Global CNS gene delivery and evasion of anti-AAV-neutralizing antibodies by intrathecal AAV administration in non-human primates
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Open Access
- 10 January 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in Gene Therapy
- Vol. 20 (4), 450-459
- https://doi.org/10.1038/gt.2012.101
Abstract
Injection of adeno-associated virus (AAV) into the cerebrospinal fluid (CSF) offers a means to achieve widespread transgene delivery to the central nervous system, where the doses can be readily translated from small to large animals. In contrast to studies with other serotypes (AAV2, AAV4 and AAV5) in rodents, we report that a naturally occurring capsid (AAV9) and rationally engineered capsid (AAV2.5) are able to achieve broad transduction throughout the brain and spinal cord parenchyma following a single injection into the CSF (via cisterna magna or lumbar cistern) in non-human primates (NHP). Using either vector at a dose of ∼2 × 1012 vector genome (vg) per 3–6 kg animal, approximately 2% of the entire brain and spinal cord was transduced, covering all regions of the central nervous system (CNS). AAV9 in particular displayed efficient transduction of spinal cord motor neurons. The peripheral organ biodistribution was highly reduced compared with intravascular delivery, and the presence of circulating anti-AAV-neutralizing antibodies up to a 1:128 titer had no inhibitory effect on CNS gene transfer. Intra-CSF delivery effectively translates from rodents to NHPs, which provides encouragement for the use of this approach in humans to treat motor neuron and lysosomal storage diseases.Keywords
This publication has 31 references indexed in Scilit:
- Adeno-Associated Virus Serotype 9 Transduction in the Central Nervous System of Nonhuman PrimatesHuman Gene Therapy, 2012
- Phase 1 Gene Therapy for Duchenne Muscular Dystrophy Using a Translational Optimized AAV VectorMolecular Therapy, 2012
- Optimizing Promoters for Recombinant Adeno-Associated Virus-Mediated Gene Expression in the Peripheral and Central Nervous System Using Self-Complementary VectorsHuman Gene Therapy, 2011
- Preclinical Differences of Intravascular AAV9 Delivery to Neurons and Glia: A Comparative Study of Adult Mice and Nonhuman PrimatesMolecular Therapy, 2011
- Intrathecal Delivery of a Mutant μ-Opioid Receptor Activated by Naloxone as a Possible Antinociceptive ParadigmJournal of Pharmacology and Experimental Therapeutics, 2010
- Directed Evolution of a Novel Adeno-associated Virus (AAV) Vector That Crosses the Seizure-compromised Blood–Brain Barrier (BBB)Molecular Therapy, 2010
- Differential Adeno-Associated Virus Mediated Gene Transfer to Sensory Neurons following Intrathecal Delivery by Direct Lumbar PunctureMolecular Pain, 2010
- Intravenous Administration of Self-complementary AAV9 Enables Transgene Delivery to Adult Motor NeuronsMolecular Therapy, 2009
- Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytesNature Biotechnology, 2008
- Sensory neuron targeting by self-complementary AAV8 via lumbar puncture for chronic painProceedings of the National Academy of Sciences of the United States of America, 2008