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Human interleukin-10 Delivered Intrathecally by Self-Complementary Adeno-Associated Virus 8 Induces Xenogeneic Transgene Immunity Without Clinical Neurotoxicity in Swine

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 P Maus, Andreas S Beutler

J Gene Med. 2018 Jul;20(7-8):e3026.

PMID: 29800509

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
IAR42413340	Interleukin-10 human			Price

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