence, it was suggested that an abnormal capacity of the lysosomal-autophagic system for trafficking and degradation of its cargo underpins the development of XFM aggregates in XFG. Lysosomal maxi-K+ channels play a pivotal role in regulation of Ca2+ dynamics in the lysosomes. Activation of the lysosomal maxi-K+ channels seems to be required for the fusion of lysosomes with autophagosomes and for degradation of the autophagosomal cargo. Maxi-K+ channel overexpression or its pharmacological activation with agonists rescues disease phenotypes associated with deficiencies in lysosomal degradation and trafficking. We hypothesize that pharmacological activation of lysosomal maxi- K+ channels can normalize the dysfunction in the autophagic-lysosomal system seen in XFG thus limiting the XFM production. While activation of the lysosomal channels would inhibit the XFM formation, activation of plasma membrane maxi-K+ channels may additionally contribute to IOP reduction in XFG by stimulating ocular fluid outflow. We propose the development of a topical maxi-K+ agonist that activate both plasma membrane and lysosomal maxi-K+ channels as a treatment for exfoliation glaucoma. A starting compound exemplifying a group of maxi-K+ agonists is proposed for optimization in the current study. We characterized the starting compound in a battery of established assays and determined its in vitro ADME characteristics. The compound exhibits a micromolar potency in the primary assay which indicates the need for its additional optimization. The studies outlined in this proposal seek to conduct SAR optimization and provide evidence of the in vivo efficacy for this new class of drug candidates (Aim 1) and to explore the novel in vivo biomarker that can facilitate pre-clinical and clinical development of maxi-K+ agonists as a new class of XFG therapies (Aim 2).