Gene Therapy Challenges in Arthritis

Abstract

1.1 From systemic to intra-articular gene therapy The first experiments of gene therapy (GT) in arthritis were done in the midnineties. Arthritis is a chronic, inflammatory disease responsible for joint inflammation and destruction resulting in an imbalance between pro-inflammatory and anti-inflammatory cytokines production. Moreover, we know that bone destruction is more active than bone regeneration. Therefore, there are different ways of targeting the disease. At the moment, there are three classes of drugs commonly used: 1. Non-steroidal Anti-inflammatory Agents (NSAIDs), 2. corticoids, 3. Disease Modifying Anti-rheumatic Drugs (DMARDS). Biotherapies have been used for a decade. These treatments restore the balance of many functions such as the immune system and the bone metabolism. Agents used in biotherapy include recombinant proteins, monoclonal antibodies, growth factors, and vaccines. The efficiency of these treatments depends on the stage of the disease. Serious side effects and infrequent persistent remission are known as drawbacks. Furthermore, the systemic administration of immune regulator can affect several immune responses and trigger infections. The objectives using gene therapy in arthritis are mainly 1) to obtain a therapeutic quantity of therapeutic molecule without side effects, 2) to get a long expression of the therapeutic molecule without multi injections, 3) to target the joint specifically resistant to the usual treatment (Fiocco & Punzi, 2011). Arthritis models are still being used to improve gene therapy strategies: for instance we use induced arthritis models such as collagen induced arthritis (CIA) in mice developing subchronic poly arthritis or adjuvant induced arthritis or spontaneous models such as Tumour Necrosis Factor (TNF) transgenic mice. Our team who had the first results in 1996 has seen many changes over the years in its approach due to scientific progress. Our first gene therapy experiments used the ex vivo strategy (using autolog transfected cells (immortalized fibroblast from DBA/1 mice) or heterolog transfected cells (xenogenic fibroblasts from Chinese hamster ovary (CHO) with plasmid encoding murine IL-4 or IL-13); then the viral vectors experiments were used until the risk of using this methods arose (Bessis et al., 1996). We also used a non viral vector as plasmid (Bloquel et al., 2004, 2007; Saidenberg-Kermanach et al., 2003). Several teams tried