000101251 001__ 101251
000101251 005__ 20181203020748.0
000101251 0247_ $$2doi$$a10.1093/hmg/9.5.803
000101251 022__ $$a0964-6906
000101251 037__ $$aARTICLE
000101251 245__ $$aIncreased motoneuron survival and improved neuromuscular function in transgenic ALS mice after intraspinal injection of an adeno-associated virus encoding Bcl-2
000101251 260__ $$c2000
000101251 269__ $$a2000
000101251 336__ $$aJournal Articles
000101251 500__ $$aDivision of Surgical Research and Gene Therapy Center, Lausanne University Medical School, Pavillon 4, 1011 Lausanne, Switzerland. mazzouz@chuv.hospvd.ch
000101251 520__ $$aMutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) underlie some familial cases of amyotrophic lateral sclerosis (ALS), a neurodegenerative disorder characterized by loss of cortical, brainstem and spinal motoneurons. Transgenic mice over- expressing a mutated form of human SOD1 containing a Gly-->Ala substitution at position 93 (SOD1(G93A)) develop a severe, progressive motoneuron disease. We investigated the potential of recombinant adeno-associated virus (rAAV) to transfer neuroprotective molecules in this animal ALS model. Initial experiments showed that injection of an rAAV vector encoding green fluorescent protein unilaterally into the lumbar spinal cord of wild-type mice leads to expression of the reporter gene in 34.7 +/- 5.2% of the motoneurons surrounding the injection site. Intraspinal injection of an rAAV encoding the anti-apoptotic protein bcl-2 in SOD1 (G93A) mice resulted in sustained bcl-2 expression in motoneurons and significantly increased the number of surviving motoneurons at the end-stage of disease. Moreover, the compound muscle action potential amplitude elicited by nerve stimulation and recorded by electromyographic measurements was higher in the rAAV-bcl-2-treated group than in controls. Local bcl-2 expression in spinal motoneurons delayed the appearance of signs of motor deficiency but was not sufficient to prolong the survival of SOD1 (G93A) mice. To our know-ledge, this study describes the first successful transduction and protection of spinal motoneurons by direct gene transfer in a model of progressive motoneuron disease. Our results support the use of AAVs for the delivery of protective genes to spinal cord moto-neurons as a possible way to enhance motoneuron survival and repair.
000101251 6531_ $$aAnimals
000101251 6531_ $$aBase Sequence
000101251 6531_ $$aCell Survival
000101251 6531_ $$aDNA Primers
000101251 6531_ $$aDependovirus/ genetics
000101251 6531_ $$aGenes
000101251 6531_ $$abcl-2
000101251 6531_ $$aHumans
000101251 6531_ $$aInjections
000101251 6531_ $$aSpinal
000101251 6531_ $$aMice
000101251 6531_ $$aMice
000101251 6531_ $$aInbred C57BL
000101251 6531_ $$aMice
000101251 6531_ $$aTransgenic
000101251 6531_ $$aMotor Neurons/ cytology
000101251 6531_ $$aMuscles/cytology/ innervation/physiology
000101251 6531_ $$aTransduction
000101251 6531_ $$aGenetic
000101251 700__ $$aAzzouz, M.
000101251 700__ $$aHottinger, A.
000101251 700__ $$aPaterna, J. C.
000101251 700__ $$aZurn, A. D.
000101251 700__ $$0240206$$g104359$$aAebischer, P.
000101251 700__ $$aBueler, H.
000101251 773__ $$j9$$tHum Mol Genet$$k5$$q803-11
000101251 909C0 $$xU10457$$0252067$$pLEN
000101251 909CO $$pSV$$particle$$ooai:infoscience.tind.io:101251
000101251 937__ $$aLEN-ARTICLE-2000-010
000101251 970__ $$a72/LEN
000101251 973__ $$rREVIEWED$$sPUBLISHED$$aEPFL
000101251 980__ $$aARTICLE