Effect of neurophilin ligands on motor units in mice with SOD1 ALS mutations

Background: Mice with trangenes that express mutations in the gene for cyto solic copper/zinc superoxide dismutase (SOD1) develop motor neuron degenera tion resembling human ALS. Neurophilin ligands are small molecules that pro mote neurite outgrowth. Objective: To test the hypothesis that treatment wi th two neurophilin ligands increases survival in these ALS mice by slowing the loss of motor neurons and increasing the sizes of motor units. Methods: Transgenic mice hemizygous for the G93A mutation were untreated or treated from 30 days of age with one of two doses of two neurophilin ligands (V-13 ,670; V-10,367, Vertex Pharmaceuticals, Boston, MA). Onset of behavioral ab normalities and survival were recorded. Motor unit number estimation (MUNE) was performed every 21 days starting at age 60 days. Results: In control a nimals, disease onset occurred at 77.0 days of age and death occurred at 13 7 days of age. Neither neurophilin ligand affected the disease course. In c ontrol animals, MUNE declined with time beginning before behavioral abnorma lities were noted, and motor unit size increased concomitantly. There was n o effect of drug on motor unit loss as assessed by MUNE; however, motor uni t size increased more rapidly and to a greater degree in animals treated wi th V-13,670. Conclusion: As in human ALS, the transgenic ALS mice show phys iologic changes in the motor unit prior to the development of clinical sign s: MUNE declines as motor unit size increases. Although neither neurophilin ligand significantly affected survival, one produced an increase in motor unit size. The fact that survival was not altered by the increase in motor unit size may reflect the rapid disease course in this animal model.