PMID- 24008656
OWN - NLM
STAT- MEDLINE
DCOM- 20140725
LR  - 20240104
IS  - 1525-0024 (Electronic)
IS  - 1525-0016 (Print)
IS  - 1525-0016 (Linking)
VI  - 21
IP  - 12
DP  - 2013 Dec
TI  - Therapeutic AAV9-mediated suppression of mutant SOD1 slows disease progression 
      and extends survival in models of inherited ALS.
PG  - 2148-59
LID - 10.1038/mt.2013.211 [doi]
AB  - Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic 
      lateral sclerosis (ALS) resulting in progressive motor neuron death through one 
      or more acquired toxicities. Involvement of wild-type SOD1 has been linked to 
      sporadic ALS, as misfolded SOD1 has been reported in affected tissues of sporadic 
      patients and toxicity of astrocytes derived from sporadic ALS patients to motor 
      neurons has been reported to be reduced by lowering the synthesis of SOD1. We now 
      report slowed disease onset and progression in two mouse models following 
      therapeutic delivery using a single peripheral injection of an adeno-associated 
      virus serotype 9 (AAV9) encoding an shRNA to reduce the synthesis of ALS-causing 
      human SOD1 mutants. Delivery to young mice that develop aggressive, fatal 
      paralysis extended survival by delaying both disease onset and slowing 
      progression. In a later-onset model, AAV9 delivery after onset markedly slowed 
      disease progression and significantly extended survival. Moreover, AAV9 delivered 
      intrathecally to nonhuman primates is demonstrated to yield robust SOD1 
      suppression in motor neurons and glia throughout the spinal cord and therefore, 
      setting the stage for AAV9-mediated therapy in human clinical trials.
FAU - Foust, Kevin D
AU  - Foust KD
AD  - Department of Neuroscience, The Ohio State University, Columbus, Ohio, USA.
FAU - Salazar, Desiree L
AU  - Salazar DL
FAU - Likhite, Shibi
AU  - Likhite S
FAU - Ferraiuolo, Laura
AU  - Ferraiuolo L
FAU - Ditsworth, Dara
AU  - Ditsworth D
FAU - Ilieva, Hristelina
AU  - Ilieva H
FAU - Meyer, Kathrin
AU  - Meyer K
FAU - Schmelzer, Leah
AU  - Schmelzer L
FAU - Braun, Lyndsey
AU  - Braun L
FAU - Cleveland, Don W
AU  - Cleveland DW
FAU - Kaspar, Brian K
AU  - Kaspar BK
LA  - eng
GR  - NS027036/NS/NINDS NIH HHS/United States
GR  - F32 NS073269/NS/NINDS NIH HHS/United States
GR  - 089701/Wellcome Trust/United Kingdom
GR  - R37 NS027036/NS/NINDS NIH HHS/United States
GR  - K12 GM068524/GM/NIGMS NIH HHS/United States
GR  - R21-NS067238/NS/NINDS NIH HHS/United States
GR  - R01 NS027036/NS/NINDS NIH HHS/United States
GR  - R21 NS067238/NS/NINDS NIH HHS/United States
GR  - RC2 NS069476/NS/NINDS NIH HHS/United States
GR  - RC2 NS69476-01/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130906
PL  - United States
TA  - Mol Ther
JT  - Molecular therapy : the journal of the American Society of Gene Therapy
JID - 100890581
RN  - 0 (RNA, Small Interfering)
RN  - 0 (SOD1 protein, human)
RN  - EC 1.15.1.1 (Sod1 protein, mouse)
RN  - EC 1.15.1.1 (Superoxide Dismutase)
RN  - EC 1.15.1.1 (Superoxide Dismutase-1)
RN  - Amyotrophic lateral sclerosis 1
SB  - IM
MH  - Administration, Intravenous
MH  - Amyotrophic Lateral Sclerosis/genetics/*pathology/*therapy
MH  - Animals
MH  - COS Cells
MH  - Chlorocebus aethiops
MH  - Dependovirus/*genetics
MH  - Disease Models, Animal
MH  - Disease Progression
MH  - Female
MH  - *Genetic Therapy
MH  - Genetic Vectors
MH  - HEK293 Cells
MH  - Humans
MH  - Injections, Spinal
MH  - Macaca fascicularis
MH  - Mice
MH  - Motor Neurons/*metabolism/pathology
MH  - Neuroglia/*metabolism/pathology
MH  - RNA, Small Interfering/*genetics
MH  - Superoxide Dismutase/*genetics/metabolism
MH  - Superoxide Dismutase-1
PMC - PMC3863799
EDAT- 2013/09/07 06:00
MHDA- 2014/07/26 06:00
PMCR- 2014/12/01
CRDT- 2013/09/07 06:00
PHST- 2013/07/17 00:00 [received]
PHST- 2013/08/25 00:00 [accepted]
PHST- 2013/09/07 06:00 [entrez]
PHST- 2013/09/07 06:00 [pubmed]
PHST- 2014/07/26 06:00 [medline]
PHST- 2014/12/01 00:00 [pmc-release]
AID - S1525-0016(16)30941-8 [pii]
AID - 10.1038/mt.2013.211 [doi]
PST - ppublish
SO  - Mol Ther. 2013 Dec;21(12):2148-59. doi: 10.1038/mt.2013.211. Epub 2013 Sep 6.