Researchers in the Department of Physiology in the School of Medicine have identified a novel method for the treatment of periodic paralysis. This approach focuses on a type of potassium channel that the team has newly discovered which can be modulated to relieve or prevent episodes of periodic paralysis with an FDA-approved drug.
BACKGROUND:
Periodic paralysis is a rare genetic disorder that impact skeletal muscles and leads to bouts of extreme muscle paralysis lasting from minutes to hours, and impair quality of life and cause morbidity. This disorder comes in several forms such as Hypokalemic periodic paralysis (HypoPP), Hyperkalemic periodic paralysis (HyperPP), and Andersen Tawil Syndrome; each caused by mutations in genes encoding ion channels within skeletal muscle and with an estimated prevalence of 1 in 100,000, respectively. The muscle weakness in Periodic paralysis stems from impaired electrical excitability in the muscle fibers, which has been liked to failure to maintain the usual "resting potential" for skeletal muscle, leaving the muscle unable to initiate contraction. Unfortunately, current treatment interventions are limited and mostly focus on environmental trigger avoidance, the use of potassium supplements, and certain diuretics that are restricted from patients with additional health complications. One widely accepted strategy for the treatment of periodic paralysis is to increase the muscle membrane's permeability to potassium ions using ATP-sensitive potassium channel openers; however, the necessary dosages may be high and often lead to hypotensive effects, thus making this approach not a sustainable long term treatment strategy. Currently, there is still a need for improved modes of management for patients who may experience periodic paralysis.
INNOVATION:
Researchers at UCLA led by Dr. Stephen Cannon have discovered an effective approach for the treatment of ongoing Periodic paralysis symptoms which can be used as a preventative prophylactic treatment ahead of Periodic paralysis episodes. Dr. Cannon’s team discovered that a class of potassium channels, previously not reported to occur in skeletal muscle, could be targeted for the management of Periodic paralysis. In HypoPP models, selective channel modulation with small molecules either prevented or reversed the episodic loss of force associated with the disease. Furthermore, they have discovered that Retigabine, a selective agonist and potassium channel opener, can be used to reduce or prevent partial paralysis-associated phenotype in these HypoPP models. Benefit and reduction of episodes was also found in mouse models of HyperPP and in pharmacological model of Andersen-Tawil Syndrome. This data shows promise for such an approach, in addition to Retigabine as a treatment to mitigate and prevent periodic paralysis episodes, even with commonly occurring mutations.
POTENTIAL APPLICATIONS:
- Primary treatment for recovery from episodes of Periodic Paralysis.
- Prophylactic therapy to prevent or reduce the severity and frequency of muscle weakness attacks in patients with Periodic paralysis.
ADVANTAGES:
- Retigabine can serve as an emergency treatment during a Periodic paralysis attack and as a preventive measure.
- Retigabine is FDA-approved for seizures and has existing patient data which would aid approval and safety data for its use in Periodic paralysis
- Retigabine is effective at low doses, avoiding risks associated with high-dosage treatments, such as hypotensive effects.
DEVELOPMENT-TO-DATE:
Approach has been tested and shown success in the field standard ex-vivo assays of the HypoPP, mouse models of HyperPP, and pharmacological models of Andersen-Tawil Syndrome.
Related Papers (from the inventors only):
Quiñonez M, DiFranco M, Wu F, Cannon SC. Retigabine suppresses loss of force in mouse models of hypokalaemic periodic paralysis. Brain. 2023 Apr 19;146(4):1554-1560. doi: 10.1093/brain/awac441. PMID: 36718088; PMCID: PMC10115351