A research review carried out by the Royal College of Surgeons in Ireland (RCSI) and published in 'Nature Reviews and Drug Discovery' (October 2010) has highlighted the lessons, opportunities and recent developments in the area of drug development for cardiovascular disease, auto-immune disorders and multiple sclerosis.
The review examines a class of drugs that were developed in the early 1990's for the treatment of inflammatory disorders, cancer and cardiovascular disease. These drugs targeted integrins, which are receptors in the body that determine attachment between cells and the tissues surrounding it and are essential for the regulation of cell growth and function. The development of these drugs at the initial stages was promising for the treatment of conditions such as thrombosis, multiple sclerosis, immune system disorders, cancer and osteoporosis but was soon fraught by unexpected and undesirable side effects that limited their use.
Tysabri (Natalizumab) is one such drug in this anti-integrins class. Used in the treatment of multiple sclerosis (MS); it was withdrawn from the market in 2005 after it was linked to a rare neurological virus called PML. It was reintroduced in 2006 due to its high efficacy in reducing the rate of relapses in MS but with a black box warning and a risk management strategy.
Joint lead author of the review, Professor Niamh Moran from the Department of Molecular and Cellular Therapeutics, RCSI said 'The development of new drugs is a costly activity, largely funded by pharmaceutical companies. The discovery and development of the first generation of anti-integrins occurred at a juncture in the pharmaceutical industry, as it was undergoing a transition from chemistry-led to a target-led discovery strategy. The initial drug discovery work that was carried out on several integrins was carried out in the absence of a detailed understanding of their functions, which ultimately led to their failure. The funding of academic research through agencies such as Science Foundation Ireland, the Health Research Board and the Higher Education Authority, has led to advances in scientific research and is facilitating the development of a second-generation of drugs in this class but with a stronger therapeutic profile and less unwanted side-effects.'
The complexity and diversity of integrins provide great opportunities for drug development but also many challenges. Professor Dermot Cox, joint lead author of the review said 'Identifying specific integrins involved in various disorders and their precise role is difficult because many diseases are multi-factorial and integrins are only one of many receptors involved. Their diversity and complex role in many diseases suggest great potential for this super family as drug targets, however the potential of integrins is far from exhausted and further research is needed.'
Deciphering the role of GPCRs in obesity pathology for drug development