[Perampanel for Sporadic Amyotrophic Lateral Sclerosis].

ABSTRACT

Disease-specific and site-selective deficiency of an RNA editing enzyme, adenosine deaminase acting on RNA 2 (ADAR2), has been demonstrated in sporadic amyotrophic lateral sclerosis (sALS) motor neurons. ADAR2 regulates Ca2+ influx through α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors via adenosine-to-inosine conversion at the glutamine/arginine site of GluA2 mRNA, which makes ADAR2 a key factor in acquired Ca2+ resistance in motor neurons. Deficient ADAR2 of sALS motor neurons is supposed to lead to excessive Ca2+ influx through AMPA receptors, resulting in TDP-43 pathology and nuclear pore complex pathology, and eventually motor neuronal death. We considered that AMPA receptor antagonists could strongly prevent excessive Ca2+ influx through AMPA receptors and block motor neuronal degeneration in sALS. Perampanel, a selective non-competitive AMPA receptor antagonist, has been reported to prevent deterioration in a mouse model for sALS, in which ADAR2 is conditionally knocked out in motor neurons. Because of the therapeutic potency of perampanel for sporadic ALS, we have performed a multicenter randomized, double-blinded, placebo-controlled, parallel-group phase 2 clinical trial. The primary outcome measure is the change in ALS functional rating scale-revised after 48 weeks of treatment. The results of this study will be available in early 2020.