孤発性ALSに対するペランパネル

Perampanel for Sporadic Amyotrophic Lateral Sclerosis

孤発性筋萎縮性側索硬化症（ALS）の運動ニューロンではAMPA型グルタミン酸受容体を構成しているGluA2のQ/R部位の編集率が低下しており，AMPA受容体を介したCa^2＋流入が過剰となり，最終的に運動ニューロン死に至ると考えられる。実際，AMPA受容体拮抗薬ペランパネルの全身投与は，ALSの病態モデルマウスの病態進行を有意に阻止した。現在，孤発性ALSを対象としたペランパネルの無作為化二重盲検臨床試験を行い，2020年春にはその結果が得られる。

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.