Spinocerebellar Ataxias (SCA) are dominantly inherited disorders resulting in progressive ophthalmoplegia, dysarthria, and gait imbalance. In disease mouse models, large conductance calcium-activated potassium (BK) channel dysfunction is common to multiple polyQ SCAs. Restoration of BK channel expression and function results in improved motor function and delayed cerebellar degeneration. The goal of this work is to identify compounds that augment BK channel function as therapy for SCA.

In conjunction with Nanion Technologies, we have demonstrated feasibility of a BK channel screen using the SyncroPatch 384i. With a 2-component internal solution, seal rate is excellent and activated BK currents are maintained for up to 2.5 hours. The current could be blocked by TEA, and weakly augmented (as expected) by NS1619. These preliminary studies are indicative of a viable platform for HTS against BK and identification of both agonists and antagonists.

Here, we introduce a next-generation APC platform for HTS to identify compounds that augment BK channel current in the presence of low intracellular calcium. The most promising agents will be further tested with dose-response curves and then confirmed by manual patch clamp. Future development will focus on improving drug-like properties with finalized compounds tested in SCA mouse models. In this manner, we will make significant progress towards specific therapy for this debilitating group of disorders.