ALS is a progressive neurodegenerative disease characterized by increasing muscle weakness and muscle tissue atrophies, which lead to one’s death in a couple of years. ALS develops mainly in middle-aged or older people. At this time, there are no effective treatments stopping the progression. Most ALS patients (more than 90%) have sporadic ALS which is not transmittable, however the cause of ALS has not been understood for a long time. These collaborative researchers disclosed in various papers published in Nature etc.*2) about the expression of unedited GluA2 originally produced in GluA2 subunit of glutamate AMPA receptors, and that this is a specific molecular abnormality caused by lower gene expression of ADAR2 which is a RNA editing enzyme. The expression of unedited GluA2 is the cause of cell death and pathology of TDP-43 which is a neuropathological benchmark, thus this cell death cascade is deeply related to the cause of sporadic ALS. These findings mean the normalization of ADAR2 activation is the target gene therapy*3).
Gene Therapy Research Institution plays an active role in early implementation of gene therapy by preparing the application of advanced medical care, and confirming the results of this preclinical research.
*1) Kwak, S. et al: EMBO Mol Med 5, 1710–1719, 2013
*2) Kwak, S. et al: Nature 427, 801, 2004
*3) Kwak, S. et al: Neurobiol Dis 45, 1121–1128, 2012
■Outline of the research
Research performer: The University of Tokyo and Jichi Medical University
Collaborative researcher: Gene Therapy Research Institution
Research subject: Preclinical research of ALS gene therapy by administering AAV vector-ADAR2 expression
Research content: Preclinical research of gene therapy by using AAV vector-ADAR2 expression for ALS (crab-eating monkeys), and to ensure a safe study by intrathecal administration.
Research term (plan): August 2014 to June 2015
Number of cases (plan): 3, 4 cases