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

From the Department of Neurology (Dr. Shefner), Upstate Medical University, Syracuse, NY; Cecil B. Day Laboratory for Neuromuscular Research (Drs. Brown and Cudkowicz, K. Pastuszak, M. Upton–Rice, and R. Matthews) and Neurology Clinical Trial Unit (Drs. Cudkowicz and Schoenfeld), Massachusetts General Hospital, Boston; and Vertex Pharmaceuticals (Drs. Cole and Chaturvedi), Boston, MA.

Address correspondence and reprint requests to Dr. J.M. Shefner, Department of Neurology, Upstate Medical University, 750 East Adams Street, Syracuse, NY 13210; e-mail: shefnerj{at}upstate.edu

Background:— Mice with trangenes that express mutations in the gene for cytosolic copper/zinc superoxide dismutase (SOD1) develop motor neuron degeneration resembling human ALS. Neurophilin ligands are small molecules that promote neurite outgrowth.

Objective:— To test the hypothesis that treatment with 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 abnormalities and survival were recorded. Motor unit number estimation (MUNE) was performed every 21 days starting at age 60 days.

Results:— In control animals, disease onset occurred at 77.0 days of age and death occurred at 137 days of age. Neither neurophilin ligand affected the disease course. In control animals, MUNE declined with time beginning before behavioral abnormalities were noted, and motor unit size increased concomitantly. There was no effect of drug on motor unit loss as assessed by MUNE; however, motor unit size increased more rapidly and to a greater degree in animals treated with V-13,670.

Conclusion:— As in human ALS, the transgenic ALS mice show physiologic changes in the motor unit prior to the development of clinical signs: 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.

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