Anetta E. Wronska

Statins lower cholesterol, reducing the risk of heart disease, and are among the most frequently prescribed drugs. Approximately 10% of individuals develop statin-associated muscle symptoms (SAMS; myalgias, rhabdomyolysis, and muscle weakness), often rendering them statin intolerant. The mechanism underlying SAMS remains poorly understood. Patients with mutations in the skeletal muscle ryanodine receptor 1 (RyR1)/calcium release channel can be particularly intolerant of statins. High-resolution structures revealed simvastatin binding sites in the pore region of RyR1. Simvastatin stabilized the open conformation of the pore and activated the RyR1 channel. In a mouse expressing a mutant RyR1-T4709M found in a patient with profound statin intolerance, simvastatin caused muscle weakness associated with leaky RyR1 channels. Cotreatment with a Rycal drug that stabilizes the channel closed state prevented simvastatin-induced muscle weakness. Thus, statin binding to RyR1 can cause SAMS, and patients with RyR1 mutations may represent a high-risk group for statin intolerance.

RyR1-related myopathies (RyR1-RMs) include a wide range of genetic disorders that result from mutations in the RYR1 gene. Pathogenic variants lead to defective intracellular calcium homeostasis and muscle dysfunction. Fixing intracellular calcium leaks by stabilizing the RyR1 calcium channel has been identified as a promising therapeutic target. Gene therapy via prime editing also holds great promise as it can cure diseases by correcting genetic mutations. However, as more than 700 variants have been identified in the RYR1 gene, a universal treatment would be a more suitable solution for patients. Our investigation into the RyR1-S2843A mutation has yielded promising results. Using a calcium leak assay, we determined that the S2843A mutation was protective when combined with pathogenic mutations and significantly reduced the Ca²⁺ leak of the RyR1 channel. Our study demonstrated that prime editing can efficiently introduce the protective S2843A mutation. In vitro experiments using the RNA electroporation of the prime editing components in human myoblasts achieved a 31% introduction of this mutation. This article lays the foundation for a new therapeutic approach for RyR1-RM, where a unique once-in-a-lifetime prime editing treatment could potentially be universally applied to all patients with a leaky RyR1 channel.