Spinal Muscular Atrophy (SMA) is a genetic disease that is caused by a mutation in the SMN1 gene that greatly reduces the synthesis of the SMN protein. This leads to a loss of motoneurons which reduces lifespan. Recent FDA-approved SMN-targeted treatments prevent motoneuron loss and improve lifespan, but motor strength deficits persist, especially for patients who do not receive these SMN-targeted treatments early in life.
We have pursued a SMN-independent therapeutic approach that can rescue motor strength deficits and improve quality of life. We developed GV-58 as a Cav2-selective gating modifier that stabilizes the open state of the channel, increasing calcium influx into the motor nerve terminal only during normal action potential activity. Such an approach could be used independently or in combination with SMN-targeted therapies.
We used the severe SMA mouse model, SMN?7, to test the effects of GV-58. SMN?7 mice have profound neuromuscular deficits and generally live for only about 2 weeks. First, we evaluated the in vivo effect on grip strength at P10 before and after an acute subcutaneous injection GV-58 alone or in combination with a potassium channel blocker (DAP). This single injection increased grip strength by 36%. In these mice, we also evaluated the effects of GV-58 + DAP in ex vivo neuromuscular synapses using electrophysiology to measure the magnitude of transmitter release. We found that quantal content (a measurement of the magnitude of synaptic vesicle release during stimulation) was very weak in SMN?7 mice but increased significantly by an average of 44% after application of GV-58 + DAP.
Therefore, we have developed a peripherally targeted calcium channel gating modifier that can be used alone or in combination with a potassium channel blocker to increase neuromuscular transmitter release and behavioral measures of muscle strength in SMA model mice.