Translating Gene Therapy to the Clinic (eBook)

Techniques and Approaches

Michael Franklin, Jeffrey Laurence (Herausgeber)

eBook Download: PDF | EPUB

2014 | 1. Auflage
346 Seiten
Elsevier Science (Verlag)
978-0-12-800564-4 (ISBN)

Translating Gene Therapy to the Clinic, edited by Dr. Jeffrey Laurence and Michael Franklin, follows the recent, much-lauded special issue of Translational Research in emphasizing clinical milestones and critical barriers to further progress in the clinic. This comprehensive text provides a background for understanding the techniques involved in human gene therapy trials, and expands upon the disease-specific situations in which these new approaches currently have the greatest therapeutic application or potential, and those areas most in need of future research. It emphasizes methods, tools, and experimental approaches used by leaders in the field of translational gene therapy. The book promotes cross-disciplinary communication between the sub-specialties of medicine, and remains unified in theme.

Presents impactful and widely supported research across the spectrum of science, method, implementation and clinical application
Offers disease-based coverage from expert clinician-scientists, covering everything from arthritis to congestive heart failure, as it details specific progress and barriers for current translational use
Provides key background information from immune response through genome engineering and gene transfer, relevant information for practicing clinicians contemplating enrolling patients in gene therapy trials

Translating Gene Therapy to the Clinic, edited by Dr. Jeffrey Laurence and Michael Franklin, follows the recent, much-lauded special issue of Translational Research in emphasizing clinical milestones and critical barriers to further progress in the clinic. This comprehensive text provides a background for understanding the techniques involved in human gene therapy trials, and expands upon the disease-specific situations in which these new approaches currently have the greatest therapeutic application or potential, and those areas most in need of future research. It emphasizes methods, tools, and experimental approaches used by leaders in the field of translational gene therapy. The book promotes cross-disciplinary communication between the sub-specialties of medicine, and remains unified in theme. Presents impactful and widely supported research across the spectrum of science, method, implementation and clinical application Offers disease-based coverage from expert clinician-scientists, covering everything from arthritis to congestive heart failure, as it details specific progress and barriers for current translational use Provides key background information from immune response through genome engineering and gene transfer, relevant information for practicing clinicians contemplating enrolling patients in gene therapy trials

Front Cover 1
Translating Gene Therapy to the Clinic: Techniques and Approaches 4
Copyright 5
Contents 6
Preface 12
REFERENCES 13
About the Editors 14
Contributors 16
Chapter 1 - Translating Genome Engineering to Survival 18
1.1 ORIGINS 18
1.2 SYNCHRONICITY OF DISCOVERIES 19
1.3 GENE ADDITION 19
1.4 FROM GENE ADDITION TO GENE EDITING 21
1.5 THERAPY FOR GENETIC DISORDERS 21
1.6 ROADMAP TO THE FUTURE 24
CONFLICT OF INTEREST 25
ACKNOWLEDGMENTS 25
REFERENCES 25
Chapter 2 - Pluripotent Stem Cells and Gene Therapy 28
2.1 GENETIC APPROACHES TO PLURIPOTENCY 29
2.2 TRANSCRIPTION FACTORS IMPORTANT FOR REPROGRAMMING TO PLURIPOTENCY 30
2.3 METHODS FOR GENETIC REPROGRAMMING 30
2.4 CLINICAL TRANSLATION OF IPSCS 35
2.5 CONCLUSION 40
REFERENCES 40
Chapter 3 - Genome Engineering for Therapeutic Applications 44
3.1 INTRODUCTION 44
3.2 CUSTOMIZABLE DNA-TARGETING PROTEINS 45
3.3 GENOME EDITING WITH ENGINEERED NUCLEASES 49
3.4 SYNTHETIC TRANSCRIPTION FACTORS FOR THERAPEUTIC APPLICATIONS 52
3.5 CONCLUSION 55
ACKNOWLEDGMENTS 55
REFERENCES 56
Chapter 4 - Immune System Obstacles to In vivo Gene Transfer with Adeno-Associated Virus Vectors 62
4.1 INTRODUCTION 62
4.2 AAV VECTORS 63
4.3 INNATE IMMUNITY IN AAV GENE TRANSFER 66
4.4 T-CELL RESPONSES TO VECTORS 67
4.5 HUMORAL IMMUNITY 69
4.6 CONCLUSIONS 74
ACKNOWLEDGMENT 75
REFERENCES 75
Chapter 5 - Risks of Insertional Mutagenesis by DNA Transposons in Cancer Gene Therapy 82
5.1 INSERTIONAL MUTAGENESIS—THE DOWNSIDE OF GENE THERAPY? 82
5.2 SLEEPING BEAUTY TRANSPOSON/TRANSPOSASE SYSTEM ADAPTED FOR GENE THERAPY 85
5.3 PLASTICITY OF GENOMES AND GENE EXPRESSION IN HUMANS 92
5.4 TRANSPOSON-MEDIATED GENE THERAPY IN THE CLINIC 94
5.5 CONCLUSIONS 96
ACKNOWLEDGMENT 96
REFERENCES 96
Chapter 6 - Arthritis Gene Therapy: A Brief History and Perspective 102
6.1 INTRODUCTION 102
6.2 CONCEPTION AND STRATEGIES 102
6.3 TECHNOLOGY DEVELOPMENT 104
6.4 UNRESOLVED ISSUES 106
6.5 CLINICAL TRIALS 107
6.6 VETERINARY APPLICATIONS 110
6.7 OTHER APPLICATIONS OF INTRA-ARTICULAR GENE THERAPY 110
6.8 COMMERCIALIZATION 111
6.9 PERSPECTIVES 111
ACKNOWLEDGMENTS 112
REFERENCES 112
Chapter 7 - Type 1 Diabetes Mellitus: Immune Modulation as a Prerequisite for Successful Gene Therapy Strategies 116
7.1 INTRODUCTION 116
7.2 EFFECTIVE IMMUNE THERAPY/MODULATION: A PREREQUISITE FOR SUCCESSFUL GENE THERAPY OF TYPE 1 DIABETES 117
7.3 TARGETED ISLET ANTIGEN RECOGNITION AND ANTIGEN-BASED THERAPIES 118
7.4 BROAD IMMUNOSUPPRESSIVE THERAPIES 120
7.5 IMMUNOTHERAPIES THAT TARGET EVENTS IN T CELL RESPONSE 122
7.6 PROSPECTS FOR IMMUNOTHERAPY IN PROTECTING NEO-BETA CELLS 125
7.7 CONCLUSION 127
ACKNOWLEDGMENT 127
REFERENCES 127
Chapter 8 - Gene Therapy for Diabetes 132
LIST OF ABBREVIATIONS 132
8.1 INTRODUCTION 132
8.2 GENERATION OF . CELLS FROM PANCREATIC MATURE NON-. CELLS 133
8.3 GENERATION OF . CELLS FROM TISSUE PROGENITOR CELLS 135
8.4 GENERATION OF . CELLS FROM STEM CELLS 136
8.5 GENERATION OF NEW . CELLS BY INDUCING THEIR REPLICATION 139
8.6 CLOSING REMARKS 141
ACKNOWLEDGMENTS 142
REFERENCES 142
Chapter 9 - Gene Therapy for Neurological Diseases 146
9.1 INTRODUCTION 146
9.2 VIRAL VECTORS FOR NEUROLOGICAL DISEASES 147
9.3 GENE THERAPY FOR CHRONIC PAIN 150
9.4 GENE THERAPY FOR EPILEPSY 152
9.5 PARKINSON’S DISEASE 157
9.6 CONCLUSIONS 159
REFERENCES 159
Chapter 10 - Genetic and Cell-Mediated Therapies for Duchenne Muscular Dystrophy 164
10.2 GENE REPLACEMENT THERAPIES 167
10.3 STRATEGIES AIMED AT CORRECTING THE DEFECTIVE DYSTROPHIN GENE 173
10.4 CELL-BASED THERAPIES FOR DMD 179
10.5 ALTERNATIVE STRATEGIES TO RESTORATION OF DYSTROPHIN EXPRESSION INTO MUSCLE 181
10.6 CONCLUSION 183
ACKNOWLEDGMENTS 184
REFERENCES 184
Chapter 11 - Gene Therapy for Retinal Disease 190
11.1 INTRODUCTION TO THE RETINA AND INHERITED RETINAL DISEASES 191
11.2 CELL-SPECIFIC TARGETING WITHIN THE RETINA 193
11.3 PROMOTER CHOICE FOR EXPRESSION IN SPECIFIC RETINAL CELL TARGETS 195
11.4 AAV TREATMENT OF AUTOSOMAL RECESSIVE MODELS OF RETINAL DISEASE 196
11.5 AAV TREATMENT OF AUTOSOMAL DOMINANT MODELS OF RETINAL DISEASE 197
11.6 AAV DELIVERY OF LARGE GENES TO THE RETINA 198
11.7 NEUROPROTECTION OF THE RETINA USING AAV 199
11.8 HUMAN AAV CLINICAL TRIALS FOR THE TREATMENT OF IRD 200
11.9 SUMMARY 202
REFERENCES 202
Chapter 12 - Gene Therapy for Hemoglobinopathies: Progress and Challenges 208
12.1 WHY GENE THERAPY FOR HEMOGLOBINOPATHIES? 208
12.2 CHALLENGES TO HUMAN GENE THERAPY FOR HEMOGLOBINOPATHIES 209
12.3 PRECLINICAL STUDIES IN ANIMAL MODELS AND HUMAN CELLS 209
12.4 TARGETED REACTIVATION OF FETAL HEMOGLOBIN 212
12.5 CLINICAL TRIALS FOR THE HEMOGLOBINOPATHIES 212
12.6 GENOME TOXICITY 215
12.7 PHENOTYPIC VARIABILITY AND GENE TRANSFER IN PATIENTS AFFECTED BY HEMOGLOBINOPATHIES 215
12.8 FUTURE PERSPECTIVES 217
12.9 CONCLUSION 219
ACKNOWLEDGMENT 219
REFERENCES 219
Chapter 13 - Hemophilia Gene Therapy 224
13.1 INTRODUCTION 224
13.2 HEMOPHILIA B GENE TRANSFER 224
13.3 AAV AND HEMOPHILIA A 227
13.4 RAAV DOSE AND THE IMMUNE RESPONSE 228
13.5 AAV-MEDIATED TRANSFER LASTS A LONG TIME 229
13.6 SUMMARY 229
REFERENCES 229
Chapter 14 - Gene Transfer for Clinical Congestive Heart Failure 232
14.1 INTRODUCTION 232
14.2 GENERAL CONSIDERATIONS FOR CARDIAC GENE TRANSFER 233
14.3 CANDIDATES FOR CHF GENE TRANSFER 233
14.4 VECTORS AND METHODS FOR CARDIAC GENE TRANSFER 236
14.5 GENE TRANSFER CLINICAL TRIALS FOR CHF 238
14.6 CONCLUSION 239
REFERENCES 239
Chapter 15 - Gene Therapy for the Prevention of Vein Graft Disease 244
15.1 INTRODUCTION TO VEIN GRAFT DISEASE 245
15.2 PATHOPHYSIOLOGY OF VEIN GRAFT DISEASE 246
15.3 GENE DELIVERY STRATEGIES 248
15.4 ANIMAL MODELS OF VEIN GRAFT DISEASE 251
15.5 GENE TARGETS AND PRECLINICAL STUDIES 251
15.6 THE PREVENT TRIALS 257
15.7 ADDITIONAL CONSIDERATIONS FOR TRANSLATION 258
15.8 CONCLUSIONS 259
REFERENCES 260
Chapter 16 - Gene Therapy in Cystic Fibrosis 264
16.1 A BRIEF HISTORY OF CYSTIC FIBROSIS GENETICS 264
16.2 CFTR MUTATIONS 265
16.3 CF GENE THERAPY CHALLENGES 265
16.4 CF GENE THERAPY IN CLINICAL TRIALS 268
16.5 MUTANT PROTEIN REPAIR 272
16.6 CONCLUSION 274
REFERENCES 274
Chapter 17 - Genetic Engineering of Oncolytic Viruses for Cancer Therapy 278
17.1 INTRODUCTION 278
17.2 CONDITIONALLY REPLICATING ADENOVIRUSES (CRADS) 278
17.3 HERPES SIMPLEX VIRUS (HSV) 283
17.4 VACCINIA VIRUS (VV) 285
17.5 REOVIRUS TYPE 3 DEARING (RT3D OR REOLYSIN®) 287
17.6 VACCINE STRAINS OF MEASLES VIRUS (VMV) 288
17.7 VESICULAR STOMATITIS VIRUS (VSV) 290
17.8 CHALLENGES TO ONCOLYTIC VIROTHERAPY 290
17.9 CONCLUSIONS AND FUTURE DIRECTIONS 291
ACKNOWLEDGMENTS 292
REFERENCES 292
Chapter 18 - T Cell-Based Gene Therapy of Cancer 298
18.1 INTRODUCTION: T CELL-BASED IMMUNOTHERAPY 298
18.2 EX VIVO T CELL EXPANSION 299
18.3 MODIFICATION STRATEGIES FOR T CELL REDIRECTION 300
18.4 APPROACHES TO ENHANCE T CELL ACTIVITY 306
18.5 MITIGATION OF ADVERSE EVENTS AND SAFETY CONSIDERATIONS 308
18.6 TRANSLATION OF ENGINEERED T CELL THERAPY TO THE CLINIC 310
18.7 CONCLUSIONS AND FUTURE DIRECTIONS 313
DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST 314
REFERENCES 314
Chapter 19 - Current Status of Gene Therapy for Brain Tumors* 322
19.1 INTRODUCTION 323
19.2 GENE DELIVERY VEHICLES FOR BRAIN TUMORS 323
19.3 GENE THERAPY STRATEGIES FOR BRAIN TUMORS 329
19.4 STATUS OF CLINICAL TRIALS FOR GBM 335
19.5 CURRENT CHALLENGES AND FUTURE DIRECTIONS 336
REFERENCES 337
Index 342

Preface

In the summer of 1968 two staff scientists at Oak Ridge National Laboratory, Stanfield Rogers and Peter Pfuderer, suggested in a letter to Nature that “viral RNA or DNA information” could be used in the control of genetic deficiency diseases as well as nonheritable disorders such as cancer.1 Their proposition was based, like many scientific breakthroughs, on an experiment of nature: the observation that circulating arginine levels are elevated in humans following infection with Shope papilloma virus, which was thought to induce a virus-specific arginase. Theirs was a prescient thought, borne on the eve of the birth of recombinant DNA technology. But it took some four decades to begin realizing its promise.

The first approved use of gene therapy occurred in 1991 under the direction of W. French Anderson. Ashanti DeSilva was a four year old girl with the enzyme-based immune deficiency disorder ADA-SCID. Retrovirus-mediated transfer of an adenosine deaminase gene into her autologous T cells led to a clinical response, albeit incomplete and temporary.2 This was followed by a “loss of innocence” attendant on the treatment, in 1999, of Jesse Gelsinger, an 18 year old man with ornithine transcarbamylase deficiency.3 He died as a consequence of an adenovirus vector-associated inflammatory process. Shortly there after five infants with SCID-X1 developed acute leukemia after receiving a murine retrovirus-based gene therapy to replace a defective interleukin 2 receptor H chain.3 But then only one of those five patients died from their leukemia. And with a final enrollment of 20 SCID-X1 infants, and correction of severe immune deficiency in 17 of them over a median follow up of 9 years, gene therapy was finally established as a realistic therapeutic for those without alternatives.4

Since that time over 1800 gene therapy trials in 31 countries have been initiated or completed.4 And the field’s promise is not restricted to “simple” replacement or excision of a defective gene. For example, genetic engineering techniques have been used to inculcate tumor recognition or virus resistance in autologous lymphocytes of patients with metastatic cancer5 and advanced AIDS.6 Although there are currently no U.S. FDA licensed gene therapy products, in 2012 Glybera (alipogene tiparvovec) became the first example of this technology to be approved for clinical use, in Europe, after its endorsement by the European Medicines Agency.7 Based on an adeno-associated virus type 2 (AAV2) vector, Glybera corrected a defect in the lipoprotein lipase gene that otherwise leads to severe pancreatitis. Like most new technologies Glybera is expensive—about $1.6 million per patient—partially related to the ultra-orphan nature of the target disorder. (There are only a few hundred cases annually in the resource rich world.7,8) But its clinical success, as well as preliminary data from phase 1/2 and phase 3 clinical trials for more common conditions, as outlined in our text, has led to an explosion in commercial interest; between 2013 and early 2014 US companies have invested some $600 million in gene therapy research.9

The text you are about to explore is an introduction for the translational and basic researcher as well as the clinician to the vast field of gene therapy technology. It is the first book in a new series, Advances in Translational Medicine. The project is a direct outgrowth of our editing of an illustrious journal, Translational Research, The Journal of Laboratory and Clinical Medicine. It is coincident with the journal’s celebration of a legacy of 100 years in the promotion of excellence in clinical and translational research. This first volume is also a perfect opportunity to congratulate the Central Society for Clinical and Translational Research (CSCTR), a key partner with the journal. Albeit technically only in its 87th year, CSCTR traces its heritage to the Central Interurban Clinical Club, the establishment of which, in 1919, places it not far off the 100-year mark. Its fundamental goals, shared by our journal and this series, are critical and constant. Above all, champion the young investigator, bring in new ideas, establish diverse collaborations, and limit inbreeding. The special topics issues published annually in Translational Research are highly quoted. They achieved sufficient notice that the book division of Elsevier, publisher of our journal, began this series based upon expanded versions of our special issues and invited reviews.

Early on, the national importance of our society was well recognized. It also had an unanticipated impact on gene therapy related issues. The policies of genetic modification in clinical trials are regulated by the Declaration of Helsinki. And in 1966, only four societies were requested to endorse this declaration relating to “ethical principles for medical research involving human subjects”; the American Medical Association, the American Society for Clinical Investigation, and the American Federation for Clinical Research joined us. This declaration, along with the 2001 HUGO (Human Genome Organization) consensus, covers the types of somatic gene therapies discussed in our text. Germline gene approaches by which gametes (sperm or ova) are modified, permitting a therapeutic manipulation to be passed on to future generations, are proscribed for ethical reasons in many countries, and are not covered here.

The authors of the following chapters are leaders in the field of gene therapy. They cover a range of topics and technologies with a depth and clarity to be commended, providing helpful illustrations and comprehensive citations to the literature. Several chapters focus on specific diseases, while others cover new technologies or barriers to progress. It strives to cover, in depth, disease-specific areas of particular promise. Its initial focus is on mechanisms of introducing a gene, generally via a viral vector, that either: (1) causes a protein to be expressed in a patient with a defective protein product, or two little of the normal one; or (2) introduces editing genes, “molecular scissors” that excise or disrupt genes causing a disease. As the field has evolved to encompass non-DNA-based technologies, utilizing antisense oligonucleotides, small interfering RNAs, etc. that do not alter a gene, but directly interact with RNAs or proteins, are also presented here.

These chapters also provide roadmaps to the ontogeny of current gene therapy trials and methods by which a group might design their own. I have borrowed a recently published patient-centered approach to designing a gene therapy for epilepsy10 as an example of how the introductory chapters of this text set the stage for strategies to tackle your own areas of therapeutic interest.

1. Choose an animal model that accurately reflects the clinical problem in which to conduct preclinical studies.

2. Decide on a therapeutic approach. This is simpler when a single-gene defect is involved, limiting a functional protein product correctable by a relatively small increase in that product, as in hemophilia B. In a complex phenomenon such as epilepsy, one needs to decide if the target might best be decreasing neuronal excitation or increasing neuronal inhibitory pathways. Targeting of an entire cohort of genes could be contemplated.10

3. Choose a safe, effective vector. At the moment this usually means AAV, in which case limited payload size is a major impediment, or a lentivirus. But retrovirus, adenovirus, herpes simplex virus, plasmid, and other transport systems are also in various stages of clinical testing, and are outlined herein.

4. Consider all potential obstacles and explore them. Our text considers issues of payload toxicity, vector targeting, sufficiency of gene product expression, and the limits of in vitro and animal models. It also touches upon potential regulatory issues and good manufacturing-practice costs, but related details are left to other sources. For example, the American Society of Gene & Cell Therapy offers Web sites with information on issues related to the conduct of clinical gene therapy trials and the regulatory issues they raise.

This book provides coverage of the full spectrum of scientific and clinical progress, emphasizing new approaches in the field that currently have the greatest therapeutic application or potential and those areas most in need of future research. Serving both as an introduction to the field of gene therapy and as a general reference, it should prove an invaluable resource for both the expert and new investigator entering the field, as well as the clinician considering enrolling patients in clinical trials.

Jeffrey Laurence, M.D., August 2014

References

1. Rogers S, Pfuderer P. Use of viruses as carriers of added genetic information. Nature. 1968;219:749–751.

2. Blaese R.M, Culver K.W, Miller A.D, et al. T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science. 1995;270:475–480.

3. Sheridan C. Gene therapy finds its niche. Nat Biotech. 2011;29:121–128.

4. Ginn S.L, Alexander I.E, Edelstein M.L, Abedi M.R, Wixon J. Gene therapy clinical trials worldwide to 2012—an update. J Gene Med. 2013;15:65–77.

5. Robbins P.F, Morgan R.A, Feldman S.A, et al. Tumor regression...

Erscheint lt. Verlag	14.11.2014
Sprache	englisch
Themenwelt	Informatik ► Weitere Themen ► Bioinformatik
	Medizin / Pharmazie ► Medizinische Fachgebiete ► Onkologie
	Studium ► 2. Studienabschnitt (Klinik) ► Humangenetik
	Naturwissenschaften ► Biologie ► Genetik / Molekularbiologie
ISBN-10	0-12-800564-5 / 0128005645
ISBN-13	978-0-12-800564-4 / 9780128005644

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