Issue 3 2005

The promise and pitfalls

Issue 3 2005 / 22 August 2005 / Craig S. Mickanin, Research Investigator and Mark A. Labow, Executive Director, Genomic and Proteomic Sciences, Novartis Institutes for BioMedical Research

Perhaps the most significant technological advancement in the study of gene function in the post-genome era has been the discovery that RNA interference (RNAi) can be exploited for depletion of endogenous mRNA in mammalian cells. As the pharmaceutical industry has fallen under intense pressure to both identify and validate high-quality drug targets, the lure of bona fide genome-wide functional analysis and target identification using small interfering RNA (siRNA) has fueled the interest in what can now be truly called ‘functional’ genomics.

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Tagged with: Craig S. Mickanin, Functional genomics, Mark A. Labow, Novartis Institutes for BioMedical Research

Biomarkers of efficacy and safety

Issue 3 2005 / 22 August 2005 / Dr Graham R Betton, Senior Principal Scientist, Safety Assessment, AstraZeneca Pharmaceuticals

This article reviews the types of biomarkers currently available and approaches to discovering new biomarkers.

The category of type 0 biomarkers refers to pre-existing factors that influence disease susceptibility, outcome or therapeutic response (efficacy or toxicity) (Downing 2000). These markers may be genetic or acquired during life (e.g. viral infection, mutations in cancer) and constitute risk factors for disease. They equally form the basis of animal disease models, e.g. Zucker diabetic rats. The completion of the human genome and ongoing identification of the genetic polymorphisms and mutations within the germ line and cancer tissues has confirmed the previously unidentified existence of many patient subsets (Bertucci 2003). Consequently target selection for drug discovery has become more complex and the diagnostic challenges of personalised medicine and acquisition of human tissue banks from ethical and consented sources, compliant with the UK Human Tissue Act 2004, are now a priority for drug discovery. Personalised medicine is also a challenge for the commercial viability of niche new medical entities (NMEs) (Ross 2003, Lesko 2004). If clinical trial recruitment can be selectively based on patient subsets expressing the drug target, a better efficacy response could be anticipated, increasing the power of the clinical trial and attaining evidence for efficacy more rapidly as less patients need to be recruited. However smaller trials may impair the safety profiling of an NME. The technical means of screening hundreds of patient disease material samples (biofluids or tissue biopsies) is highly dependant on reagents (in particular antibodies) and tissue samples with reliable quality and provenance. The creation of tissue microarrays (TMAs) of clinical diagnostic biopsies and immunohistochemical staining for target protein expression allows for both the overall (brown) intensity of expression and heterogeneity of expression (e.g. cancer cell versus stroma, see Figure 1) and can enable early selection of target patient populations and individual cases.

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Tagged with: AstraZeneca, Biomarkers, Graham R Betton

Plasma protein biomarker discovery

Issue 3 2005 / 22 August 2005 / Gilbert S. Omenn, M.D.,Ph.D University of Michigan

Less than a week after Nature and Science published the special issues on the ’blueprint‘ for the human genome sequence 15-16 Feb, 2001, the Financial Times of 21 February, 2001, ran a major article about proteomics, calling proteins “the real stuff of life”. Proteins are, indeed, the effector molecules for most cellular actions and interactions. As attention has migrated from genome sequences to genetic variation and functional genomics, proteomics has gradually emerged as a potentially powerful set of technologies for biomarker discovery and mechanistic studies important to drug development and drug safety surveillance1-4.

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Tagged with: Gilbert S. Omenn, Proteomics, University of Michigan

Initiatives from Spain

Issue 3 2005 / 22 August 2005 / José M Mato, Isabel Pérez-Mato, Félix Elortza, CIC bioGUNE and Julio Font, Noray Bioinformatics, S.L

The availability of the complete sequence of some model organism genomes, including the human genome, offers new opportunities for biological research. The goal is to establish technology to identify all the proteins involved in a particular biological process and the interactions between them.

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Tagged with: CIC bioGUNE, Félix Elortza, Isabel Pérez-Mato, José M Mato, Julio Font, Noray Bioinformatics S.L, Proteomics

Analysing the monographs

Issue 3 2005 / 22 August 2005 / Erwin Adams, Ann Van Schepdael and Jos Hoogmartens, Laboratory for Pharmaceutical Chemistry and Drug Analysis, Catholic University of Leuven, Belgium

The European Pharmacopoeia (Ph. Eur.)1 monographs are subject to regular adaptation in order to cope with progressing quality requirements. This contribution outlines the evolution in analytical requirements and techniques in monographs for organic substances. These monographs generally carry the subheadings definition, characters, identification, tests, assay and impurities.

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Tagged with: Ann Van Schepdael, Catholic University of Leuven, Erwin Adams, European Pharmacopoeia, Jos Hoogmartens

The AstraZeneca ACMF

Issue 3 2005 / 22 August 2005 / Dr Dalin Nie, Associate Director, and Deborah S. Hartman, Director, Lead Discovery, AstraZeneca Pharmaceuticals, Wilmington

Compound management is an emerging discipline that represents a core component of the drug discovery process, from early phases involving high throughput screening (HTS) to late-stage lead optimisation screening cascades.

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Tagged with: AstraZeneca, Dalin Nie, Deborah S. Hartman, Drug discovery, Lab Automation

Taking care of innovation

Issue 3 2005 / 22 August 2005 / Thomas Keller, MPhil, PhD, Head of Applied Technology Group UK, European & International Operations, GlaxoSmithKline R&D

The most important factors for ensuring a successful future are innovation and an effective governance structure. Within this model1 in the pharmaceutical industry, the introduction of new technology is one of the key factors. This provides an organisation with efficient and reliable systems to facilitate the incorporation of new scientific concepts and practices and these are vital to ensure the company’s continued success.

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Tagged with: GlaxoSmithKline R&D, Project Management, Thomas Keller

Support for lead optimisation and target validation

Issue 3 2005 / 22 August 2005 / Stefan Prechtl, Group Leader, High Content Analysis and Philip Denner, Schering AG

High-Content Analysis (HCA) provides a drug discovery tool capable of rapid screening of drug effects in pharmacologically relevant cell culture systems. Interest in HCA has been increasing during the past few years. This reflects the confidence that HCA-technology has established due to the stability and reliability offered to the drug discovery process. HCA offers the capability to support an experienced and open minded cell biologist in challenging the current limits of cell biology. HCA is a versatile tool providing statistically secured data of cellular and subcellular events, respectively.

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Tagged with: HCS (High Content Screening), Philip Denner, Schering AG, Stefan Prechtl

The road ahead and how to get there

Issue 3 2005 / 22 August 2005 / James Herrington and Owen B. McManus, Department of Ion Channels, Laszlo Kiss, Pain Research, Merck Research Laboratories

Ion channels are membrane spanning proteins with narrow hydrophilic pores that support the passive flux of inorganic ions across the cell membrane.

Channels are dynamic proteins which can exist in multiple states such as the open, closed and inactivated states and structural studies1 have shown substantial conformational differences between channel states (Figure1). Therapeutically used drugs often selectively bind to a specific channel state. Functionally, ion channels can be classified according to how they transition, or ’gate‘, between these states. Voltage-gated ion channels gate in response to changes in membrane potential whereas ligand-gated channels gate in response to the binding or unbinding of a ligand. In the open state, channels achieve remarkable transport efficiency as more than 1 million ions can pass through a single channel per second. Channels can also display exclusive ion selectivity, permitting some inorganic ions to pass but not others. To date, upwards of 300 different human ion channel genes have been identified yet merely 5 per cent of drugs marketed today target ion channels. During the past 15 years, major advances in both our understanding of the role of ion channels in disease, as well as ion channel screening technologies, have made this a molecular target class ripe for drug development.

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Tagged with: Ion Channel Drug Discovery, James Herrington, Laszlo Kiss, Merck Research Laboratories, Owen B. McManus

The rise of Raman

Issue 3 2005 / 22 August 2005 / Marleen de Veij, Dr. Peter Vandenabeele and Prof. Dr. Luc Moens, Laboratory of Analytical Chemistry, Ghent University

Traditionally, analyses in pharmaceutical research and industry were often performed using Nuclear Magnetic Resonance (NMR) or Mass Spectrometry (MS). However, researchers are aware that Raman Spectroscopy possesses advantageous characteristics for the pharmaceutical world.

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Tagged with: Ghent University, Luc Moens, Marleen de Veij, Peter Vandenabeele, Raman Spectroscopy

A Pfizer perspective

Issue 3 2005 / 22 August 2005 / Joep Timmermans, Ph.D., Senior Manager/Team Leader, Process Analytical Support Group – Americas Implementation Team, Pfizer Global Manufacturing

While the current attention and focus on Process Analytical Technologies (PAT) may make you believe otherwise, PAT measurement systems have been used in the pharmaceutical industry, Pfizer included, for some time, albeit often to a limited extent.

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Tagged with: Joep Timmermans, PAT, Pfizer Global Manufacturing

International standards: a tool for compliance

Issue 3 2005 / 22 August 2005 / Dr Hans H. Schicht, Dr. sc. techn., Dr. Hans Schicht Ltd. Contamination Control Consulting

Regulatory guidance documents, such as Annex 1 to the GMP guideline of the European Union1 and FDA’s comparable Guidance for Industry2 establish the objectives to be met by pharmaceutical contamination control systems – especially those for the production of sterile medicinal drugs.

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Tagged with: Cleanrooms, Dr. Hans Schicht Ltd, Hans H. Schicht