Fatal Meningitis in Swine after Intrathecal Administration of Adeno-associated Virus Expressing Syngeneic Interleukin-10

Mark D. Unger, Josef Pleticha, James E. Collins, Anibal G. Armien, Jennifer L. Brazzell, Laura K. Newman, Lukas F. Heilmann, Jodi A. Scholz, Timothy P. Maus, Andreas S. Beutler

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2 Scopus citations

Abstract

Interleukin-10 (IL-10) delivered by intrathecal (i.t.) gene vectors is a candidate investigational new drug (IND) for several chronic neurological disorders such as neuropathic pain. We performed a preclinical safety study of IL-10. A syngeneic large animal model was used delivering porcine IL-10 (pIL-10) to the i.t. space in swine by adeno-associated virus serotype 8 (AAV8), a gene vector that was previously found to be nontoxic in the i.t. space. Unexpectedly, animals became ill, developing ataxia, seizures, and an inability to feed and drink, and required euthanasia. Necropsy demonstrated lymphocytic meningitis without evidence of infection in the presence of normal laboratory findings for body fluids and normal histopathology of peripheral organs. Results were replicated in a second animal cohort by a team of independent experimenters. An extensive infectious disease and neuropathology workup consisting of comprehensive testing of tissues and body fluids in a specialized research veterinary pathology environment did not identify a pathogen. These observations raise the concern that i.t. IL-10 therapy may not be benign, that previously used xenogeneic models testing the human homolog of IL-10 may not have been sensitive enough to detect toxicity, and that additional preclinical studies may be needed before clinical testing of IL-10 can be considered. Porcine interleukin-10 (IL-10) was delivered to the intrathecal (i.t.) space in swine by AAV8. Animals developed ataxia and seizures requiring euthanasia. Necropsy demonstrated sterile lymphocytic meningitis. Syngeneic i.t. IL-10 therapy may not be benign. Previous xenogeneic models testing the human homolog may not have been sensitive enough to detect toxicity.

Original languageEnglish (US)
Pages (from-to)2526-2532
Number of pages7
JournalMolecular Therapy
Volume25
Issue number11
DOIs
StatePublished - Nov 1 2017

Keywords

  • interleukin-10
  • intrathecal
  • large-animal model
  • meningitis
  • preclinical toxicology
  • swine

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    Unger, M. D., Pleticha, J., Collins, J. E., Armien, A. G., Brazzell, J. L., Newman, L. K., Heilmann, L. F., Scholz, J. A., Maus, T. P., & Beutler, A. S. (2017). Fatal Meningitis in Swine after Intrathecal Administration of Adeno-associated Virus Expressing Syngeneic Interleukin-10. Molecular Therapy, 25(11), 2526-2532. https://doi.org/10.1016/j.ymthe.2017.07.016