Mislocalization and aggregation of the protein TDP-43 is observed in ~97% of people living with amyotrophic lateral sclerosis (ALS) and is associated with a loss of mitochondrial ultrastructure and function. RNS60, an experimental treatment for acute ischemic stroke and ALS, has previously been reported to enhance mitochondrial function in preclinical models. Therefore, we studied the effects of RNS60 on mitochondrial health in a TDP-43 mouse model of ALS.

In this study, RNS60 treatment significantly preserved the structural integrity of mitochondria in upper motor neurons and spinal cord motor neurons compared to vehicle treated controls. Moreover, RNS60 treatment also enhanced mitochondrial membrane polarization, which indicates improved mitochondrial function in motor neurons. Consistent with earlier findings, RNS60 treatment reduced the extent of glial inflammation (astrogliosis and microgliosis, which are key pathological drivers of neurodegeneration) in the motor cortex and spinal cord, preserved more motor neurons compared to control, and enhanced the proportion of intact neuromuscular junctions in limb and diaphragm muscles.

These results suggest that RNS60 treatment protects motor neurons in ALS by preserving mitochondrial structure and function, preserving neuromuscular junction integrity, and reducing gliosis. The protective effect on the diaphragm neuromuscular junctions might explain the observed slowing of forced vital capacity, a marker of respiratory function, in people living with ALS treated with RNS60 compared to those treated with placebo in a prior clinical Phase 2 Study^1,2