Kumar D.,Harvard University |
Kumar D.,EMD Serono, Inc. |
Lassar A.B.,Harvard University
Cell Reports | Year: 2014
The formation of cartilage is restricted to the core of the limb bud mesenchyme by ectodermal Wnts, which can irreversibly silence expression of the prochondrogenic transcription factor Sox9. In contrast, fibroblast growth factor (FGF) signals from the apical ectodermal ridge maintain the competence of chondrogenic precursors to undergo chondrogenesis once these cells go out of the range of ectodermal Wnt signals. We have found that Wnt signals induce both a repressive chromatin mark (H3K27me3) and DNA methylation over the Sox9 promoter and that Wnt-induced irreversible silencing of the Sox9 gene requires DNA methylation of this locus, which is specifically countered by FGF signals. FGF blocks the recruitment of the de novo DNA methyltransferase, DNMT3A, to the Sox9 promoter by inducing the interaction and phosphorylation of DNMT3A by ERK1/ERK2 and thereby controls whether expression of Sox9 is either irreversibly or reversibly silenced by Wnt signals in limb bud mesenchymal cells. © 2014 The Authors.
Lucas M.C.,Cubist Pharmaceuticals Inc. |
Tan S.-L.,EMD Serono, Inc.
Future Medicinal Chemistry | Year: 2014
Following on the heels of the US FDA approval of tofacitinib (Xeljanz, Pfizer, USA), an inhibitor of the JAK family members, and ibrutinib (Imbruvica, Janssen, Belgium), an inhibitor of BTK, for the treatment of rheumatoid arthritis and chronic lymphocytic leukemia, respectively, there is now renewed interest in the biopharmaceutical industry in the development of orally active small-molecule agents targeting key protein kinases implicated in immune regulation. One such 'immunokinase' target is SYK, a non-receptor tyrosine protein kinase critical for transducing intracellular signaling cascades for various immune recognition receptors, such as the B-cell receptor and the Fc receptor. Here, we review and discuss the progress and challenges in the development of small-molecule inhibitors of SYK and their potential as a new class of disease-modifying immunosuppressive agents for certain inflammatory and autoimmune disorders. © 2014 Future Science Ltd.
Smith M.Y.,EMD Serono, Inc. |
Morrato E.,Aurora University
Drug Safety | Year: 2014
Regulators are increasingly mandating the use of pharmaceutical risk-minimization programs for a variety of medicinal products. To date, however, evaluations of these programs have shown mixed results and relatively little attention has been directed at diagnosing the specific factors contributing to program success or lack thereof. Given the growing use of these programs in many different patient populations, it is imperative to understand how best to design, deliver, disseminate, and assess them. In this paper, we argue that current approaches to designing, implementing, and evaluating risk-minimization programs could be improved by applying evidence- and theory-based 'best practices' from implementation science. We highlight commonly encountered challenges and gaps in the design, implementation, and evaluation of pharmaceutical risk-minimization initiatives and propose three key recommendations to address these issues: (1) risk-minimization program design should utilize models and frameworks that guide what should be done to produce successful outcomes and what questions should be addressed to evaluate program success; (2) intervention activities and tools should be theoretically grounded and evidence based; and (3) evaluation plans should incorporate a mixed-methods approach, pragmatic trial designs, and a range of outcomes. Regulators, practitioners, policy makers, and researchers are encouraged to apply these best practices in order to improve the public health impact of this important regulatory tool. © 2014 The Author(s).
Townsend M.,EMD Serono, Inc.
Journal of Alzheimer's Disease | Year: 2011
Alzheimer's disease (AD) continues to be one of most difficult human diseases to treat. The past 18 months have been a cruel reminder of the challenges of finding new and effective treatments. In 2010, several large Phase III clinical trials were terminated for lack of therapeutic efficacy. Concurrently, an NIH expert review panel was resigned to conclude that there was insufficient scientific evidence to recommend any treatment choices for slowing the progression of AD. Why has this disease proved so daunting? The answer is complex. To begin, it is still not clear whether AD is one disease with a single cause or multiple syndromes with common symptoms and/or a common pathology. Resolving this question is a prerequisite for forecasting whether to expect a 'magic bullet' therapy or only incremental progress in select patient populations. This review will explore some of the details of recent clinical trials and consider some of the lessons learned. As therapies approach clinical trials, it is essential to understand the expectations of regulatory agencies such as the FDA and EMA to obtain approval. Lastly, we will cover some of the essential gaps in our scientific understanding about the disease process and the impact this has on target validation. The hope of finding of a quick cure for AD without a complete understanding of the disease may have been too optimistic. However, a prudent review of the scientific evidence, a clear understanding of the expectations of regulators, and careful attention to patient needs may still lead to good therapies in the foreseeable future. © 2011 - IOS Press and the authors. All rights reserved.
Palmer S.S.,EMD Serono, Inc. |
Barnhart K.T.,University of Pennsylvania
Fertility and Sterility | Year: 2013
A biomarker can be used for early diagnosis of a disease, identification of individuals for disease prevention, as a potential drug target, or as a potential marker for a drug response. A biomarker may also limit the use of drug (and therefore costs) to the population of patients for which the drug will be safe and efficacious. A biomarker in reproduction could be used to improve assessment of exposure, identify subgroups susceptible to treatment, predict outcome, and/or differentiate subgroups with potentially different etiologies of disease. Despite many potential uses there is low participation in reproductive biology to develop molecular biomarkers, which may be directly related to the low number of new molecular entities entering clinical trials. As the number of candidate markers in reproductive medicine is increasing, it is important to understand the pathway of development from discovery to clinical utility and recognize that the vast majority of potential markers will not be clinically useful, owing to a variety of pitfalls. Extensive testing, validation, and modification needs to be performed before a biomarker is demonstrated to have clinical utility. New opportunities and partnerships exist and should hasten the development of biomarkers in reproduction. As more biomarkers are moved into practice, a better-educated biomarker consumer will enhance the possibility that biomarker(s) will realize their great potential. Copyright © 2013 American Society for Reproductive Medicine, Published by Elsevier Inc.