Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited treatment options. Glial cell line-derived neurotrophic factor (GDNF) is an anti-inflammatory neuroprotective molecule that promotes neuronal survival. GDNF has been proposed as a therapeutic agent for ALS; however, systemic administration of GDNF is challenging due to its short plasma half-life and limited ability to cross the blood-brain barrier (BBB). Therefore, we evaluated the treatment effect of a novel, stabilized variant of GDNF in the SOD1 mouse model of ALS.
Six-week-old male mice, 1) B6SJL/J mice (TBS-vehicle, IP, BIW), 2) B6SJL-Tg (SOD1*G93A)1Gur/J mice (SOD1) (TBS-vehicle, IP, BIW), and 3) SOD1 mice (GDNF 10 mg/kg, IP, BIW) were dosed for 8 weeks (n=11). GDNF exposure was confirmed in serum and spinal cord tissue of treated mice, indicating accumulation in the CNS. At the end of the study, vehicle-treated SOD1 mice exhibited significantly decreased grip strength and electrophysiology outcomes compared to B6SJL/J mice. In contrast, GDNF-treated SOD1 mice preserved their grip strength, demonstrating significantly greater strength at the end of the study compared to vehicle-treated SOD1 mice (p = 0.0013). GDNF-treated SOD1 mice demonstrated improved compound muscle action potentials and significantly better response to repetitive nerve stimulation (RNS) across various frequency settings compared to vehicle-treated SOD1 mice. These findings suggest that GDNF treatment enhanced neuromuscular transmission and increased fatigue resistance. In addition, GDNF treatment led to a shift in the immune microenvironment of the quadriceps, resulting in the repolarization of macrophages toward an anti-inflammatory and pro-repair state, as indicated by the expression of CD86 and CD206. Overall, these data suggest that treatment with a stable GDNF molecule has the potential to preserve muscle strength, facilitate signal conduction to skeletal muscle, and remodel the inflammatory environment in skeletal muscle. Therefore, a stable GDNF could serve as a promising therapeutic strategy for treating ALS.