Motor neurons of sporadic amyotrophic lateral sclerosis (ALS) patients exhibit inefficient RNA editing at the GluA2 glutamine/arginine (Q/R) site, which is the disease-specific molecular abnormalities. RNA editing at this site is specifically catalyzed by adenosine deaminase acting on RNA 2 (ADAR2), and motor neurons devoid of ADAR2 activity express abnormally Ca²⁺-permeable AMPA receptors that contain Q/R site-unedited GluA2. We developed conditional ADAR2 knockout (AR2) mice, in which the ADAR2 gene was targeted in cholinergic neurons including spinal motor neurons, and AR2 mice exhibited ALS-like progressive motor dysfunction resulting from death of motor neurons.
Therefore, enhancement of ADAR2 activity in the motor neurons would be a therapeutic strategy for ALS, and we attempt to deliver the ADAR2 gene to the mouse motor neurons using an adeno-associated virus serotype 9 (AAV9) vector. A single intravenous injection of AAV9-ADAR2 in the AR2 mice caused expression of exogenous ADAR2 in the central neurons, and effectively prevented death of motor neurons and the resultant progressive motor dysfunction. Moreover, motor neurons exhibited normal nuclear localization of TDP-43 instead of TDP-43 pathology seen in the motor neurons of untreated AR2 mice. This AAV9-mediated ADAR2 gene delivery may therefore enable the development of a gene therapy for ALS.