Endogenous regulation of a therapeutic transgene restores homeostasis in arthritic joints

A. V. Miagkov, A. W. Varley, R. S. Munford, S. S. Makarov

Research output: Contribution to journalArticle

40 Citations (Scopus)

Abstract

The treatment of chronic inflammatory diseases is complicated by their unpredictable, relapsing clinical course. Here, we describe a new strategy in which an inflammation-regulated therapeutic transgene is introduced into the joints to prevent recurrence of arthritis. To this end, we designed a recombinant adenoviral vector containing a two-component, inflammation-inducible promoter controlling the expression of human IL-10 (hIL-10) cDNA. When tested in vitro, this system had a low-level basal activity and was activated four to five orders of magnitude by various inflammatory stimuli, including TNF-α, IL-1β, IL-6, and LPS. When introduced in joints of rats with recurrent streptococcal cell wall-induced arthritis, the IL-10 transgene was induced in parallel with disease recurrence and effectively prevented the influx of inflammatory cells and the associated swelling of the joints. Levels of inflammation-inducible hIL-10 protein within the joints correlated closely with the severity of recurrence. An endogenously regulated therapeutic transgene can thus establish negative feedback and restore homeostasis in vivo while minimizing host exposure to the recombinant drug.

Original languageEnglish (US)
Pages (from-to)1223-1229
Number of pages7
JournalJournal of Clinical Investigation
Volume109
Issue number9
DOIs
StatePublished - 2002

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Transgenes
Arthritis
Homeostasis
Joints
Inflammation
Recurrence
Interleukin-10
Therapeutics
Interleukin-1
Cell Wall
Interleukin-6
Chronic Disease
Complementary DNA
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Endogenous regulation of a therapeutic transgene restores homeostasis in arthritic joints. / Miagkov, A. V.; Varley, A. W.; Munford, R. S.; Makarov, S. S.

In: Journal of Clinical Investigation, Vol. 109, No. 9, 2002, p. 1223-1229.

Research output: Contribution to journalArticle

Miagkov, A. V. ; Varley, A. W. ; Munford, R. S. ; Makarov, S. S. / Endogenous regulation of a therapeutic transgene restores homeostasis in arthritic joints. In: Journal of Clinical Investigation. 2002 ; Vol. 109, No. 9. pp. 1223-1229.
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