000163760 001__ 163760
000163760 005__ 20181203022321.0
000163760 022__ $$a1525-0024
000163760 02470 $$2ISI$$a000286923000011
000163760 0247_ $$2doi$$a10.1038/mt.2010.260
000163760 037__ $$aARTICLE
000163760 245__ $$aNeuroprotection by Gene Therapy Targeting Mutant SOD1 in Individual Pools of Motor Neurons Does not Translate Into Therapeutic Benefit in fALS Mice
000163760 269__ $$a2010
000163760 260__ $$bElsevier$$c2010
000163760 336__ $$aJournal Articles
000163760 520__ $$aA major challenge in neurological gene therapy is delivery of the transgene to sufficient cell numbers in an atraumatic manner. This is particularly difficult for motor neuron (MN) diseases that have cells located across the entire spinal cord, brain stem, and cortex. We have used the familial mouse model of amyotrophic lateral sclerosis (ALS) to examine the feasibility of body-wide intramuscular injections of adeno-associated virus serotype 6 (AAV6), a vector capable of axonal retrograde transport, to deliver therapeutic genetic information across the lower MN axis. Neonatal muscle delivery of AAV expressing small hairpin RNAs (shRNAs) against the toxic transgene in this model, human mutant superoxide dismutase 1 (mSOD1), led to significant mSOD1 knockdown in the muscle as well as innervating MNs. This knockdown conferred neuroprotection and halted muscle atrophy in individually targeted MN pools. However, despite the vector being targeted to MNs that innervate muscle groups controlling eating, breathing, and locomotion, this approach was unable to therapeutically impact on disease progression in the ALS mouse model. These results stress the complexity of gene delivery for mSOD1 silencing and suggest that critical thresholds of protein knockdown and transduction across various cell types are required to translate local neuroprotective effects into functional improvements.
000163760 6531_ $$aAmyotrophic-Lateral-Sclerosis
000163760 6531_ $$aAdenoassociated Virus Vectors
000163760 6531_ $$aTransgenic Als Mice
000163760 6531_ $$aMouse Model
000163760 6531_ $$aDisease Progression
000163760 6531_ $$aProlongs Survival
000163760 6531_ $$aRna Interference
000163760 6531_ $$aSkeletal-Muscle
000163760 6531_ $$aDelivery
000163760 6531_ $$aDegeneration
000163760 700__ $$aTowne, Chris
000163760 700__ $$0242580$$aSetola, Veronica$$g181819
000163760 700__ $$aSchneider, Bernard L.
000163760 700__ $$0240206$$aAebischer, Patrick$$g104359
000163760 773__ $$j19$$k2$$q274-83$$tMolecular therapy : the journal of the American Society of Gene Therapy
000163760 909C0 $$0252067$$pLEN$$xU10457
000163760 909CO $$ooai:infoscience.tind.io:163760$$pSV$$particle
000163760 917Z8 $$x150283
000163760 937__ $$aEPFL-ARTICLE-163760
000163760 973__ $$aEPFL$$rREVIEWED$$sPUBLISHED
000163760 980__ $$aARTICLE