Genome-editing regulation of alternative splicing provides new therapeutic opportunities for episodic ataxia type II

We aim at developing a gene therapy beneficial for all episodic ataxia type 2 (EA2) patients. Efficient communication between brain cells relies on calcium channels, molecules that regulate neurotransmitter release from brain cells. There are three types of calcium channels. EA2, which causes recurrent disabling attacks of imbalance, vertigo and ataxia, is due to genetic defects in the most efficient of these channels, the P/Q-type. When the function of P/Q-type channels is impaired, brain cells produce more of the other two types of calcium channels in the attempt to restore normal brain communication. This is however without success. Crucially, each type of calcium channel comes in many different variants. We have recently found that some of these variants support brain communication with higher efficiency than others and that only P/Q-type channels are present in the brain with high efficient variants. We reasoned that the calcium channels up-regulated in EA2 would substitute more effectively for the defective P/Q-type channels if we could switch them into their highly efficient variants. To this end, we will use genome editing, a technology that allows researchers to modify genes of interest. We will use it to switch the non-P/Q-type calcium channels from low to high efficient variants, and we will test whether this improves locomotor disabilities in rodents. Due to its extreme flexibility, genome editing is a most promising technology for developing therapeutic applications. More than eighty genetic defects impairing the function of P/Q-type channels have been identified in EA2 patients. Because we take advantage of a general up-regulation of non-P/Q-type calcium channels, rather than targeting individual genetic defects, our approach may open the possibility of a gene therapy beneficial for all EA2 patients.