Treatment of osteoarthritis by inhibition of aggrecanases using targeted delivery of engineered TIMP-3

点击翻译按钮获取中文摘要

Context of researchOsteoarthritis (OA) is the most common form of arthritis affecting nearly 9 million people in the UK, yet there are no effective treatments. As such, there is a significant unmet clinical need for new and better therapies to slow progression of disease and improve patient quality of life. The possibility of using endogenous inhibitors of the enzymes responsible for cartilage destruction, such as TIMP-3, has been an intriguing possibility for decades. However, despite many years of research a number of challenges have prevented development of TIMP-3 as a therapy for OA, including unacceptable side-effects and problems in producing sufficient quantities of protein. We have now overcome these difficulties by engineering TIMP-3 to selectively target aggrecanases only for inhibition and developing a novel method of protein production that results in a 10-fold increase in production of recombinant TIMP-3. The aim of this project is to develop a new therapeutic strategy for the treatment of OA using this engineered TIMP-3 to inhibit aggrecanases. The strategy proposed here is to employ a novel method (the LAP technology) of delivering this molecule to arthritic joints in vivo. This approach enables the delivery of high local concentrations of therapeutic molecules at site(s) of disease, thus eliminating side-effects and increasing therapeutic efficacy.Aims and ObjectivesThe aim of this proposal is to develop a new therapeutic strategy for treatment of OA. Our hypothesis is that local delivery of engineered TIMP-3 will ameliorate cartilage destruction in joints affected by OA by achieving high local concentrations of TIMP-3 that will inhibit aggrecanase activity. These aims will be achieved by the completion of the following objectives:1. Express and purify substantial quantities of latent engineered TIMP-3 using the LAP fusion protein technology. 2. Determine the effects of latent engineered TIMP-3 on the development and progression of OA in a mouse model of disease.3. Characterise the inhibitory effects of engineered TIMP-3 on members of the ADAM and ADAMTS families of enzymes involved in the pathogenesis of OA. Potential applications and benefitsThere are no effective treatments for OA and current therapies aim to alleviate the pain experienced by people with OA. However, these therapies have no effect on halting disease progression with the result that end-stage OA is currently treated by joint-replacement surgery. The applications of this work may translate into a new therapy for OA, perhaps in combination with existing therapies, to create a treatment regimen that reduces cartilage degradation and subsequent subchondral bone thickening in arthritic joints. This could significantly reduce joint damage so that disease progression is curtailed, thus providing patients with improved quality of life and possibly delaying or avoiding joint replacement surgery. There are a number of advantages to the approach proposed here. Firstly, the risks of side effects of this treatment are minimized by using a recombinant form of a naturally occurring protein that is not recognised by the host immune system. Secondly, local activation of therapeutic molecules at the site(s) of disease will result in high local concentrations and further minimise the risks of off-target effects. Finally, we have engineered the TIMP-3 molecule to increase its specificity thus avoiding the side-effects previously seen with synthetic enzyme inhibitors. Furthermore, this strategy has a great deal of translational potential. The research outlined in this proposal could lead to clinical trials for the development of a new strategy for treating OA in the medium term (7-10 years).