Autoregulatory Gene Therapy Inhibits Joint Inflammation in RA Model

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Autoregulatory Gene Therapy Inhibits Joint Inflammation in RA Model

NEW YORK (Reuters Health) May 29 - US researchers have developed an

anti-inflammatory transgene whose expression is regulated by an

inflammation-inducible promoter. When the gene therapy was administered in a

rat model of rheumatoid arthritis (RA), interleukin-10 (IL-10) expression

was induced only during disease activity.

Dr. Sergei S. Makarov, of the University of North Carolina at Chapel Hill,

and associates constructed an adenoviral (Ad) vector containing a

two-component, inflammation-inducible promoter. The promoter used a

complement factor 3 (C3) acute-phase protein gene to control the expression

of the HIV Tat protein. Tat, in turn, transactivated the expression of the

IL-10 via the HIV promoter.

As described in The Journal of Clinical Investigation for May, the

researchers induced an acute, transient, monoarticular arthritis in rat

ankle joints by intra-arterial injection of streptococcal cell wall (SCW)

fragments. Under normal circumstances, when SCW fragments are injected

intravenously several weeks later, chronic inflammatory arthritis is

reactivated.

The investigators injected the Ad.C3-tat/HIV-IL-10 construct into primed

ankle joints, then reactivated the arthritis 2 days later. The

vector-promoter protected the joints against reactivation-induced

leukocytosis and swelling.

Before reactivation, IL-10 levels in the joints were at the lower limits of

detection. The level increased strikingly on days 1 and 2 after

reactivation, up to 288-fold, then returned to baseline on day 4.

According to the authors, the strategy inhibits inflammation while

minimizing the risks associated with persistent overproduction of IL-10.

Once a construct is developed using a safer vector than adenovirus, they

believe that potential clinical targets for the autoregulated gene therapy

will include other chronic inflammatory diseases, such as Crohn's disease

and organ transplant rejection.

J Clin Invest 2002;109:1223-1229.