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Mol Ther. 2015 Mar;23(3):477-87. doi: 10.1038/mt.2014.210. Epub 2014 Oct 31.

Improving single injection CSF delivery of AAV9-mediated gene therapy for SMA: a dose-response study in mice and nonhuman primates.

Author information

1
The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.
2
Department of Molecular & Cellular Biochemistry, The Ohio State University Medical Center, Columbus, Ohio, USA.
3
1] The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA [2] Molecular, Cellular & Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio, USA.
4
Department of Neuroscience, The Ohio State University, Columbus, Ohio, USA.
5
Mannheimer Foundation, Inc., Homestead, Florida, USA.
6
1] The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA [2] Molecular, Cellular & Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio, USA [3] Department of Neuroscience, The Ohio State University, Columbus, Ohio, USA.

Abstract

Spinal muscular atrophy (SMA) is the most frequent lethal genetic neurodegenerative disorder in infants. The disease is caused by low abundance of the survival of motor neuron (SMN) protein leading to motor neuron degeneration and progressive paralysis. We previously demonstrated that a single intravenous injection (IV) of self-complementary adeno-associated virus-9 carrying the human SMN cDNA (scAAV9-SMN) resulted in widespread transgene expression in spinal cord motor neurons in SMA mice as well as nonhuman primates and complete rescue of the disease phenotype in mice. Here, we evaluated the dosing and efficacy of scAAV9-SMN delivered directly to the cerebral spinal fluid (CSF) via single injection. We found widespread transgene expression throughout the spinal cord in mice and nonhuman primates when using a 10 times lower dose compared to the IV application. Interestingly, in nonhuman primates, lower doses than in mice can be used for similar motor neuron targeting efficiency. Moreover, the transduction efficacy is further improved when subjects are kept in the Trendelenburg position to facilitate spreading of the vector. We present a detailed analysis of transduction levels throughout the brain, brainstem, and spinal cord of nonhuman primates, providing new guidance for translation toward therapy for a wide range of neurodegenerative disorders.

PMID:
25358252
PMCID:
PMC4351452
DOI:
10.1038/mt.2014.210
[Indexed for MEDLINE]
Free PMC Article

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