Researching with rats in 2013, Shin KWAK, extraordinary professor, Clinical Research Center for Medicine, International University of Health and Welfare (Visiting research fellow, Faculty of Medicine, The University of Tokyo, and advisor, Gene Therapy Research Institution) and his research group developed adeno-associated virus (rAAV9/3) vector with Shin-ichi MURAMATSU, extraordinary professor, Jichi Medical University (member of the board, Gene Therapy Research Institution). rAAV9/3 vector promotes gene expression by generating ADAR2 (RNA editing enzyme) only in motor neurons in the brain and spinal cord. When administering this vector into blood vessels of model rats with sporadic ALS, the normalization of the function of TDP-43, which is a specific alteration for ALS was confirmed. The research group succeeded in stopping the alteration, the defluxion of motor neurons, and the progression of ALS for the first time in the world. They verified their 2013 research*1) with model rats as safe by replicating their study with large animals (crab-eating monkeys).
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
