Widespread and Efficient Transduction of Spinal Cord and Brain Following Neonatal AAV Injection and Potential Disease Modifying Effect in ALS Mice

被引：52

作者：

Ayers, Jacob I. ^{[1
,2
]}

Fromholt, Susan ^{[1
,2
]}

Sinyavskaya, Olga ^{[1
,2
]}

Siemienski, Zoe ^{[1
,2
]}

Rosario, Awilda M. ^{[1
,2
]}

Li, Andrew ^{[1
,2
]}

Crosby, Keith W. ^{[1
,2
]}

Cruz, Pedro E. ^{[1
,2
]}

DiNunno, Nadia M. ^{[1
,2
]}

Janus, Christopher ^{[1
,2
]}

Ceballos-Diaz, Carolina ^{[1
,2
]}

Borchelt, David R. ^{[1
,2
]}

Golde, Todd E. ^{[1
,2
]}

Chakrabarty, Paramita ^{[1
,2
]}

Levites, Yona ^{[1
,2
]}

机构：

[1] Univ Florida, Coll Med, Ctr Translat Res Neurodegenerat Dis, Dept Neurosci, Gainesville, FL 32610 USA

[2] Univ Florida, Coll Med, McKnight Brain Inst, Gainesville, FL 32610 USA

来源：

MOLECULAR THERAPY | 2015年 / 23卷 / 01期

关键词：

ADENOASSOCIATED VIRAL VECTORS; AMYOTROPHIC-LATERAL-SCLEROSIS; REGULATORY T-LYMPHOCYTES; CENTRAL-NERVOUS-SYSTEM; GENE DELIVERY; MOUSE MODEL; AMYLOID-BETA; HIPPOCAMPAL EXPRESSION; ALZHEIMERS-DISEASE; MUSCULAR-ATROPHY;

D O I：

10.1038/mt.2014.180

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：

The architecture of the spinal cord makes efficient delivery of recombinant adeno-associated virus (rAAV) vectors throughout the neuraxis challenging. We describe a paradigm in which small amounts of virus delivered intraspinally to newborn mice result in robust rAAV-mediated transgene expression in the spinal cord. We compared the efficacy of rAAV2/1, 2/5, 2/8, and 2/9 encoding EGFP delivered to the hindlimb muscle (IM), cisterna magna (ICM), or lumbar spinal cord (IS) of neonatal pups. IS injection of all four capsids resulted in robust transduction of the spinal cord with rAAV2/5, 2/8, and 2/9 vectors appearing to be transported to brain. ICM injection resulted in widespread expression of EGFP in the brain, and upper spinal cord. IM injection resulted in robust muscle expression, with only rAAV2/8 and 2/9 transducing spinal motor and sensory neurons. As proof of concept, we use the IS paradigm to express murine Interleukin (IL)-10 in the spinal cord of the SOD1-G93A transgenic mouse model of amyotrophic lateral sclerosis. We show that expression of IL-10 in the spinal axis of SOD1-G93A mice altered the immune milieu and significantly prolonged survival. These data establish an efficient paradigm for somatic transgene delivery of therapeutic biologics to the spinal cord of mice.

引用

页码：53 / 62

页数：10

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