These are exciting times in biomedical research. The completion of the sequencing of the human and murine genomes has permitted a comprehensive assessment of the molecular targets amenable to pharmacologic intervention. The ever increasing range of experimental tools available for detailed and multiplexed array-based analysis of biological systems has vastly increased our ability to validate these targets by in vitro, in vivo, and ex vivo analysis. And the emerging discipline of systems biology is permitting us to integrate various and disparate metabolic pathways into a holistic view of living systems—this will enable us to better understand and predict the potential benefits and liabilities of drug candidates.
The promise of protein-based genetically engineered drugs for the treatment of grievous disease is finally being realized and the constant advances in basic and applied research are significantly improving the development time and success rate of the more traditional synthetic “small molecule” drugs. There is also the intriguing possibility of the convergence of these two different modalities as efforts continue to develop oral delivery systems for protein therapeutics and to enable protein-based drugs to enter the cell. We are getting close to the ideal of being able to fit the tool to the task and develop the appropriate therapeutic agent for a particular target in the context of a specific disease—and ultimately for a specific patient as the field of personalized medicine continues to evolve.
In this issue we have drawn together some of the latest thinking in the development of drugs to treat inflammatory diseases with contributions from experts in leading academic and industry groups. The first section reviews the underlying patho-physiological mechanisms of the major autoimmune diseases. Fergus Shanahan and Silvia Melgar describe the biology of the inflammatory bowel diseases and highlight the critical role of the intestinal micro-flora and its potential as an unexplored source of therapeutically useful molecules. Ernie Brahn and Soo In-Choi describe the latest thinking and emerging therapies in the complex set of syndromes which is collectively described as rheumatoid arthritis. Liam O'Mahony and colleagues provide an overview of the allergic diseases and the challenges of developing improved therapeutics for the treatment of asthma. Anthony Slavin and colleagues complete the section by describing the molecular mechanisms of multiple sclerosis and the exciting recent advances in new therapeutic options for patients with this debilitating disease.
In the second section we have focused on the actual mechanics of successful drug development. Richard Aranda and colleagues have provided a comprehensive review of specific pathways involved in lymphocyte activation and highlight a case study of the successful development of a protein-based therapeutic that targets T cell co-stimulation. This is followed by a detailed review of the best practices involved in the development of a synthetic “small molecule” drug by Roland Burli and colleagues.
Finally, in the third section, we have highlighted some of the most recent developments in how to successfully move a drug from bench to bedside. This is a key consideration as the overall attrition rate for all drug development programs is still extremely high and the costs are significant. Herein, we describe the novel techniques that will enable us to answer the simple yet elusive question of “Has the drug found its target in vivo and done its job?”. This question is variously manifested in the general discipline of biomarkers, an approach which can be very powerful when properly implemented. A successful biomarker strategy will allow us to conclude to what extent a drug has found, bound and modulated the function of its target in a patient. We will then either have a successful new therapeutic product or we can confidently terminate a clinical trial—an immensely valuable data point from a scientific perspective and one that will allow the diversion of resources to other avenues of investigation. Towards this end, Helen McBride describes the various imaging technologies that can be used pre-clinically to demonstrate target engagement and therapeutic effect in vivo and how it can be best translated to the clinic. Todd Covey and colleagues then highlight the fascinating technology of single cell network profiling that has the potential to describe exactly how a test agent is affecting all aspects of the biology of a particular cell.
Finally, Jerry Siu and his colleagues highlight several case studies that exemplify the current best practices in moving a molecule from research into clinical development and provide an insight into how the field of personalized medicine is developing.
I would like to take this opportunity to thank all of our contributors for the significant time and effort they put towards this special monographic issue of “AutoImmunity”. It is impossible to cover all the current novel and exciting research in inflammation research in one issue and there is much we could not include—most notably nucleic acid-based drugs and stem cell technologies, which both continue to gain scientific credibility as potential therapeutic agents.
Nonetheless, I hope we will succeed in apprising you of the great advances that continue to be made in the development of drugs for inflammatory diseases and what a tremendous impact this can have on the life of a seriously ill patient.