Myasthenia gravis (MG) is a neuromuscular disease resulting in compromised transmission of electrical signals at the neuromuscular junction from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function, and present symptoms of severe muscle weakness and fatigue. Even with currently available immunological based treatments, there is an unmet need for treatment.
Here we present a comparative study of a ClC-1 inhibitor and an FcRn blocker, alone and in combination, in a generalized MG (EAMG rat model of MG) investigating muscle strength (Grip strength) and muscle electrical signals (CMAP) during 14-day repeated dosing. Groups of EAMG rats were treated with either a ClC-1 channel inhibitor (skeletal muscle specific chloride channel), an FcRn blocker (1G3, an anti-rat FcRn mAb), alone and in combination. Vehicle and dexamethasone were included as controls. FcRn plays a critical role in IgG homeostasis and blocking it shortens the half-life of IgG with positive effects on autoimmune diseases like MG. The ClC-1 channel plays an important role in stabilizing the resting membrane potential during activity of skeletal muscle, regulating muscle fiber excitability. ClC-1 inhibition has been shown to improve muscle function and performance in rat models of MG and in patients with MG.
In summary we show that administration of a ClC-1 inhibitor alone or in combination with an FcRn blocker improves neuromuscular transmission and muscle function in the EAMG model.