Human interleukin-10 delivered intrathecally by self-complementary adeno-associated virus 8 induces xenogeneic transgene immunity without clinical neurotoxicity in swine

Mark D. Unger, Josef Pleticha, Lukas F. Heilmann, Laura K. Newman, Timothy Maus, Andreas S Beutler

Research output: Contribution to journalArticle

Abstract

Introduction: Intrathecal interleukin (IL)-10 delivered by plasmid or viral gene vectors has been proposed for clinical testing because it is effective for chronic pain in rodents, is a potential therapeutic for various human diseases, and was found to be nontoxic in dogs, when the human IL-10 ortholog was tested. However, recent studies in swine testing porcine IL-10 demonstrated fatal neurotoxicity. The present study aimed to deliver vector-encoded human IL-10 in swine, measure expression of the transgene in cerebrospinal fluid and monitor animals for signs of neurotoxicity. Results: Human IL-10 levels peaked 2 weeks after vector administration followed by a rapid decline that occurred concomitant with the emergence of anti-human IL-10 antibodies in the cerebrospinal fluid and serum. Animals remained neurologically healthy throughout the study period. Conclusions: The findings of the present study suggest that swine are not idiosyncratically sensitive to intrathecal IL-10 because, recapitulating previous reports in dogs, they suffered no clinical neurotoxicity from the human ortholog. These results strongly infer that toxicity of intrathecal IL-10 in large animal models was previously overlooked because of a species mismatch between transgene and host. The present study further suggests that swine were protected from interleukin-10 by a humoral immune response against the xenogeneic cytokine. Future safety studies of IL-10 or related therapeutics may require syngeneic large animal models.

Original languageEnglish (US)
Article numbere3026
JournalJournal of Gene Medicine
Volume20
Issue number7-8
DOIs
StatePublished - Jul 1 2018

Fingerprint

Dependovirus
Transgenes
Interleukin-10
Immunity
Swine
Cerebrospinal Fluid
Animal Models
Dogs
Viral Genes
Humoral Immunity
Chronic Pain
Rodentia
Plasmids
Cytokines
Safety

Keywords

  • adeno-associated virus vector
  • animal model
  • interleukin-10
  • intrathecal
  • swine
  • xenogeneic

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Drug Discovery
  • Genetics(clinical)

Cite this

Human interleukin-10 delivered intrathecally by self-complementary adeno-associated virus 8 induces xenogeneic transgene immunity without clinical neurotoxicity in swine. / Unger, Mark D.; Pleticha, Josef; Heilmann, Lukas F.; Newman, Laura K.; Maus, Timothy; Beutler, Andreas S.

In: Journal of Gene Medicine, Vol. 20, No. 7-8, e3026, 01.07.2018.

Research output: Contribution to journalArticle

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