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High cerebrospinal fluid levels of interleukin-10 attained by AAV in dogs

Gene Therapy volume 22, pages 202–208 (2015)Cite this article

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Abstract

Intrathecal (IT) gene transfer using adeno-associated virus (AAV) may be clinically promising as a treatment for chronic pain if it can produce sufficiently high levels of a transgene product in the cerebrospinal fluid (CSF). Although this strategy was developed in rodents, no studies investigating CSF levels of an analgesic or antiallodynic protein delivered by IT AAV have been performed in large animals. Interleukin-10 (IL-10) is an antiallodynic cytokine for which target therapeutic levels have been established in rats. The present study tested IT AAV8 encoding either human IL-10 (hIL-10) or enhanced green fluorescent protein (EGFP) in a dog model of IT drug delivery. AAV8/hIL-10 at a dose of 3.5 × 1012 genome copies induced high hIL-10 levels in the CSF, exceeding the target concentration previously found to be antiallodynic in rodents by >1000-fold. AAV8/EGFP targeted the primary sensory and motor neurons and the meninges. hIL-10, a xenogeneic protein in dogs, induced anti-hIL-10 antibodies detectable in the CSF and serum of dogs. The high hIL-10 levels demonstrate the efficacy of AAV for delivery of secreted transgenes into the IT space of large animals, suggesting a strong case for further development toward clinical testing.

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Acknowledgements

The study was supported by NIH Grant R01NS063022 and funds from the Schulze Family Foundation. We thank the anonymous reviewer for pointing toward the literature on cytokine exit from the CSF to the general circulation and references 23 and 24 included in the revised version of the manuscript.

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Authors and Affiliations

  1. Departments of Anesthesiology and Oncology, Mayo Clinic, Rochester, MN, USA

    J Pleticha, L F Heilmann, R Rezek & A S Beutler

  2. Department of Anesthesiology, University of California, San Diego, La Jolla, CA, USA

    S A Malkmus, S L Veesart, Q Xu & T L Yaksh

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  1. J Pleticha
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Correspondence to A S Beutler.

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Pleticha, J., Malkmus, S., Heilmann, L. et al. High cerebrospinal fluid levels of interleukin-10 attained by AAV in dogs. Gene Ther 22, 202–208 (2015). https://doi.org/10.1038/gt.2014.96

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