Implementing an integrated system for the analysis and prediction of drug-disease associations for rare diseases with unidentified molecular bases

http://www.orpha.net/actor/EuropaNews/2012/120523.html#28659

The authors of an open-access online proceeding from the Pacific Symposium on Biocomputing (2012)describe the process of establishing an integrated system for the analysis and prediction of drug-disease associations for rare and orphan diseases for which the molecular basis is not known using the PhenomeNET network of phenotypic similarity to suggest genotype-disease association and combining with the drug-gene associations available from the PharmGKB database. 

Also of interest:

http://psb.stanford.edu/psb-online/proceedings/psb12/abstracts/2012_p388.html

http://psb.stanford.edu/psb-online/proceedings/psb12/hoehndorf.pdf 

Pac Symp Biocomput. 2012: 388-99, Hoehndorf R, Oellrich A, Rebholz-Schuhmann D, Schofield PN, Gkoutos GV, Dept of Genetics, U Cambridge, UK

Linking pharmgkb to phenotype studies and animal models of disease for drug repurposing

The European Commission's new Health in Europe: Information and Data Interface (HEIDI) tool includes a section for rare diseases

https://webgate.ec.europa.eu/sanco/heidi/index.php/Heidi/Rare_diseases 

Heidi (Health in Europe: Information and Data Interface) is a recently developed internet-based wiki tool specifically designed for European health information and data. Emerging from two former EC Public Health Programme projects (the Eugloreh report and EUPhix) Heidi offers articles and data on health status, diseases, determinants, health systems and policies, trends, institutional and policy aspects, and more. There is a special section for rare diseases available via the Contents tab. Data can be accessed by employing either search or browse functions. The information contained in Heidi, presented in the form of texts, tables, graphs, charts, and maps, is provided by various health professionals. Experts are called upon to contribute their expertise by becoming editors for Heidi. It is hoped that this new information tool can help develop evidence-based policies to improve the health of Europeans.

Visit Heidi 

A new patient report weighs the benefits and risks of new medicines for serious and rare diseases

http://www.orpha.net/actor/EuropaNews/2012/120523.html#28484 (emphasis added)

A project supported by Genetic Alliance UK, a national charity of 154 patient organisations supporting all those affected by genetic conditions, and facilitated by the Welsh Institute for Health and Social Care, examines the benefit/risk ratio of new medicinal products for rare and serious diseases. The report exposes the findings determined by a Citizen’s Jury composed of twelve rare and/or serious genetic disease patients or family members, who explored certain key questions: How do patients with rare and/or serious conditions perceive the risks and benefits of new medicines? To what extent should regulators be more permissive in their marketing authorisation decisions? How should patients be involved in the assessment of risks and benefits, and regulatory decision making? After exploring hypothetical case studies and hearing from expert and advocate witnesses on the existing regulatory system and its various strengths and weaknesses, followed by a period of reflection and debate, the jury was able to establish four key recommendations: Regulators should include psychosocial factors in their decision making; Regulators should be more permissive for people with rare and/or serious conditions; Patients should be more involved from setting the research agenda, to post-marketing authorisation decisions; and Patients should be supported in their decision making.

Also of interest:

http://www.geneticalliance.org.uk/latest-news.htm 

Desensitization for hypersensitivity reactions to medications

http://content.karger.com/produktedb/produkte.asp?doi=335637 (excerpts follow)

Chem Immunol Allergy. 2012;97: 217-33, Del Carmen Sancho M, Breslow R, Sloane D, Castells M, Harvard Med School, Div of Rheumatology, Allergy and Immunology, Brigham and Women's Hospital, Boston

Rapid drug desensitization (RDD) is a technique that induces temporary tolerance to a drug

Through RDD, patients with IgE and non-lgE hypersensitivity reactions (HSRs) including anaphylaxis can safely be administered important medications while minimizing or completely inhibiting adverse reactions. 

Some of these reactions are mast cell-mediated HSRs, a subset of which occur through an IgE-dependent mechanism, and are thus true allergies. Others involve mast cells, but an IgE mechanism cannot be demonstrated. Both types of reactions are amenable to RDD, and our group has successfully performed several hundred desensitizations to chemotherapy, antibiotics and biological agents including monoclonal antibodies with a standardized 12-step protocol that can be universally applied to all desensitizations. 

The molecular basis of RDD has now been studied, and an in vitro mouse mast cell model has shown that RDD is an antigen-specific process that does not induce subclinical mast cell mediator release, and that blocks the release of acute and late mast cell mediators by preventing calcium influx and antigen/lgE/and IgE receptor internalization.

Mast Cell Tryptase Induces Microglia Activation via Protease-activated Receptor 2 Signaling

http://content.karger.com/ProdukteDB/produkte.asp?Doi=171029

Cell Physiol Biochem. 2012;29(5-6):931-40, Zhang S, Zeng X, Yang H, Hu G, He S, Clinical Research Center, First Affiliated Hospital of Nanjing Medical U, China

Mast cell tryptase can stimulate peripheral mononuclear cells activation to cause widespread inflammation. 

microglia plays a pivotal role in immune surveillance of CNS

tryptase stimulated microglia activation and subsequently produced proinflammatory factors TNF-alpha, IL-6  [on cells cultured in the lab]

Our results suggest that tryptase can induce microglia activation and pro-inflammatory mediator release via PAR-2-MAPK-NF-kappa B signaling pathway, which will contribute to the development of microglia-mediated inflammation in brain.

New study: Cladribine Plus Pegylated Interpheron Alfa-2a in Systemic Mastocytosis

http://clinicaltrials.gov/ct2/show/NCT01602939  (some excerpts follow)

This study is currently recruiting participants.

The aim of this study is to evaluate the efficacy in terms of clinical and biological response rates of Cladribine plus Pegylated Interpheron alpha-2a therapy in patients with advanced systemic mastocytosis carrying D816V or other exon 17 KIT mutations.

Contact: Luis Escribano, MD, PhD

+34925269335

lescribanom@sescam.jccm.es

Contact: Iván Alvarez-Twose, MD

+34925269336

ivana@sescam.jccm.es

Mast cells and company

http://www.frontiersin.org/Inflammation/10.3389/fimmu.2012.00016/full

Front Immunol. 2012;3:16, Jönsson F, Daëron M, Institut Pasteur, Département d'Immunologie, Unité d'Allergologie Moléculaire et Cellulaire Paris

Classically, allergy depends on IgE antibodies and on high-affinity IgE receptors expressed by mast cells and basophils. This long accepted IgE/FcεRI/mast cell paradigm, on which the definition of immediate hypersensitivity was based in the Gell and Coomb's classification, appears too reductionist. Recently accumulated evidence indeed requires that not only IgE but also IgG antibodies, that not only FcεRI but also FcγR of the different types, that not only mast cells and basophils but also neutrophils, monocytes, macrophages, eosinophils, and other myeloid cells be considered as important players in allergy. This view markedly changes our understanding of allergic diseases and, possibly, their treatment.