Molecular and Cellular Therapeutics E-Book

David Whitehouse

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 680

Veröffentlichungsjahr: 2012

Beschreibung

Molecular and Cellular Therapeutics aims to bring together key developments in the areas of molecular diagnostics, therapeutics and drug discovery. The book covers topics including diagnostics, therapeutics, model systems, clinical trials and drug discovery. The developing approaches to molecular and cellular therapies, diagnostics and drug discovery are presented in the context of the pathologies they are devised to treat.

Leseprobe

Contents

Cover

Title Page

Copyright

List of contributors

Preface

1: Cytochrome P450 pharmacogenetics: from bench to bedside

1.1 Introduction

1.2 Cytochrome P450 pharmacogenetics

1.3 Conclusion

2: Cancer biomarkers for diagnosis, prognosis and therapy

2.1 Introduction

2.2 Cancer biomarkers – an overview

2.3 Types of conventional cancer biomarkers

2.4 Recent developments on common cancer biomarkers

2.5 Omics approaches in cancer biomarker discovery

2.6 Challenges in cancer biomarker discovery

2.7 Omics-based next-generation molecular markers in cancers and their applications

2.8 Therapeutic applications of cancer biomarkers

2.9 Recent trends and future directions

2.10 Conclusions

3: HER2 targeted therapy-induced gastrointestinal toxicity: from the clinical experience to possible molecular mechanisms

3.1 Introduction

3.2 The use of HER2 as a biomarker

3.3 The normal GI tract

3.4 What is GI Toxicity?

3.5 Mucositis

3.6 Mucositis and grading in the clinic

3.7 Toxicities of HER2 targeted therapies

3.8 Toxicity of traditional anti-cancer therapy in combination with HER2 inhibition

3.9 Toxicity clustering

3.10 Mechanisms of HER2 targeted therapy-induced toxicity

3.11 Toxicity of tyrosine kinase inhibitors versus monoclonal antibodies

3.12 Predisposing factors to toxicity

3.13 Development of models for HER2 targeted therapy-induced toxicity

3.14 Summary

4: Antibody-targeted photodynamic therapy

4.1 Introduction

4.2 Antibody-targeted PDT using whole immunoglobulins

4.3 Antibody-targeted PDT using recombinant fragments

4.4 PICs in humans

4.5 The outlook for targeted PDT

4.6 Conclusions

5: Anti-ageing strategy of the lung for chronic inflammatory respiratory disease – targeting protein deacetylases

5.1 Introduction

5.2 The molecular mechanism of the ageing process

5.3 Inflammaging: ageing and inflammation

5.4 Defect of anti-ageing molecules in COPD

5.5 Anti-ageing strategy for COPD

5.6 Conclusion and future directions

Acknowledgements

6: RNA interference: from basics to therapeutics

6.1 Introduction

6.2 RNAi-pathway and mechanism

6.3 Role of RNAi

6.4 Role of small RNAs

6.5 Role of RNAi in virus infections

6.6 Scope of RNAi for therapy

6.7 Strategies/criteria to design RNAi for therapy

6.8 RNAi in therapy

6.9 Conclusions

Declaration

7: Delivery of RNAi effectors by tkRNAi

7.1 Introduction

7.2 Cancer

7.3 Transkingdom RNAi (tkRNAi)

7.4 Conclusion

8: Human stem cell therapy

8.1 Introduction

8.2 Sources of stem cells

8.3 Stem cell therapy for cardiovascular disease

8.4 Stem cell therapy for diabetes

8.5 Cancer

8.6 Neurological diseases

8.7 Blindness

8.8 Ageing

8.9 Conclusions

9: Gene therapy in organ transplantation

9.1 Introduction

9.2 Basic mechanisms of organ allograft failure

9.3 Gene therapy approaches in solid organ transplantation

9.4 Clinical applications of gene therapy in transplantation

9.5 Why has clinical translation of gene therapy in organ transplantation been limited?

Acknowledgements

10: Advances in the treatment of Alzheimer's disease

10.1 Introduction

10.2 Inhibition of production, increasing the clearance, and prevention of aggregation of amyloid

10.3 Improving neuronal function

10.4 Neuroprotective mechanisms

10.5 Reducing neurofibrillary tangles

10.6 Conclusions

11: Novel molecular therapeutics in Parkinson's disease

11.1 Parkinson's disease etiology and pathogenesis

11.2 Targeting protein quality control systems in PD

11.3 Vesicular trafficking defects in models of Parkinson's disease

11.4 a-syn post-translational modifications

11.5 Sirtuins as targets in PD

11.6 Mitochondrial dysfunction in PD

11.7 Crossing the blood–brain barrier

11.8 Concluding remarks

12: Emerging insights and therapies for human microbial disease

12.1 Introduction

12.2 Antibacterial agents

12.3 Targeting bacterial lifestyle and virulence

12.4 Phage therapy

12.5 Antibody-based techniques

12.6 Antifungal agents

12.7 Antiviral therapy

12.8 Broad range therapy

12.9 Conclusions

13: Vaccine design and vaccination

13.1 Introduction

13.2 Immunity to extracellular and intracellular pathogens

13.3 Vaccines in current use in humans

13.4 Current strategies in novel vaccine development

13.5 Concluding remarks

Index

This edition first published 2012 © 2012 by John Wiley & Sons, Ltd

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Library of Congress Cataloging-in-Publication Data

Molecular and cellular therapeutics / [edited by] David B. Whitehouse and Ralph Rapley. p. ; cm. Includes bibliographical references and index. ISBN 978-0-470-74814-5 (cloth) – ISBN 978-1-119-96729-3 (ePDF) – ISBN 978-1-119-96730-9 (Wiley Online Library) – ISBN 978-1-119-96780-4 (ePub) – ISBN 978-1-119-96781-1 (Mobi) I. Whitehouse, David, 1946- II. Rapley, Ralph. [DNLM: 1. Biological Therapy–methods. 2. Molecular Biology–methods. 3. Molecular Targeted Therapy–methods. 4. Translational Research. WB 365] 572.8–dc23 2011038356

A catalogue record for this book is available from the British Library.

Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books.

List of contributors

Vaishali AgteAgharkar Research Institute, G. G. Agarkar Road, Pune 411004, India

Varsha AgteMITCON Institute of Management and Technology, Balewadi, Pune 411045, India

Noor Al-DasooqiDepartment of Medical Oncology, Royal Adelaide Hospital, Level 4 East Wing, North Terrace, Adelaide 5000, South Australia, Australia

Debmalya BarhCentre for Genomics and Applied Gene Technology, Institute of Integrative Omics and Applied Biotechnology (IIOAB), Nonakuri, Purba Medinipur, WB-721172, India

Joanne M. BowenDiscipline of Physiology, University of Adelaide, North Terrace, Adelaide 5005, South Australia Australia

Catherine J. BreslinStrathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, Scotland, UK

Henrique ChengDepartment of Comparative Biomedical Sciences, School of Veterinary Medicine, Skip Bertman Drive, Louisiana State University, Baton Rouge LA 79803, USA

Mahendra DeonarainDivision of Cell and Molecular Biology, Faculty of Natural Sciences, Imperial College London, Exhibition Road, London SW7 2AZ, UK

Dipali DhawanDepartment of Cellular and Molecular Biology, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Thaltej-Gandhinagar Highway, Thaltej, Ahmedabad 380054, Gujarat, India

Joanne L. FothergillInstitute of Infection and Global Health, University of Liverpool, Liverpool L69 3GA, UK

Johannes H. FruehaufSkip Ackerman Center for Molecular Therapeutics, Beth Israel Deaconess Medical Center, Boston, MA, USA

Rachel J. GibsonDiscipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, North Terrace, Adelaide 5000, South Australia, Australia

Susana GonçalvesCell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal

Matthew D. GriffinRegenerative Medicine Institute (REMEDI), National Centre for Biomedical Engineering Science (NCBES), Orbsen Building, University Road, National University of Ireland, Galway, Ireland

Praveensingh B. HajeriDepartment of Surgery, University of Minnesota, Minneapolis MN:55455, USA

Kazuhiro ItoAirway Disease, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK

Dorothy M. KeefeDepartment of Medical Oncology, Royal Adelaide Hospital, Level 4 East Wing, North Terrace, Adelaide 5005, South Australia Australia

Andrea KrühnCharité Campus Mitte, Institute of Pathology, Charitéplatz 1, 10117 Berlin, Germany

Hermann LageCharité Campus Mitte, Institute of Pathology, Charitéplatz 1, 10117 Berlin, Germany

Simon P. MackayStrathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, Scotland, UK

Niall McMullanSchool of Life Sciences, University of Hertfordshire, College Lane, Hatfield, Herts AL10 9AB, UK

Nicolas MercadoAirway Disease, National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY, UK

Hugo Vicente MirandaCell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal

Tiago F. OuteiroCell and Molecular Neuroscience Unit, Instituto de Medicina Molecular, Av. Prof. Egas Moniz, 1649-028 Lisboa, Portugal

Harish PadhDepartment of Cellular and Molecular Biology, B. V. Patel Pharmaceutical Education and Research Development (PERD) Centre, Thaltej-Gandhinagar Highway, Thaltej, Ahmedabad 380054, Gujarat, India

M. Ian PhillipsCenter for Rare Disease Therapies Keck Graduate Institute of Applied Life Sciences, 535 Watson Drive, Claremont, CA 91711, USA

Michael S. RafiiDirector, Memory Disorders Clinic, Assistant Professor of Neurosciences, University of California, San Diego 9500 Gilman Drive, #0949 La Jolla, California 92093, USA

Thomas RitterRegenerative Medicine Institute (REMEDI), National Centre for Biomedical Engineering Science (NCBES), Orbsen Building, University Road, National University of Ireland, Galway, Ireland

Imtiaz M. ShahStrathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, Scotland, UK

Sunit Kumar SinghLaboratory of Neurovirology and Inflammation Biology, Section of Infectious Diseases, Centre for Cellular and Molecular Biology (CCMB), Council of Scientific and Industrial Research (CSIR), Uppal Road, Hyderabad-500007, AP, India

Ioanna StamatiDivision of Cell and Molecular Biology, Faculty of Natural Sciences, Imperial College London, Exhibition Road, London SW7 2AZ, UK

Yao-Liang TangDivision of Cardiovascular Disease, Internal Medicine, University of Cincinnati, 231 Albert Sabin Way, ML0542, Cincinnati OH 45267, USA

Craig WinstanleyInstitute of Infection and Global Health, University of Liverpool, Liverpool L69 3GA, UK

Gokhan YahiogluPhotoBiotics Ltd, Montague House, Chancery Lane, Thrapston, Northamptonshire NN14 4LN, UK

Preface

The inspiration for this volume emerged from a combination of the completion of the Human Genome Project and advances in cellular and molecular medicine. Together these disciplines have established the basis for a new wave of translational research where the aim is for advances in basic science to impact directly on improved clinical outcomes. Although medical pathology has historically been divided into subsets dependent on the organ system involved and disease aetiologies, it is becoming increasingly evident that diagnoses and treatment of disease, whether acquired or heritable, should additionally be based on the detailed knowledge of epidemiology and genetics, lifestyle, molecular and cellular pathology. The objective of the book is to provide an exciting insight into advances in key areas of molecular and cellular aspects of applied medical research. Based on a series of authoritative chapters that provide opinion and data across a broad field of medicine, the aim is to enable the reader to acquire a usable platform of knowledge sufficient, for example, to gain access to the specialist literature.

The first two chapters address molecular aspects of pharmacogenetics and biomarkers.

The opening chapter from Imtiaz Shah and colleagues describes some of the potential practical outputs of the Human Genome Project. Person to person variability in response to drugs has long been recognized and the authors summarize the recent research finding on genotype testing in relationship to variability in drug response with reference to the CYP genes. Continuing with the theme of molecular analysis in relation to physiological states, Debmalya Barh and colleagues reviews the field of biomarkers. These substances which can indicate disease states and treatment outcomes are of increasing importance in medicine. The chapter provides an introductory review of biomarkers in general whilst focusing on cancer related molecular markers, their classification, detection approaches and applications. Chapters 3 and 4 review aspects of cancer therapy. In Chapter 3, Noor Al-Dasooqi and colleagues focus on HER2 targeted therapy and the role of HER2 in cancer. The central theme addresses the gastrointestinal toxicities associated with commonly used HER2 targeted therapy drugs and the possible underlying mechanisms. Although drugs that target HER2 and other EGF receptors have proved to be effective in managing a range of cancers, toxic side effects remain a significant problem. In Chapter 4, Mahendra Deonarain and colleagues sustain the theme of cancer therapy with a review of photodynamic therapy (PDT). The complexity of PDT targeting, lack of potency and side effects have limited the technology and restricted its general usage by oncologists. The problem of targeting disease cells is addressed and the translational research harnessing monoclonal antibodies and antibody fragments is described.

In Chapter 3 Kazuhiro Ito and Nicolas Mercado review the free-radical theory of ageing in relation to inflammatory disease. The most ageing-associated disease is recognized as chronic inflammatory disease where oxidative stress is likely to contribute to the inflammation. The authors describe the analysis of oxidative stress reduced anti-ageing molecules such as those that are involved in epigenetic control of pro-inflammatory gene expression and control of protein function.

The next two chapters are focused on RNAi, which is widely acknowledged as a potential basis for powerful new therapies. Sunit Singh and Praveensingh Hajeri (Chapter 6) provide a sterling review of the topic. Whilst the techniques have proven potential for providing therapeutic solutions, the authors do not shy from highlighting the hurdles to be overcome in designing strategies for knocking down specific gene expression. In Chapter 7 Hermann Lage and colleagues review the development and potential applications for Transkingdom RNAi (TkRNAi). The tkRNAi approach described represents a new strategy for delivery of RNAi effectors, in particular for the treatment of bowel disease.

There follow two chapters on key areas of current medical research, stem cells and gene therapy. In Chapter 8 Ian Phillips and colleagues comprehensively review the history of stem cell biology and the current advances. The chapter addresses the key questions that need to be answered before new human stem cell therapies can be used routinely, including the choice of stem cells, the ease of preparing, storage and delivery of stem cells, and the effectiveness of the therapies. In Chapter 9 Thomas Ritter and Matthew Griffin tackle gene therapy. Whilst gene therapy technologies have been successfully applied in many preclinical models for the treatment of various diseases – including the prevention of allogeneic organ graft rejection – mainly for safety reasons the translation into the clinic has lagged behind. The authors examine the role that gene therapy and gene transfer technologies may play in the successful application of new strategies to improve the success rates and long-term, immunosuppression-free survival of organ allografts.

In Chapters 10 and 11 advances in the two most common neurodegenerative diseases are presented. Neurodegenerative disease, in particular Alzheimer's disease, is an area where the burden of disease cost is set to increase significantly over the next 50 years. First Michael Rafii discusses promising new treatments for Alzheimer's disease, the most common form of progressive dementia in older people. The major therapeutic strategies are reviewed as are the complexities of dealing with such a heterogeneous condition. In Chapter 11 Tiago Outeiro and colleagues review current and new therapeutic approaches to Parkinson's disease, the second most common neurodegenerative disease that is estimated to affect some 2% of the world population aged over 65.

A vital facet of twentyfirst century medicine is the control of infectious diseases. The last two chapters deal with approaches to bacterial infection and vaccine development. In Chapter 12 Joanne Fothergill and Craig Winstanley address the challenges for the development of new drugs in the face of increasing incidence of antibacterial resistance. In addition to traditional strategies to drug discovery, approaches based on genomic information are addressed. The authors provide a snapshot of some of the approaches being taken to the identification of new therapeutic targets that might enable development of new and better strategies to combat infections in a post-antibiotic era. Niall McMullan (Chapter 13) reviews advances in vaccine development. The last 30 years has seen promising developments in vaccinology. The integration of reverse genetics approaches and reverse vaccinology offer the prospect of rapid methods for developing new vaccines. Recent successes with these new strategies in human clinical trials and the licensing of new animal vaccines offer real hope for major breakthroughs in the control of infectious diseases.

There can be no doubt that therapeutic and diagnostic strategies and approaches that have emerged since the completion of the Human Genome Project have been both wide ranging and highly focused. The notion of ‘bench to bedside’ which is underpinned by the outputs of translational research has gathered momentum and credibility as evidenced by the contents of the chapters presented.

David Whitehouse and Ralph Rapley

1

Cytochrome P450 pharmacogenetics: from bench to bedside

Imtiaz M. Shah, Catherine J. Breslin and Simon P. Mackay

1.1 Introduction

With the elucidation of the human genome sequence over the past decade, pharmacogenetics has evolved into an important area of translational medicine research (International Human Genome Sequencing Consortium, 2004; Grant and Hakonarson, 2007; Shurin and Nabel, 2008). Most patient populations display interindividual variability to drug response and efficacy, with genetic factors accounting for up to 30% in these differences (Evans and McLeod, 2003). Mutations within the genetic DNA sequence (genetic polymorphism) can alter the transcribed mRNA structure and subsequent protein function. This altered genotype expression can result in variability in drug activity (O’Shaughnessy, 2006). Pharmacogenetics is the study of such genetic factors and its effects on drug response. The most common genetic polymorphism is a single nucleotide polymorphism (SNP). This results in a single nucleotide substitution within the DNA structure and accounts for 90% of human genetic variation (Eichler et al., 2007; McCarroll et al., 2006). SNPs are associated with variability in drug response between different patient populations and are an important basis for pharmacogenomics research (Twyman, 2004). This variability in patient genetic profiles can lead to potential risks of drug toxicity or treatment failure (Hoffman, 2007). Current pharmacogenetics research is focusing on patient genotype testing and utilizing this genetic information to provide more ‘personalized’ drug therapy in clinical practice (Feero, Guttmacher and Collins, 2010; Hoffman, 2007).

1.1.1 The Human Genome Project

The Human Genome Project (HGP) has made a crucial contribution to research advances in the rapidly evolving areas of pharmacogenetics and translational medicine. This major international scientific collaboration, which was completed in 2003, has elucidated the complete DNA sequence of the human genome (International Human Genome Sequencing Consortium, 2004). The results of this project have started to provide important genotype–phenotype correlations from genome wide association studies (GWAS), and will potentially lead to major advances in drug development and translational research (The Wellcome Trust Case Control Consortium, 2007; Chung et al., 2010). The HGP is being followed on by the larger 1000 Genomes Project, which will allow more detailed genetic analysis of different ethnic populations (Gamazon et al., 2009).

The HGP analysis commenced in 1995 with the aim of sequencing three billion base pairs (bps) of DNA. The sequencing strategy involved subcloning the human genome into bacterial artificial chromosomes, which were then sequenced (shotgun method) and correctly aligned (Lander et al., 2001). Once the initial sequence was determined, advanced computational algorithms were used to generate a final sequence map. The genome was sequenced five times to minimize any errors. The main findings from the HGP have shown that humans have between 20 000 and 25 000 genes (International Human Genome Sequencing Consortium, 2004). The average human gene spans between 27 000 and 29 000 bases of DNA and consists of four to six exons. The main coding sequence is approximately 1340 bps. Genes are not evenly distributed throughout the genome, with some chromosomes containing more genetic information (chromosomes 1, 2, 11) than others (chromosomes 13, 18, 21).

The relatively small number of genes is not indicative of a similarly small number of proteins. Genes can undergo alternative splicing, thereby increasing the number of different protein products (Barash et al., 2010; Tress et al., 2007). RNA studies have shown that there may be an average of three different transcripts from one gene. The HGP has also identified approximately two million SNPs, which has allowed genetic linkage studies and location of specific diseases to their chromosome loci (Sachidanandam et al., 2001). GWAS and SNP analysis have now started to elucidate genetic associations with common clinical diseases (The Wellcome Trust Case Control Consortium, 2007; Chung et al., 2010). These genomic studies will potentially lead to the identification of new protein targets for drug discovery and play an important role in translational medicine research (Hopkins and Groom, 2002; Schilsky, 2010).

1.2 Cytochrome P450 pharmacogenetics

Genetic polymorphisms and variation in protein structure expression can result in altered drug–protein interactions and affect subsequent drug response. There are three main pharmacogenetic mechanisms that can influence drug activity. These molecular changes can result in genetic polymorphisms affecting the drug metabolizing enzymes (DMEs), drug transporter proteins and the drug receptors. This can result in altered pharmacokinetic properties (metabolism and transport) or pharmacodynamic properties (action) of the drug.