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Comparison of drug and cell-based delivery: engineered adult mesenchymal stem cells expressing soluble tumor necrosis factor receptor II prevent arthritis in mouse and rat animal models

Liu, LN and Wang, G and Hendricks, K and Lee, K and Bohnlein, E and Junker, Uwe and Mosca, JD (2013) Comparison of drug and cell-based delivery: engineered adult mesenchymal stem cells expressing soluble tumor necrosis factor receptor II prevent arthritis in mouse and rat animal models. Stem Cells Translational Medicine, 2 (5). pp. 362-375. ISSN 2157-6564

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease with unknown etiology where tumor necrosis factor-alpha (TNFα) plays a critical role. Etanercept®, the biologic drug form of soluble tumor necrosis factor receptor-II (sTNFRII) is used to treat RA based on the rational that sTNFRII binds TNFα and blocks inflammation. We compared and benchmarked sTNFRII protein delivery from genetically engineered mesenchymal stem cells (MSCs) to Etanercept®. Blocking TNFα-dependent ICAM-1 surface expression on transduced human MSCs and culture media inhibition of nitric oxide production from ΤΝFα−treated bovine chondrocytes showed functionality of the sTNFRII construction. Implanted TNFRII-transduced MSCs removed mouse serum circulating TNFα generated from either implanted TNFα expressing cells or lipopolysaccharide (LPS) induction better than Etanercept® (TNFα, 100%; IL1α, 90%; and IL6, 60% within 6 hrs.), suggesting faster clearance of the sTNFR:TNFα complex from the animals. In vivo efficacy of sTNFRII-transduced MSCs was illustrated in two (immune-deficient and immune-competent) arthritic rodent models. In the BalbC/SCID mouse antibody-induced arthritis (AbIA) model, intramuscular injection of sTNFR transduced human MSCs reduced joint inflammation by 90% compared to untransduced human MSCs; in the antigen-induced arthritis (AIA) Fisher rat model, both sTNFR transduced rat MSCs and Etanercept® inhibited joint inflammation by 30%. In vitro chondrogenesis assays showed the ability of TNFα and IL1α, but not IFNγ to inhibit human MSC differentiation to chondrocytes, illustrating an additional negative role for inflammatory cytokines in joint repair. The data supports the utility of human MSCs as therapeutic gene delivery vehicles and their potential used in alleviating inflammation within the arthritic joint.

Item Type: Article
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Additional Information: The results summarized in this publication are from a collaboration with Osiris Therapeutics Inc. during the years 1997 - 1999.
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Date Deposited: 13 Oct 2015 13:13
Last Modified: 13 Oct 2015 13:13
URI: https://oak.novartis.com/id/eprint/10086

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