title: Intrathecal Delivery of ssAAV9-DAO Extends Survival in SOD1G93AALS Mice.
abstract: Amyotrophic lateral sclerosis (ALS) is an adult-onset, irreversible neurodegenerative disease that leads to progressive paralysis and inevitable death 3-5 years after diagnosis. The mechanisms underlying this process remain unknown, but new evidence indicates that accumulating levels of D-serine result from the downregulation of D-amino acid oxidase (DAO) and that this is a novel mechanism that leads to motoneuronal death in ALS via N-methyl-D-aspartate receptor-mediated cell toxicity. Here, we explored a new therapeutic approach to ALS by overexpressing DAO in the lumbar region of the mouse spinal cord using a single stranded adeno-associated virus serotype 9 (ssAAV9) vector. A single intrathecal injection of ssAAV9-DAO was made in SOD1G93Amice, a well-established mouse model of ALS. Treatment resulted in moderate expression of exogenous DAO in motorneurons in the lumbar spinal cord, reduced immunoreactivity of D-serine, alleviated motoneuronal loss and glial activation, and extended survival. The potential mechanisms underlying these effects were associated with the down-regulation of NF-κB and the restoration of the phosphorylation of Akt. In conclusion, administering ssAAV9-DAO may be an effective complementary approach to gene therapy to extend lifespans in symptomatic ALS.
authors.affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China.
authors.forename: Wan
authors.initials: W
authors.lastname: Wang
authors.affiliation: Neurological Laboratory of Hebei Province, Shijiazhuang, 050000, Hebei, People's Republic of China.
authors.forename: Weisong
authors.initials: W
authors.lastname: Duan
authors.affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China.
authors.forename: Di
authors.initials: D
authors.lastname: Wen
authors.affiliation: Neurological Laboratory of Hebei Province, Shijiazhuang, 050000, Hebei, People's Republic of China.
authors.forename: Yakun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Neurological Laboratory of Hebei Province, Shijiazhuang, 050000, Hebei, People's Republic of China.
authors.forename: Zhongyao
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China.
authors.forename: Haojie
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China.
authors.forename: Hongying
authors.initials: H
authors.lastname: Cui
authors.affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China.
authors.forename: Can
authors.initials: C
authors.lastname: Cui
authors.affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China.
authors.forename: Huiqian
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Neurology, Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People's Republic of China. hebeichunyanli@aliyun.com.|Institute of Cardiocerebrovascular Disease, West Heping Road 215, Shijiazhuang, 050000, Hebei, People's Republic of China. hebeichunyanli@aliyun.com.|Neurological Laboratory of Hebei Province, Shijiazhuang, 050000, Hebei, People's Republic of China. hebeichunyanli@aliyun.com.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Li
mesh_terms: D000581:Amidohydrolases / Q000008:administration & dosage / Q000096:biosynthesis* / Q000235:genetics; D000690:Amyotrophic Lateral Sclerosis / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D000229:Dependovirus / Q000235:genetics; D005260:Female; D018014:Gene Transfer Techniques; D057809:HEK293 Cells; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D013482:Superoxide Dismutase / Q000235:genetics; D015996:Survival Rate / Q000639:trends
chemical_list: C109415:SOD1 G93A protein; D013482:Superoxide Dismutase; D000581:Amidohydrolases; C407355:D-amino acid amidase
keywords: Adeno-associated virus; Akt; Amyotrophic lateral sclerosis; D-Amino acid oxidase; NF-κB