Tamoxifen Treatment in Patients With Motor Neuron Disease
Tamoxifen has been reported to decrease TDP-43 aggregates in animal models of ALS via tamoxifen-induced autophagy \cite{Wang_2013}. In a small clinical trial, eighteen ALS patients without mutations in superoxide dismutase-1 (SOD-1) or fused in sarcoma (FUS) gene, were randomized to receive either 40 mg/day tamoxifen or placebo, with all participants receiving riluzole twice daily for a period of 1, 3 or 12 months \cite{Chen_2020}. The primary end-points of time to death or need for mechanical ventilation, was not statistically different between the tamoxifen vs placebo group at any of the time points. However, at a 1, 3 and 6 month evaluation, one of the two secondary end points, ALSFRS-R score, but not forced vital capacity (FVC), decreased less in the tamoxifen group, while there were no statistically significant differences of any end point observed at 12 months. The authors conclude that larger studies would be required to confirm the modest, although transient, improvement in ALSFRS-R scores in the tamoxifen group and whether enhanced autophagy to decrease TDP-43 results in clinical improvement of ALS, particularly if administered at the earliest stages of the disease.
Perampanel selective non-competitive AMPA receptor antagonist
Downreguation of adenosine deaminase acting on RNA 2 (ADAR2) occurs in sporadic ALS (sALS) \cite{Kawahara_2004} . ADAR2 is an RNA adenosine-to-inosine (A-to-I) mRNA editing enzyme. Modifying mRNA adenosine to inosine (translated into guanosine), results in new protein isoforms, and it is a dynamic process which diversifies the proteome \cite{Rosenthal2012}. The influx of Ca2+ through α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors is regulated by ADAR2 A-to-I editing. However, in sALS, ADAR2 is deficient and the majority of patients with sALS have a GluA2 subunit of the glutamate AMPA receptor that is unedited \cite{Kawahara_2004}. The outcome of this loss of glutamate AMPA editing is that Ca2+ permeability is elevated, and this has been associated with TDP-43 pathology. Perampanel is a non-competitive, selective antagonist of the AMPA receptor. In mice in which the AMPA receptor is knocked out in motor neurons to model sALS, perampanel greatly attenuates neuopathology, decreased motor neuron death and prevented the TDP-43 mislocalization from the nucleus to the cytoplasm \cite{Akamatsu2016}. Currently, there is an ongoing phase 2 clinical trial of perampanel, Perampanel for Sporadic Amyotrophic Lateral Sclerosis (ALS): A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group Phase 2 Trials, (ClinicalTrials.gov Identifier NCT0301941) consisting of placebo, 4mg and 8mg per day for 48 weeks and the primary endpoint of change in ALS functional rating scale. The results are currently unavailable \cite{Aizawa2019}.