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

J. Pleticha, S. A. Malkmus, L. F. Heilmann, S. L. Veesart, R. Rezek, Q. Xu, T. L. Yaksh, Andreas S Beutler

Research output: Contribution to journalArticle

9 Citations (Scopus)

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 × 10 12 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.

Original languageEnglish (US)
Pages (from-to)202-208
Number of pages7
JournalGene Therapy
Volume22
Issue number2
DOIs
StatePublished - Feb 7 2015

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Dependovirus
Interleukin-10
Cerebrospinal Fluid
Dogs
Transgenes
Rodentia
Meninges
Motor Neurons
Sensory Receptor Cells
Chronic Pain
Analgesics
Proteins
Genome
Cytokines
Antibodies
Therapeutics
Serum
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics

Cite this

Pleticha, J., Malkmus, S. A., Heilmann, L. F., Veesart, S. L., Rezek, R., Xu, Q., ... Beutler, A. S. (2015). High cerebrospinal fluid levels of interleukin-10 attained by AAV in dogs. Gene Therapy, 22(2), 202-208. https://doi.org/10.1038/gt.2014.96

High cerebrospinal fluid levels of interleukin-10 attained by AAV in dogs. / Pleticha, J.; Malkmus, S. A.; Heilmann, L. F.; Veesart, S. L.; Rezek, R.; Xu, Q.; Yaksh, T. L.; Beutler, Andreas S.

In: Gene Therapy, Vol. 22, No. 2, 07.02.2015, p. 202-208.

Research output: Contribution to journalArticle

Pleticha, J, Malkmus, SA, Heilmann, LF, Veesart, SL, Rezek, R, Xu, Q, Yaksh, TL & Beutler, AS 2015, 'High cerebrospinal fluid levels of interleukin-10 attained by AAV in dogs', Gene Therapy, vol. 22, no. 2, pp. 202-208. https://doi.org/10.1038/gt.2014.96
Pleticha J, Malkmus SA, Heilmann LF, Veesart SL, Rezek R, Xu Q et al. High cerebrospinal fluid levels of interleukin-10 attained by AAV in dogs. Gene Therapy. 2015 Feb 7;22(2):202-208. https://doi.org/10.1038/gt.2014.96
Pleticha, J. ; Malkmus, S. A. ; Heilmann, L. F. ; Veesart, S. L. ; Rezek, R. ; Xu, Q. ; Yaksh, T. L. ; Beutler, Andreas S. / High cerebrospinal fluid levels of interleukin-10 attained by AAV in dogs. In: Gene Therapy. 2015 ; Vol. 22, No. 2. pp. 202-208.
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