Not an Easy Target or Molecular Therapeutics

Not an Easy Target: Paxton Quigley's Self-Protection for Women

Author: Paxton Quigley

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New interesting textbook: IIS 6 or Pocket PCRef

Molecular Therapeutics: 21st Century Medicine

Author: Michelle McCulley

Molecular therapeutics refers to the developments in molecular biology that are focused on treating disease with new molecular-based drugs.

By taking advantage of recent advances and increased understanding in the field of human genetics, this book provides essential background knowledge and key literature on a broad range of novel approaches and disciplines. These include making recombinant proteins, xenotransplantation gene therapy and therapeutic cloning. Molecular Therapeutics: 21st Century Medicine describes the techniques - including their associated benefits, problems, pitfalls - and discusses their applicability with respect to treating microbial, inherited, multifactoral and acquired diseases. The book also pays specific attention to the ethical issues associated with this new field.

• Cutting-edge topics and clinically relevant materials engage and maintain student interest

• Self-assessment questions are included throughout the book

• Features an additional web site, with a web forum, regular updates and PowerPoint slides of figures from the book

Molecular Therapeutics: 21st Century Medicine is a comprehensive, accessible and engaging guide to the rapidly developing field of molecular therapeutics. It is essential reading for all students in this area of research and also of interest for health professionals involved in these novel therapies.

Doody Review Services

Reviewer:Eugene A Davidson, PhD(Georgetown University School of Medicine)
Description:This book, derived from lecture notes used for an undergraduate level course, is an overview of current approaches to treatment of disease with a focus on genetic/recombinant methods.
Purpose:The apparent goal is to introduce students to current methods used to combat disease. In general, an awareness of these topics is of value, and the authors have partially achieved their goal.
Audience:Students taking a course in modern approaches to disease control are the intended audience, although it is not clear what the general concentration aim of such students may be. The material is presented at a level suitable for beginning undergraduates and presumably represents the distilled efforts of the authors who have extensive background in teaching such material.
Features:Disease control is a universal health goal. Targets in this ongoing struggle begin with childhood threats/vaccinations and continue through gene replacement, cancer management, transplantation, etc. In developing strategies to combat these problems, new methods are coming into use and this book provides a student-oriented overview of some of the common approaches. Each of the chapters has a reference set, several cover associated ethical issues, and the book concludes with a discussion of legal concerns. Naive students (presumed audience) will develop an understanding of many of the modern methods used, an appreciation of the diverse ethical issues, and some sense of the regulatory and legal hurdles encountered. With the clear understanding that all of the coverage issuperficial, most of the references are not to primary sources but to web-based sites, and essentially none of the science is critically assessed, this book can provide good background information for an uniformed audience. Students in the sciences need a more critical assessment of these issues.
Assessment:This book is suitable for uninformed students not majoring in a scientific discipline. The lack of critical assessment is a serious drawback and diminishes somewhat a generally good overview.

Table of Contents:

Prologue     xi
Introduction     1
Microbial diseases     2
Cancer and heart disease     3
Cancer     4
Heart disease     5
Genetic diseases     5
Dominant diseases     6
Recessive diseases     6
Role of molecular biology in therapeutics     7
Prenatal diagnosis and pre-implantation     11
Should we treat inherited diseases?     11
Genetic screening     12
Pre-implementation genetic diagnosis     13
Counselling     15
Simple protein replacement therapy     17
Preventing transfusion-transmissible infectious diseases in the UK     18
Ensuring the safety of organ transplants     19
Preventing transfusion-transmissible infectious diseases worldwide     20
HIV     20
Recombinant protein production     23
Choice of organism     23
Somatostatin: an example of protein produced in E. coli     27
Insulin: an example of a recombinant protein     27
Alternatives to E. coli for the production of recombinant proteins     29
Insect cells     29
Whole insects     30
Mammalian cells     30
Plants     30
Transgenic animals     31
Problems with recombinant protein production     31
Problems with glycosylation     32
Effect of glycosylation     33
Erythropoietin: an example of protein produced in mammalian cells     35
Production method     36
Preparation of Factor VIII     36
Transgenic pigs and Factor VIII     37
All recombinants must be tested before they are given to humans     38
Why make recombinant proteins?     39
Recombinant products     40
Generics     40
Recombinant vaccines     43
Vaccine history     43
Vaccines     45
Vaccine methods     46
Types of vaccine     47
The limitations of vaccine programmes     48
The role of the WHO     50
Problems specific to developing countries     51
Economics and logistics of vaccinology     52
Recombinant vaccines     54
Simple recombinant protein vaccines     55
Gene vaccines: the vaccinia virus approach     57
DNA vaccines     57
Edible vaccines from transgenic plants     58
Rational design: bioinformatics and proteomics     59
Other interesting area for vaccine development     60
Conclusion     60
Therapeutic antibodies and immunotherapy     63
Monoclonal antibodies     63
Monoclonal production     64
Therapeutic monoclonal antibodies     66
Human monoclonals     66
Humanised antibodies     67
Transgenic monoclonals     69
The uses of monoclonal antibodies in therapy     69
Specific examples of therapeutic strategies     70
Unconjugated antibodies - treatment of kidney rejection     70
HIV treatment     71
Cancer therapy and monoclonal antibodies     71
Herceptin in breast cancer therapy     71
Treatment of multi-drug-resistant cancer cells     72
Anti-endotoxin antibodies     73
Conjugated antibodies     73
Delivery of radionuclides to leukaemia and lymphoma patients     74
Drug delivery     74
Toxin delivery     75
Bispecific antibodies     75
Other recombinant proteins used in immunotherapy     76
Cytokines     76
Colony-stimulating factors and growth factors     79
Transgenic animals     83
Why do we want to engineer the genomes of animals?     83
Experimental procedure     85
Method 1: Germline manipulation     85
Method 2: Using embryonic stem cells     87
DNA constructs, insertional mutagenesis and homologous recombination     90
Uses of inducible and tissue-specific promoters     91
Introduction of the DNA into the cells     92
Uses of transgenics     93
Recombinant protein production     93
Animal models of human diseases     94
Transplantation: a form of gene therapy     99
Introduction     99
Bone marrow     100
Logistical problems with BMT     102
Solid organ transplantation     102
Heart transplantation     103
Lung     104
Kidney     105
Liver     105
Ovarian tissue     106
Other cells and tissues     106
Summary of the problems associated with transplantation     107
Transplantation statistics     108
Legislation     108
Religious beliefs and transplantation      110
Xenotransplantation     113
Introduction     113
Rationale for the use of non-human donors     114
Organs from non-human primates     114
Pigs     115
Can we pretreat the recipient to prevent rejection?     116
Problems with pigs     117
Will pig hearts function in humans?     117
Xenozoonoses     117
Religious objections     118
Animal activists     119
Government legislation     119
When will xenotransplantation start?     120
Patient attitudes     120
Ethics     121
Alternatives to xenotransplants     121
Reproductive cloning     125
History     125
Problems     127
Why was there so much interest in Dolly?     128
Was Dolly a lone example?     129
Why is cloning useful?     129
Is human cloning a reality?     130
Why can we not produce human clones that are identical?     131
So why clone humans?     132
What are the ethical and moral problems?     132
Stem cell therapy     137
The potency of cells     137
Cloning      137
Potency of stem cells     138
Potential sources of stem cells     138
Stem cells and therapeutic cloning     138
Legislation and therapeutic cloning     140
Other sources of stem cells     142
What can be done?     142
Experiments on embryonic cells     143
Experiments on fetal tissue and cord blood     143
Stem cells from adult tissues     143
Safety and technical problems     144
Perceived scope of therapy     145
Clinical trials of stem cell therapy     145
What are the future prospects for stem cell research?     146
Gene augmentation therapy     149
Introduction     149
Strategy     150
DNA delivery     151
Viral vectors and gene therapy     152
Artificial viruses     155
Non-viral delivery in gene therapy     155
What tissues can we currently target?     157
Targeting gene expression     159
Problems associated with augmentation therapy     160
Gene augmentation therapy vs. recombinant DNA therapy or transplantation     161
Current criteria for the use of gene therapy      162
The bystander effect     163
Candidates for gene therapy     163
Gene therapy trials for inherited diseases     165
Introduction     165
Examples of disease treated with retroviral gene therapy     166
Severe combined immunodeficiency     166
Hypercholesterolaemia     169
Cystic fibrosis     170
Rationale for adenoviral vectors     171
Early animal trials     171
Is CF gene therapy 'safe but not useful'?     172
Problems also found in in vivo delivery     172
Animal trials with Factor IX     173
Adenoviruses have also been used to introduce genes into brain     174
Duchenne's muscular dystrophy     175
Problems with adenoviruses     175
The uses of adeno-associated viruses     176
Haemophilia B treatment with Factor IX gene augmentation     176
AAV therapy for DMD     177
Liposome vector trials     178
Trials with polymer mareix delivery     178
Gene silencing technologies     181
Antisense therapy     181
Modification of antisense molecules     183
Replacement of oxygens in the phosphate bridge      184
Modifications can be made to the bases themselves     184
Other types of modifications     185
The ideal oligonucleotide     185
Uptake     185
Uses of antisense oligonucleotides     187
Examples     187
Catalytic antisense molecules     191
Triple helix (triplex) technology     191
Problems     193
Advantages over antisense strategies     193
Experimental data     194
Ribozymes     196
Examples of ribozyme therapies     197
Small interfering RNAs (siRNAs)     198
Clinical trials and siRNA     202
Is RNAi better than antisense?     202
Gene therapy for cancer     205
What causes cancer?     205
Cancer: a multifactorial disease     206
Cancer statistics     207
Best treatment currently available     208
Avoidance     208
Screening     208
Surgery     209
Chemotherapy     209
Radiotherapy     210
Do chemo- and radiotherapy cause problems?     210
New cancer therapies     210
Cancer models in animals      211
What kinds of gene therapy can we use to treat cancer?     212
Perceived problems in cancer gene augmentation therapy     213
Killing cells with ganciclovir or suicide therapy     213
Prodrug activation therapy     214
Enhancing the immune system with gene therapy     215
Gene silencing technologies and cancer     217
Conclusion     219
Single-nucleotide polymorphisms (SNPs) and therapy     223
Legislation, clinical trials and ethical issues     231
Legislative bodies     231
Clinical trials     233
The problems of placebo controlled trials     236
The need for informed consent     238
Trials in developing countries     239
Recent trial issues     241
Conclusion     242
Epilogue     245
Sourcing references     245
Index     247