title: Intramuscular Delivery of scAAV9-hIGF1 Prolongs Survival in the hSOD1G93AALS Mouse Model via Upregulation of D-Amino Acid Oxidase.
abstract: Self-complementary adeno-associated viral vector 9 (scAAV9) has been confirmed to be an efficient AAV serotype for gene transfer to the central nervous system (CNS). Neurotrophic factors have been considered to be therapeutic targets for amyotrophic lateral sclerosis (ALS). In the present study, we intramuscularly injected scAAV9 encoding human insulin-like growth factor 1 (hIGF1) into an hSOD1G93AALS mouse model. We observed that scAAV9-hIGF1 significantly reduced the loss of motor neurons of the anterior horn in the lumbar spinal cord and delayed muscle atrophy in ALS mice. Importantly, IGF1 significantly delayed disease onset and prolonged the life span of ALS mice. In addition, scAAV9-hIGF1 protected motor neurons from apoptosis through upregulation of D-amino acid oxidase (DAO), which controls the level of D-serine. Moreover, to further verify these results, we used CRISPR-Cas9 system to target the central nervous system knockdown of IGF1. This experiment supported the continued investigation of neurotrophic factor gene therapies targeting the central nervous system as a potential treatment for ALS.
authors.affiliation: Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.|Department of Neurology, The First Hospital of Shijiazhuang City, Shijiazhuang, China.
authors.forename: HuiQian
authors.initials: H
authors.lastname: Lin
authors.affiliation: Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: HaoJie
authors.initials: H
authors.lastname: Hu
authors.affiliation: Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.|Key Laboratory of Hebei Neurology, Shijiazhuang, China.
authors.forename: WeiSong
authors.initials: W
authors.lastname: Duan
authors.affiliation: Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.|Key Laboratory of Hebei Neurology, Shijiazhuang, China.
authors.forename: YaLing
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.|Key Laboratory of Hebei Neurology, Shijiazhuang, China.
authors.forename: GuoJun
authors.initials: G
authors.lastname: Tan
authors.affiliation: Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.|Key Laboratory of Hebei Neurology, Shijiazhuang, China.
authors.forename: ZhongYao
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.|Key Laboratory of Hebei Neurology, Shijiazhuang, China.
authors.forename: YaKun
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: BinBin
authors.initials: B
authors.lastname: Deng
authors.affiliation: Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.|Key Laboratory of Hebei Neurology, Shijiazhuang, China.
authors.forename: XueQin
authors.initials: X
authors.lastname: Song
authors.affiliation: Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: Wan
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: Di
authors.initials: D
authors.lastname: Wen
authors.affiliation: Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, China. hebeichunyanli@aliyun.com.|Key Laboratory of Hebei Neurology, Shijiazhuang, China. hebeichunyanli@aliyun.com.
authors.forename: ChunYan
authors.initials: C
authors.lastname: Li
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000473:pathology*; D000818:Animals; D017209:Apoptosis; D003605:D-Amino-Acid Oxidase / Q000378:metabolism*; D000229:Dependovirus / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D018014:Gene Transfer Techniques; D006801:Humans; D007273:Injections, Intramuscular; D007334:Insulin-Like Growth Factor I / Q000008:administration & dosage*; D008297:Male; D008822:Mice, Transgenic; D009046:Motor Neurons / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism; D009133:Muscular Atrophy / Q000473:pathology; D010641:Phenotype; D000094704:RNA, Guide, CRISPR-Cas Systems / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013482:Superoxide Dismutase / Q000378:metabolism*; D016019:Survival Analysis; D014161:Transduction, Genetic; D015854:Up-Regulation
chemical_list: C583557:IGF1 protein, human; D000094704:RNA, Guide, CRISPR-Cas Systems; D012694:Serine; D007334:Insulin-Like Growth Factor I; D013482:Superoxide Dismutase; D003605:D-Amino-Acid Oxidase
keywords: Amyotrophic lateral sclerosis; CRISPR-Cas9; D-amino acid oxidase; Gene therapy; Insulin-like growth factor 1; ScAAV9