Taxonomy of rare genetic metabolic bone disorders

The Summary: This article reports a taxonomic classification of rare skeletal diseases based on metabolic phenotypes. It was prepared by The Skeletal Rare Diseases Working Group of the International Osteoporosis Foundation (IOF) and includes 116 OMIM phenotypes with 86 affected genes. Introduction: Rare skeletal metabolic diseases comprise a group of diseases commonly associated with severe clinical consequences. In recent years, the description of the clinical phenotypes and radiographic features of several genetic bone disorders was paralleled by the discovery of key molecular pathways involved in the regulation of bone and mineral metabolism. Including this information in the description and classification of rare skeletal diseases may improve the recognition and management of affected patients. Methods: IOF recognized this need and formed a Skeletal Rare Diseases Working Group (SRD-WG) of basic and clinical scientists who developed a taxonomy of rare skeletal diseases based on their metabolic pathogenesis. Results: This taxonomy of rare genetic metabolic bone disorders (RGMBDs) comprises 116 OMIM phenotypes, with 86 affected genes related to bone and mineral homeostasis. The diseases were divided into four major groups, namely, disorders due to altered osteoclast, osteoblast, or osteocyte activity; disorders due to altered bone matrix proteins; disorders due to altered bone microenvironmental regulators; and disorders due to deranged calciotropic hormonal activity. Conclusions: This article provides the first comprehensive taxonomy of rare metabolic skeletal diseases based on deranged metabolic activity. This classification will help in the development of common and shared diagnostic and therapeutic pathways for these patients and also in the creation of international registries of rare skeletal diseases, the first step for the development of genetic tests based on next generation sequencing and for performing large intervention trials to assess efficacy of orphan drugs.

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A multicenter study on dental trauma in permanent incisors among Special Olympics athletes in Europe and Eurasia

Objectives: Special Olympics athletes, as part of the population with intellectual disabilities, are reported to be more vulnerable to dental injuries due to poor lip closure, slow response to environmental obstacles, oral pathologic reflexes or dental features. The aim of this study was to assess the prevalence of dental trauma among Special Olympics athletes in countries of Europe and Eurasia. Material and Methods: A retrospective longitudinal multi centre study was performed with data collected through standardized Special Smiles screening forms and procedures from consenting 15.941 athletes participating in the annual Special Olympics held in 49 countries from Europe and Eurasia between 2007 and 2012. The data was compiled in an Excel worksheet and transferred to an SPSS data file in order to be analysed. Results: A total of 2190 athletes presented dental injury (13,02 %) with a std. deviation. of 5,02%. No significant differences (p= 0,136) in mean dental injury between age groups (One-way ANOVA test) were found. Conclusions: The present data suggest that dental trauma is an actual problem among individuals with special needs. The distribution of prevalence among the different countries had a remarkable variability, but it is evident that a relatively high proportion of this population is in need of a dental trauma preventive program. Clinical Relevance: Indication on an European large scale that dental trauma is a problem in the special needs population.

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The preclinical discovery of rituximab for the treatment of non-Hodgkin's lymphoma.

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The preclinical discovery of rituximab for the treatment of non-Hodgkin's lymphoma.

Expert Opin Drug Discov. 2015 Jul;10(7):791-808

Authors: Smolewski P, Robak T

Abstract
INTRODUCTION: Monoclonal antibodies (MoAbs) were developed in the 1980s in order to treat malignancies. An important target for MoAbs was the CD20 B-cell lineage antigen. Rituximab (RTX) is a chimeric mouse anti-human MoAb that targets the CD20 antigen on the surface of malignant and normal B lymphocytes, and has rapidly become the widest used immunotherapeutic drug. RTX has had a significant impact on how B-cell non-Hodgkin's lymphomas (NHLs) and chronic lymphocytic leukemia is now treated.
AREAS COVERED: In this review, the authors demonstrate the mechanisms of action of RTX, and the preclinical data that have led to clinical trials and its final approval for the treatment of B-cell NHLs.
EXPERT OPINION: The discovery of RTX opened a new era for treatment of B-cell malignancies and became the starting point for the development of new, more active classes of anti-CD20 agents. Furthermore, it has contributed to the construction of a number of MoAbs specific for other antigens that target different types of neoplastic cells.

PMID: 26083358 [PubMed - indexed for MEDLINE]

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Rational drug discovery design approaches for treating Parkinson's disease.

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Rational drug discovery design approaches for treating Parkinson's disease.

Expert Opin Drug Discov. 2015 Jul;10(7):713-41

Authors: Van der Schyf CJ

Abstract
INTRODUCTION: Parkinson's disease (PD) is a severe progressive neurodegenerative disorder. As yet, no therapeutic agent can prevent the characteristic neuronal cell loss in PD brain. The introduction of levodopa to the clinic several decades ago has greatly mitigated the symptomatic burden in PD patients. But the discovery of neuroprotective and disease-modifying therapies has lagged behind, becoming one of the most desired prizes in the drug discovery arms race for neurodegenerative disorders, including PD.
AREAS COVERED: In this review, the author provides an overview of the rational drug discovery approaches that are designed to prevent the onset or alter the course of the disease, and/or target its non-motor symptoms.
EXPERT OPINION: Largely due to the intertwined etiology that is a hallmark of PD's pathology, neuroprotective drug discovery is challenging, while very limited targeting strategies exist for the non-motor symptoms that afflict sufferers of PD. Rational approaches toward PD neurotherapeutics should target previously identified or emerging pathological pathways that are discovered in the course of investigating the underlying mechanisms in PD disease progression. Each of these pathways contributes to events that ultimately lead to the complex disease burden seen in PD and can form the basis for rational and highly targeted drug development.

PMID: 26054694 [PubMed - indexed for MEDLINE]

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Animal models for ebolavirus countermeasures discovery: what defines a useful model?

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Animal models for ebolavirus countermeasures discovery: what defines a useful model?

Expert Opin Drug Discov. 2015 Jul;10(7):685-702

Authors: Shurtleff AC, Bavari S

Abstract
INTRODUCTION: Ebolaviruses are highly pathogenic filoviruses, which cause disease in humans and nonhuman primates (NHP) in Africa. The Zaire ebolavirus outbreak in 2014, which continues to greatly affect Western Africa and other countries to which the hemorrhagic fever was exported due to travel of unsymptomatic yet infected individuals, was complicated by the lack of available licensed vaccines or therapeutics to combat infection. After almost a year of research at an increased pace to find and test vaccines and therapeutics, there is now a deeper understanding of the available disease models for ebolavirus infection. Demonstration of vaccine or therapeutic efficacy in NHP models of ebolavirus infection is crucial to the development and eventual licensure of ebolavirus medical countermeasures, so that safe and effective countermeasures can be accelerated into human clinical trials.
AREAS COVERED: The authors describe ebolavirus hemorrhagic fever (EHF) disease in various animal species: mice, guinea pigs, hamsters, pigs and NHP, to include baboons, marmosets, rhesus and cynomolgus macaques, as well as African green monkeys. Because the NHP models are supremely useful for therapeutics and vaccine testing, emphasis is placed on comparison of these models, and their use as gold-standard models of EHF.
EXPERT OPINION: Animal models of EHF varying from rodents to NHP species are currently under evaluation for their reproducibility and utility for modeling infection in humans. Complete development and licensure of therapeutic agents and vaccines will require demonstration that mechanisms conferring protection in NHP models of infection are predictive of protective responses in humans, for a given countermeasure.

PMID: 26004783 [PubMed - indexed for MEDLINE]

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Privileged scaffolds in lead generation.

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Privileged scaffolds in lead generation.

Expert Opin Drug Discov. 2015 Jul;10(7):781-90

Authors: Zhao H, Dietrich J

Abstract
INTRODUCTION: The term "privileged scaffold" was coined in 1988 and the strategy was to construct high-affinity ligands from core structures that can bind more than one receptor. Since then, the privileged scaffold-based design has evolved from a stand-alone technology to an integral component of various lead generation platforms.
AREAS COVERED: In this review, the authors discuss the applications of the privileged scaffold concept in current lead generation. Specifically, the authors cover the role that privileged scaffolds have played in the mass production of compounds to feed high-throughput screening (HTS) and its role in the design of ligands targeting protein-protein interactions, multiple ligands and warhead-based ligands. It is not the intention of the authors to review all privileged scaffolds known to date. Rather, the aim of this review is to highlight the strategic value of the concept of privileged scaffolds in various contemporary lead generation platforms.
EXPERT OPINION: The privileged scaffolds as described by the original definition proved abundant in the available chemical space. HTS and other screening methods, in addition to greatly enhanced compound collections, make privileged scaffold-based design less relevant in finding high-affinity ligands than originally envisioned. However, the principle of privileged scaffolds has greatly enhanced and empowered current lead generation technologies.

PMID: 25959748 [PubMed - indexed for MEDLINE]

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Challenges in early clinical drug development for ischemia-reperfusion injury in kidney transplantation.

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Challenges in early clinical drug development for ischemia-reperfusion injury in kidney transplantation.

Expert Opin Drug Discov. 2015 Jul;10(7):753-62

Authors: O'Neill S, Gallagher K, Hughes J, Wigmore SJ, Ross JA, Harrison EM

Abstract
INTRODUCTION: In an effort to expand the donor pool, kidneys from donation after cardiac death (DCD) donors are increasingly utilised in renal transplantation. These kidneys suffer greater ischemia-reperfusion injury (IRI) and have a higher incidence of delayed graft function. In the last 25 years, relatively few pharmacological therapies to reduce IRI have been tested in randomised controlled trials in renal transplantation and currently no pharmacological agents are routinely utilised for this purpose.
AREAS COVERED: The authors look at why promising treatments in pre-clinical studies have not translated to significant clinical benefit in human trials. This may reflect a translational disconnect between the pre-clinical models used and clinical problems that are encountered in the transplant population. They also discuss the issues in conducting clinical trials and its implication on drug development.
EXPERT OPINION: Translating pharmacological strategies for reducing IRI is highly challenging at every stage of development from pre-clinical studies to clinical trials. Scientific knowledge of the complexity of IRI is rapidly evolving and new treatments are expected to emerge. There are ethical barriers that prevent donor treatments, particularly in the DCD setting. However, new clinical techniques such as normothermic regional and ex-vivo perfusion represent exciting opportunities to utilise pharmacological agents earlier in the process of transplantation.

PMID: 25947288 [PubMed - indexed for MEDLINE]

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