CNS-targeted Viral Delivery of G-CSF in an Animal Model for ALS: Improved Efficacy and Preservation of the Neuromuscular Unit

被引:47
作者
Henriques, Alexandre [1 ,2 ,3 ]
Pitzer, Claudia [1 ]
Dittgen, Tanjew [1 ]
Klugmann, Matthias [4 ]
Dupuis, Luc [2 ,3 ]
Schneider, Armin [1 ]
机构
[1] SYGNIS Biosci, Dept Mol Neurol, D-69120 Heidelberg, Germany
[2] INSERM, U692, Strasbourg, France
[3] Univ Strasbourg, Fac Med, UMRS692, Strasbourg, France
[4] Univ New S Wales, Sch Med Sci, Dept Physiol, Translat Neurosci Facil, Sydney, NSW, Australia
关键词
AMYOTROPHIC-LATERAL-SCLEROSIS; COLONY-STIMULATING FACTOR; PARKINSONS-DISEASE; MOTOR-NEURONS; GENE-TRANSFER; MOUSE MODEL; TRANSDUCTION; MICE; EXPRESSION; TRIAL;
D O I
10.1038/mt.2010.271
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motoneurons. We have recently uncovered a new neurotrophic growth factor, granulocyte-colony stimulating factor (G-CSF), which protects alpha-motoneurons, improves functional outcome, and increases life expectancy of SOD-1 (G93A) mice when delivered subcutaneously. However, chronic systemic delivery of G-CSF is complicated by elevation of neutrophilic granulocytes. Here, we used adeno-associated virus (AAV) to directly target and confine G-CSF expression to the spinal cord. Whereas intramuscular injection of AAV failed to transduce motoneurons retrogradely, and caused a high systemic load of G-CSF, intraspinal delivery led to a highly specific enrichment of G-CSF in the spinal cord with moderate peripheral effects. Intraspinal delivery improved motor functions, delayed disease progression, and increased survival by 10%, longer than after systemic delivery. Mechanistically, we could show that G-CSF in addition to rescuing motoneurons improved neuromuscular junction (NMJ) integrity and enhanced motor axon regeneration after nerve crush injury. Collectively, our results show that intraspinal delivery improves efficacy of G-CSF treatment in an ALS mouse model while minimizing the systemic load of G-CSF, suggesting a new therapeutic option for ALS treatment.
引用
收藏
页码:284 / 292
页数:9
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[1]   ADENOVIRUS-ASSOCIATED DEFECTIVE VIRUS PARTICLES [J].
ATCHISON, RW ;
CASTO, BC ;
HAMMON, WM .
SCIENCE, 1965, 149 (3685) :754-&
[2]   Onset and progression in inherited ALS determined by motor neurons and microglia [J].
Boillee, Severine ;
Yamanaka, Koji ;
Lobsiger, Christian S. ;
Copeland, Neal G. ;
Jenkins, Nancy A. ;
Kassiotis, George ;
Kollias, George ;
Cleveland, Don W. .
SCIENCE, 2006, 312 (5778) :1389-1392
[3]   Viral vectors: from virology to transgene expression [J].
Bouard, D. ;
Alazard-Dany, N. ;
Cosset, F-L .
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[4]   Self-complementary AAV Virus (scAAV) Safe and Long-term Gene Transfer in the Trabecular Meshwork of Living Rats and Monkeys [J].
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Kaufman, Paul L. ;
Borras, Teresa .
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[5]   Amyotrophic lateral sclerosis:: all roads lead to Rome [J].
de Aguilar, Jose-Luis Gonzalez ;
Echaniz-Laguna, Andoni ;
Fergani, Anissa ;
Rene, Frederique ;
Meininger, Vincent ;
Loeffler, Jean-Philippe ;
Dupuis, Luc .
JOURNAL OF NEUROCHEMISTRY, 2007, 101 (05) :1153-1160
[6]   Delivery of AAV-IGF-1 to the CNS extends survival in ALS mice through modification of aberrant glial cell activity [J].
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Roskelley, Eric M. ;
Treleaven, Christopher M. ;
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Martin, Heather ;
Kim, Soo H. ;
Kaspar, Rita ;
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Griffiths, Denise A. ;
Cheng, Seng H. ;
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Kaspar, Brian K. .
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Douar, Anne-Marie ;
Fyfe, John ;
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Colle, Marie-Anne ;
Barkats, Martine .
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[9]   Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man [J].
Fischer, LR ;
Culver, DG ;
Tennant, P ;
Davis, AA ;
Wang, MS ;
Castellano-Sanchez, A ;
Khan, J ;
Polak, MA ;
Glass, JD .
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