Abstract
In rheumatoid arthritis (RA), the proliferation of fibroblast-like synoviocytes (FLS) is the cause of chronic inflammation in joints and of joint damage. Delivery of the pro-apoptotic gene PUMA to FLS via human adenovirus type 5 (HAdV5) vectors has been tested as a therapeutic approach, but efficiency is hampered by low transduction, as FLS do not express HAdV5 receptors on the cell surface. Here we show that efficient transduction of PUMA in FLS can be achieved by conjugating HAdV5 to a baculovirus, which binds to the cell surface via the envelope glycoprotein Gp64. Intra-articular injection in an adjuvant-induced rat model of RA induces apoptosis of FLS, leading to significant decrease in joint inflammation, joint damage, and bone loss with improvement in joint function and mobility. Our results demonstrate the therapeutic potential of PUMA gene therapy as a local treatment in various forms of arthritis in which abnormal FLS proliferation is implicated.
Highlights
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The baculoviral envelope glycoproteins Gp64 are localized at the head of the baculoviral particle. c Human and d rat fibroblast-like synoviocytes (FLS) non-treated or pre-treated with the proinflammatory cytokines were transduced with human adenovirus type 5 (HAdV5)-GFP alone, or with the BVCARHAdV5-GFP complex
The aim of this study is to show the feasibility of controlling arthritis severity by an apoptosis-inducing gene therapy strategy targeting the FLSs in arthritic joints
Summary
HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. In rheumatoid arthritis (RA), the proliferation of fibroblast-like synoviocytes (FLS) is the cause of chronic inflammation in joints and of joint damage. The uncontrolled proliferation and accumulation of fibroblast-like synoviocytes (FLS) are the main cause of chronic inflammation and its progression to joint damage[3, 4]. This results in part from acquired molecular changes in FLS leading to reduced sensitivity to cell death signals. These preliminary data suggested that the strategy of PUMA-induced apoptosis in FLS could block the hyperplasia of the synovial intimal lining
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