Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal neurodegenerative disorder involving the progressive loss of motor neurons of the brain and spinal cord. Because ALS treatments available to date have largely failed to demonstrate substantial benefits, there is an exigent need for new, effective treatments. Recent discoveries have converged on metabolic and energetic dysregulation as potential drug targets for treatment of this disease. The hallmarks of energetic dysregulation in ALS include lipid dysregulation, insufficient oxidative respiration, mitochondrial dysfunction, and accumulation of excitotoxic and oxidative stress, leading to neuronal death.
CNM-Au8 is a concentrated aqueous suspension of highly catalytic gold nanocrystals being developed as a neuroprotective therapeutic. The blood-brain barrier penetrant, cell-permeant gold nanocrystals of CNM-Au8 both restore energetic homeostasis via mitochondrial complex I-like activity, as well as reduce oxidative stress via catalase-like activity. Here we demonstrate CNM-Au8’s ability to promote neuronal survival and function in multiple independent in vitro models of ALS: (i) treatment of primary rat spinal motor neurons improves survival, preserves the neurite networks, and reduces cytoplasmic TDP-43 aggregate accumulation after either glutamate excitotoxic injury or exposure to beta-amyloid (A? 1-42) oligomers; (ii) treatment of spinal motor neurons from transgenic SOD1(G93A) rats protects motor neurons from death upon exposure to excitotoxic glutamate in a cAMP-dependent manner, and reduces SOD1 protein accumulation in a manner independent of cAMP; (iii) treatment of human induced pluripotent stem cell (iPSC)-derived neurons from C9ORF72 patients prevents their death in response to stress caused by mild neurotrophic factor withdrawal. Finally, we show (iv) survival and neurite outgrowth of human iPSC-derived motor neurons in co-culture with toxic, SOD1(A4V) ALS-patient derived astrocytes are substantially and dose-dependently improved with treatment of CNM-Au8. These results indicate that addressing the deficits of ALS with the energetic catalyst CNM-Au8 may be a promising new therapeutic strategy.