Grant: Project Grant

Hyperkalemic Periodic Paralysis (HyperKPP) is a neuromuscular disease that is characterized by periods of myotonia weakness and paralysis. Few treatment options are available to patients suffering of HyperKPP, and in many cases they lose efficacy over time. Using a HyperKPP mouse model, we first found that HyperKPP muscles are weaker than normal; i.e., they generate less force. Then, we found that activating two proteins in the cell membrane, an ion transporter and one ion channel, can provide a novel therapy that fully restores force development back to normal levels. There is also evidence that the activity of two of these proteins can be increased using a drug that activates protein kinase A (PKA). This is advantageous because a single drug can be used to activate PKA instead of two drugs, reducing the extent of side effects. More importantly, it is proposed to test the efficacy of three already Federal Drug Administration (FDA) approved drugs that are used to treat various diseases via an activation of protein kinase A. In a first series of experiments, we will determine in vitro how effective each of three drugs is at increasing force generation in HyperKPP muscles toward that of normal muscles. In a second series of experiments, we will treat HyperKPP mice with the most effective drug to determine how effective they are at improving force generation over long period of time; i.e., to make sure they do not lose effectiveness over time. If successful, the ultimate aim will be to initiate clinical trials.