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Guide to Human Gene Therapy
출판사 : World Scientific
저 자 : Sergei
ISBN : 9789814280907
발행일 : 2010-6
도서종류 : 외국도서
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   Guide to Human Gene Therapy 목차
1. Non-Viral Gene Therapy 1
Sean M. Sullivan
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 1
2. Plasmid DNA . . . . . . . . . . . . . . . . . . . . . . . 3
2.1 Plasmid DNA Manufacture . . . . . . . . . . . . . 5
3. Plasmid DNA Gene Transfer Methods . . . . . . . . . . 6
3.1 Plasmid DNA or “Naked DNA” as a Gene Delivery
System . . . . . . . . . . . . . . . . . . . . . . . 6
3.1.1 Electroporation of Naked DNA . . . . . . . 8
3.1.2 Sonoporation of Naked DNA . . . . . . . . 9
3.2 Plasmid DNA Formulations . . . . . . . . . . . . 9
3.2.1 Cationic Lipids . . . . . . . . . . . . . . . 9
3.2.1.1 In vitro transfection . . . . . . . . 10
3.2.1.2 Systemic in vivo gene transfer . . . 11
3.2.1.3 Local administration of cationic
lipid/pDNA transfection
complexes . . . . . . . . . . . . . 12
3.3 Polymer . . . . . . . . . . . . . . . . . . . . . . . 14
3.3.1 Cationic Polymers . . . . . . . . . . . . . . 14
3.3.2 Neutral Polymer . . . . . . . . . . . . . . . 15
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . 17
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

2. Adenoviral Vectors 21
Stuart A. Nicklin and Andrew H. Baker
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 21
2. Adenoviral Capsid Structure . . . . . . . . . . . . . . . 22
3. Adenoviral Cell Entry . . . . . . . . . . . . . . . . . . . 23
4. Production of Adenoviral Vectors . . . . . . . . . . . . . 24
5. Production of Targeted Adenoviral Vectors . . . . . . . . 26
6. Gene Therapy Applications . . . . . . . . . . . . . . . . 28
7. Immune Responses to Ad Vectors . . . . . . . . . . . . 30
8. Safety and Regulatory Issues . . . . . . . . . . . . . . . 32
9. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . 33
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 33

3. Retroviral Vectors and Integration Analysis 37
Cynthia C. Bartholomae, Romy Kirsten, Hanno Glimm,
Manfred Schmidt and Christof von Kalle
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 37
2. Design, Production and Mechanism of Transduction . . . 38
3. In vivo Application . . . . . . . . . . . . . . . . . . . . 41
4. Side Effects in Retroviral Gene Therapy . . . . . . . . . 42
4.1 Distribution of Retroviral Integration Sites
in the Cellular Genome . . . . . . . . . . . . . . . 42
4.2 Side Effects in Clinical and Preclinical Gene
Therapy Studies . . . . . . . . . . . . . . . . . . . 45
5. New Strategies for Vector Biosafety in Gene Therapy . . 47
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
4. Lentiviral Vectors 53
Janka Matrai, Marinee K. L. Chuah
and Thierry VandenDriessche
1. Basic Viral Biology . . . . . . . . . . . . . . . . . . . . 53
2. Vector Design and Production . . . . . . . . . . . . . . 56
2.1 Vector Development . . . . . . . . . . . . . . . . 56
2.2 Vector Production . . . . . . . . . . . . . . . . . . 58
3. Gene Transfer Concepts and Potential Applications . . . 59
3.1 Target Cells and Diseases . . . . . . . . . . . . . . 59
3.2 Pseudotyping . . . . . . . . . . . . . . . . . . . . 59
3.3 Cell Type Specific Targeting . . . . . . . . . . . . 60
3.4 Integration-Defective Lentiviral Vectors . . . . . . 60
4. Immune Consequences . . . . . . . . . . . . . . . . . . 62
5. Safety Issues . . . . . . . . . . . . . . . . . . . . . . . 63
6. Conclusions and Perspectives . . . . . . . . . . . . . . . 64
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 64

5. Herpes Simplex Virus Vectors 69
William F. Goins, David M. Krisky, James B. Wechuck,
Darren Wolfe, Justus B. Cohen and Joseph C. Glorioso
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 69
2. HSVBiology in the Design of Replication DefectiveVectors 74
3. HSV Vector Design Technology . . . . . . . . . . . . . 77
4. Gene Transfer/Therapy Applications . . . . . . . . . . . 79
5. Immunology . . . . . . . . . . . . . . . . . . . . . . . 80
6. Safety and Regulatory Issues . . . . . . . . . . . . . . . 81
7. Summary . . . . . . . . . . . . . . . . . . . . . . . . . 81
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 82

6. Adeno-Associated Viral (AAV) Vectors 87
Nicholas Muzyczka
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 87
2. Biology of AAV . . . . . . . . . . . . . . . . . . . . . . 88
3. Vector Technology . . . . . . . . . . . . . . . . . . . . 93
4. Vector Characteristics In Vivo . . . . . . . . . . . . . . . 96
5. Next Generation Vectors . . . . . . . . . . . . . . . . . 98
6. Conclusions and Outlook . . . . . . . . . . . . . . . . . 99
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 99

7. Regulatory RNA in Gene Therapy 103
Alfred. S. Lewin
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 103
2. Delivery of Therapeutic RNAs . . . . . . . . . . . . . . 106
3. Ribozymes . . . . . . . . . . . . . . . . . . . . . . . . 109
4. RNAi for Gene Therapy . . . . . . . . . . . . . . . . . 111
5. Gene Therapy Using miRNA . . . . . . . . . . . . . . . 114
6. Aptamers, Decoys and Bi-Functional RNAs . . . . . . . 115
7. Modification of Cis-Acting Regulatory
RNA Sequences . . . . . . . . . . . . . . . . . . . . . . 116
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . 119
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 120

8. DNA Integrating Vectors (Transposon, Integrase) 123
Lauren E. Woodard and Michele P. Calos
1. Basic Vector Biology . . . . . . . . . . . . . . . . . . . 123
1.1 Transposon Systems . . . . . . . . . . . . . . . . 124
1.2 Integrase Systems . . . . . . . . . . . . . . . . . . 126
2. Vector Design and Production . . . . . . . . . . . . . . 128
2.1 Design of Transposon Systems . . . . . . . . . . . 128
2.2 Design of Integrase Systems . . . . . . . . . . . . 128
2.3 Production of Plasmid DNA . . . . . . . . . . . . 129
3. Gene Transfer Protocols and Potential Applications . . . 130
3.1 Hepatocyte Transfection via Hydrodynamic
Injection . . . . . . . . . . . . . . . . . . . . . . . 130
3.2 Lipophilic Complexes to Transfect Endothelial
Cells and Glioblastoma . . . . . . . . . . . . . . . 131
3.3 Direct DNA Injection and Electroporation
to Target Muscle, Retina, and Joints . . . . . . . . 131
3.4 Integration into Cultured Cells for
Ex vivo Gene Therapy . . . . . . . . . . . . . . . 131
4. Immunology . . . . . . . . . . . . . . . . . . . . . . . 132
5. Safety and Regulatory Issues . . . . . . . . . . . . . . . 133
5.1 Integration Profiles and Associated Hazards . . . . 133
5.2 Efforts to Enhance Integration Specificity . . . . . 133
5.3 Effects on Tumor Latency in Mouse Models
of Cancer . . . . . . . . . . . . . . . . . . . . . . 134
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 135

9. Homologous Recombination and Targeted Gene
Modification for Gene Therapy 139
Matthew Porteus
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 139
2. Problems with Using Gene Targeting by Homologous
Recombination . . . . . . . . . . . . . . . . . . . . . . 140
3. Homologous Recombination in Embryonic
Stem Cells . . . . . . . . . . . . . . . . . . . . . . . . . 141
4. Homologous Recombination using
Adeno-Associated Virus . . . . . . . . . . . . . . . . . 144
5. Site-Specific Modification of the Genome using
Double-Strand Breaks . . . . . . . . . . . . . . . . . . 144
6. Double-Strand Break Repair . . . . . . . . . . . . . . . 144
7. Double-Strand Break Induced Homologous
Recombination . . . . . . . . . . . . . . . . . . . . . . 146
8. Re-design of Homing Endonucleases to Recognize
New Target Sites . . . . . . . . . . . . . . . . . . . . . 146
9. Development of Zinc Finger Nucleases . . . . . . . . . 147
10. Using Zinc Finger Nucleases to Stimulate
Gene Targeting . . . . . . . . . . . . . . . . . . . . . . 147
11. Using Zinc Finger Nucleases to Site-Specifically Modify
Genes by Mutagenic Non-Homologous
End-Joining . . . . . . . . . . . . . . . . . . . . . . . . 149
12. Strategies of Zinc Finger Nuclease Design . . . . . . . . 151
13. Aspects of Zinc Finger Binding Sites and Structure
of Zinc Finger Nucleases . . . . . . . . . . . . . . . . . 153
14. Zinc Finger Nuclease Toxicity: Measuring
and Minimizing . . . . . . . . . . . . . . . . . . . . . . 154
15. The Challenge of Delivery . . . . . . . . . . . . . . . . 156
16. Future Directions and Promise of Homologous
Recombination as a Gene Correction Approach
to Gene Therapy . . . . . . . . . . . . . . . . . . . . . 157
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 157
10. Gene Switches for Pre-Clinical Studies in Gene Therapy 163
Caroline Le Guiner, Knut Stieger, Alice Toromanoff,
Fabienne Rolling, Philippe Moullier and Oumeya Adjali
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 163
2. Rapamycin-Dependent Regulatable System . . . . . . . 165
2.1 Molecular Mechanisms Involved in Transgene
Regulation . . . . . . . . . . . . . . . . . . . . . 165
2.2 Pharmacology of Rapamycin . . . . . . . . . . . . 166
2.3 Translation Development of the Rapamycin
Dependent Regulation System . . . . . . . . . . . 166
3. Tetracycline-Dependent Regulatable Systems . . . . . . 168
3.1 Molecular Mechanisms Involved in Transgene
Regulation . . . . . . . . . . . . . . . . . . . . . 168
3.2 Pharmacology of Doxycycline (Dox) . . . . . . . . 171
3.3 Translational Development of Tet-dependant
Regulation Systems . . . . . . . . . . . . . . . . . 171
4. Other Regulatable Systems . . . . . . . . . . . . . . . . 175
5. General Conclusions . . . . . . . . . . . . . . . . . . . 177
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 177

11. Gene Therapy for Central Nervous System Disorders 181
Deborah Young and Patricia A. Lawlor
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 181
2. Gene Therapy for Parkinson’s Disease . . . . . . . . . . 182
3. Gene Therapy for Temporal Lobe Epilepsy . . . . . . . 186
4. Huntington’s Disease Gene Therapy . . . . . . . . . . . 187
5. Amyotrophic Lateral Sclerosis (ALS) . . . . . . . . . . 189
6. Gene Therapy for Canavan Disease . . . . . . . . . . . . 190
7. Gene Therapy for Alzheimer’s Disease . . . . . . . . . . 191
8. Conclusions and Outlook . . . . . . . . . . . . . . . . . 193
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 194

12. Gene Therapy of Hemoglobinopathies 197
Angela E. Rivers and Arun Srivastava
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 198
2. β-Thalassemia . . . . . . . . . . . . . . . . . . . . . . 198
3. Sickle Cell Disease . . . . . . . . . . . . . . . . . . . . 199
4. Gene Therapy . . . . . . . . . . . . . . . . . . . . . . . 200
4.1 Oncoretroviral Vector-Mediated Globin
Gene Transfer . . . . . . . . . . . . . . . . . . . . 202
4.2 Lentiviral Vector-Mediated Globin
Gene Transfer . . . . . . . . . . . . . . . . . . . . 203
4.3 Adeno-Associated Viral Vector-Mediated Globin
Gene Transfer . . . . . . . . . . . . . . . . . . . . 204
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 208

13. Gene Therapy for Primary Immunodeficiencies 213
Aisha Sauer, Barbara Cassani and Alessandro Aiuti
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 214
2. Adenosine Deaminase (ADA)-deficient SCID . . . . . . 215
3. X-linked Severe Combined Immunodeficiency
(SCID-X1) . . . . . . . . . . . . . . . . . . . . . . . . 218
4. Gene Therapy for Other SCIDs . . . . . . . . . . . . . . 220
4.1 V(D)J Recombination Defects . . . . . . . . . . . 220
4.2 Purine Nucleoside Phosphorylase (PNP)
Deficiency . . . . . . . . . . . . . . . . . . . . . . 222
4.3 Janus Kinase 3 (Jak3) Deficiency . . . . . . . . . . 222
4.4 IL-7R Deficiency . . . . . . . . . . . . . . . . . . 223
4.5 Zeta Associated 70 kDa Phosphoprotein
(ZAP-70) Deficiency . . . . . . . . . . . . . . . . 223
5. Wiskott-Aldrich-Syndrome (WAS) . . . . . . . . . . . . 224
6. Chronic Granulomatous Disease . . . . . . . . . . . . . 225
7. Conclusions and Outlook . . . . . . . . . . . . . . . . . 227
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 228

14. Gene Therapy for Hemophilia 233
David Markusic, Babak Moghimi and Roland Herzog
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 233
2. Limitations of Hemophilia TreatmentWith
Coagulation Factor Concentrates or Recombinant
Coagulation Factors . . . . . . . . . . . . . . . . . . . . 235
3. Gene Transfer for Correction of Hemophilia . . . . . . . 236
3.1 Ex Vivo Gene Transfer of F.VIII and F.IX . . . . . 236
3.2 In Vivo Gene Transfer of F.VIII and F.IX . . . . . . 237
4. AAV is a Preferred Gene Therapy Vector for In Vivo
Gene Transfer to Correct of Hemophilia . . . . . . . . . 238
5. Immunological Considerations for Efficient F.IX
Gene Transfer . . . . . . . . . . . . . . . . . . . . . . . 239
6. Advancements from Small and Large Animal Models
of Hemophilia . . . . . . . . . . . . . . . . . . . . . . . 242
6.1 Murine Hemophilia Models . . . . . . . . . . . . 242
6.2 Canine Hemophilia Models . . . . . . . . . . . . . 242
7. Gene Therapy Trials for Hemophilia Past, Present, and
Future . . . . . . . . . . . . . . . . . . . . . . . . . . . 244
8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . 245
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 246

15. Gene Therapy for Obesity and Diabetes 251
Sergei Zolotukhin and Clive H. Wasserfall
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 251
2. Understanding Obesity: WhyWe Get Fat . . . . . . . . 252
2.1 Genetic Factors: Human Obesity Gene Map . . . . 252
2.2 Environmental Factors: The Big Two and Other
Causal Contributors . . . . . . . . . . . . . . . . . 253
3. General Strategies in Gene Therapy for Obesity . . . . . 253
4. Gene Delivery Vehicles . . . . . . . . . . . . . . . . . . 255
5. Gene Targets for Obesity . . . . . . . . . . . . . . . . . 255
5.1 Leptin . . . . . . . . . . . . . . . . . . . . . . . . 255
5.2 Neurocytokines . . . . . . . . . . . . . . . . . . . 256
5.3 AMP-Activated Protein Kinase (AMPK) . . . . . . 256
5.4 Adiponectin . . . . . . . . . . . . . . . . . . . . . 257
5.5 Wnt-10b . . . . . . . . . . . . . . . . . . . . . . . 257
5.6 Obesity Gene Menu a la Carte . . . . . . . . . . . 258
5.7 Obesity and Diabetes . . . . . . . . . . . . . . . . 259
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 260

16. Gene Therapy for Duchenne Muscular
Dystrophy 261
Takashi Okada and Shin’ichi Takeda
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 261
1.1 Background of Duchenne Muscular Dystrophy . . 261
2. Gene-replacement Strategies using Virus Vectors . . . . 262
2.1 Choice of Vector . . . . . . . . . . . . . . . . . . 262
2.2 Modification of the Dystrophin Gene
and Promoter . . . . . . . . . . . . . . . . . . . . 264
2.3 Use of Surrogate Genes . . . . . . . . . . . . . . . 266
3. AAV-Mediated Transduction of Animal Models . . . . . 266
3.1 Vector Production . . . . . . . . . . . . . . . . . . 266
3.2 Animal Models for the Gene
Transduction Study . . . . . . . . . . . . . . . . . 267
3.3 Immunological Issues of rAAV . . . . . . . . . . . 268
3.4 Intravascular Vector Administration
by Limb Perfusion . . . . . . . . . . . . . . . . . 269
3.5 Global Muscle Therapies . . . . . . . . . . . . . . 269
4. Safety and Potential Impact of Clinical Trials . . . . . . 270
5. Development of Alternative Strategies . . . . . . . . . . 271
5.1 Design of Read-through Drugs . . . . . . . . . . . 271
5.2 Modification of mRNA Splicing . . . . . . . . . . 272
5.3 Ex Vivo Gene Therapy . . . . . . . . . . . . . . . 272
6. Future Perspectives . . . . . . . . . . . . . . . . . . . . 273
6.1 Pharmacological Intervention . . . . . . . . . . . . 273
6.2 Capsid Modification . . . . . . . . . . . . . . . . 273
7. Conclusions and Outlook . . . . . . . . . . . . . . . . . 273
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 274

17. Cancer Gene Therapy 279
Kirsten A.K. Weigel-Van Aken
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 280
2. Targeting the Tumor Cell . . . . . . . . . . . . . . . . . 280
2.1 DNA Electroporation . . . . . . . . . . . . . . . . 280
2.2 Non-Oncolytic Viral Vectors . . . . . . . . . . . . 281
2.2.1 Retrovirus . . . . . . . . . . . . . . . . . . 281
2.2.2 Lentivirus . . . . . . . . . . . . . . . . . . 282
2.3 Oncolytic Viruses . . . . . . . . . . . . . . . . . . 282
2.3.1 Herpesvirus . . . . . . . . . . . . . . . . . 283
2.3.2 Adenovirus . . . . . . . . . . . . . . . . . . 283
2.3.3 Poxvirus . . . . . . . . . . . . . . . . . . . 284
2.3.4 Measles virus . . . . . . . . . . . . . . . . 285
2.3.5 Vesicular stomatitis virus . . . . . . . . . . 285
3. Targeting the Immune System . . . . . . . . . . . . . . 286
3.1 Cancer Vaccines . . . . . . . . . . . . . . . . . . . 287
3.1.1 Vaccinia virus . . . . . . . . . . . . . . . . 287
3.1.2 Lentivirus . . . . . . . . . . . . . . . . . . 287
3.1.3 Adenovirus . . . . . . . . . . . . . . . . . . 288
3.1.4 Parvoviruses . . . . . . . . . . . . . . . . . 288
3.2 Mesenchymal Stem Cells (MSC)
as Delivery Vehicles . . . . . . . . . . . . . . . . 288
3.3 Adoptive T Cell Transfer . . . . . . . . . . . . . . 288
4. Targeting the Tumor Microenvironment . . . . . . . . . 289
5. Challenges and Risks of Cancer Gene Therapy . . . . . 289
6. Novel Strategies . . . . . . . . . . . . . . . . . . . . . . 290
6.1 Prime/Boost Regimens . . . . . . . . . . . . . . . 290
6.2 Immune Cells as Carriers for Viruses . . . . . . . . 290
7. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . 291
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 291

18. Gene Therapy for Autoimmune Disorders 295
Daniel F. Gaddy, Melanie A. Ruffner and Paul D. Robbins
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 295
2. Rheumatoid Arthritis . . . . . . . . . . . . . . . . . . . 296
2.1 Background . . . . . . . . . . . . . . . . . . . . . 296
2.2 Existing Therapies . . . . . . . . . . . . . . . . . 296
2.3 Target Tissues and Routes of Delivery . . . . . . . 297
2.3.1 Local RA Gene Therapy . . . . . . . . . . . 297
2.3.2 Systemic RA Gene Therapy . . . . . . . . . 297
2.4 Immunomodulation . . . . . . . . . . . . . . . . . 298
2.5 Overview of Preclinical Gene Therapy Studies . . 299
2.6 Overview of Clinical Gene Therapy Studies . . . . 301
3. Type I Diabetes Mellitus . . . . . . . . . . . . . . . . . 301
3.1 Background . . . . . . . . . . . . . . . . . . . . . 301
3.2 Existing Therapies . . . . . . . . . . . . . . . . . 302
3.3 Target Tissues and Routes of Delivery . . . . . . . 303
3.4 Immunomodulation . . . . . . . . . . . . . . . . . 303
3.5 Overview of Preclinical Gene Therapy Studies . . 305
3.6 Overview of Clinical Gene Therapy Studies . . . . 306
4. Conclusions and Outlook . . . . . . . . . . . . . . . . . 307
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 308

19. Gene Therapy for Inherited Metabolic Storage Diseases 311
Cathryn Mah
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 311
2. Lysosomal Storage Diseases . . . . . . . . . . . . . . . 312
3. Glycogen Storage Diseases . . . . . . . . . . . . . . . . 314
4. Animal Models . . . . . . . . . . . . . . . . . . . . . . 315
5. Cross-Correction Strategies . . . . . . . . . . . . . . . . 319
6. Direct Correction of Target Tissues . . . . . . . . . . . . 321
7. Conclusions and Outlook . . . . . . . . . . . . . . . . . 324
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 324

20. Retinal Diseases 327
Shannon E. Boye, Sanford L. Boye and William W. Hauswirth
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 327
2. Rod and Cone Photoreceptors . . . . . . . . . . . . . . 330
3. Cone Photoreceptors . . . . . . . . . . . . . . . . . . . 333
4. Retinal Ganglion Cells . . . . . . . . . . . . . . . . . . 335
5. Retinal Pigment Epithelium . . . . . . . . . . . . . . . 337
6. LCA2 Gene Therapy, a Perspective on Translational
Research . . . . . . . . . . . . . . . . . . . . . . . . . 339
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 342

21. A Brief Guide to Gene Therapy Treatments
for Pulmonary Diseases 345
Ashley T. Martino, Christian Mueller
and Terence R. Flotte
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 345
2. Common Disorders . . . . . . . . . . . . . . . . . . . . 346
2.1 Cystic Fibrosis . . . . . . . . . . . . . . . . . . . 346
2.2 Alpha-1 Antitrypsin (A1AT) . . . . . . . . . . . . 348
3. Development of Viral Vectors for Lung Disease . . . . . 348
3.1 Adenoviral Vectors . . . . . . . . . . . . . . . . . 349
3.2 Adeno-Associated Viral Vectors . . . . . . . . . . 349
3.3 Early Conclusions . . . . . . . . . . . . . . . . . 349
4. Enhancing Efficiency . . . . . . . . . . . . . . . . . . . 350
4.1 Alternative AAV Viral Vector Serotypes . . . . . . 350
4.1.1 Addition of Expression Enhancing
Elements . . . . . . . . . . . . . . . . . . . 351
4.2 Adenoviral Vectors . . . . . . . . . . . . . . . . . 351
4.3 Physiological Hurdles in the Lung
Environment . . . . . . . . . . . . . . . . . . . . 352
5. Non-Viral Vectors . . . . . . . . . . . . . . . . . . . . . 352
5.1 Cationic Liposomes . . . . . . . . . . . . . . . . . 352
5.2 Compacted DNA Nanoparticles . . . . . . . . . . 353
6. Gene Therapy Development for Alpha-1
Anti-trypsin . . . . . . . . . . . . . . . . . . . . . . . . 353
7. Lung Cancer Gene Therapy Development . . . . . . . . 354
8. Cystic Fibrosis Animal Models . . . . . . . . . . . . . . 355
9. Cell-Based Therapy for Cystic Fibrosis . . . . . . . . . 356
10. Conclusion and Outlooks . . . . . . . . . . . . . . . . . 357
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 358

22. Cardiovascular Disease 361
Darin J. Falk, Cathryn S. Mah and Barry J. Byrne
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . 361
2. Therapeutic Targets . . . . . . . . . . . . . . . . . . . . 362
2.1 Congenital Heart Disease . . . . . . . . . . . . . . 362
2.2 Coronary Artery Disease and Ischemia/
Reperfusion Injury . . . . . . . . . . . . . . . . . 365
2.3 Oxidative Stress . . . . . . . . . . . . . . . . . . . 365
2.4 Antioxidants . . . . . . . . . . . . . . . . . . . . 366
2.5 Cardiac Contractility . . . . . . . . . . . . . . . . 367
3. Animal Models . . . . . . . . . . . . . . . . . . . . . . 367
4. Vector Delivery . . . . . . . . . . . . . . . . . . . . . . 368
5. Conclusions and Outlook . . . . . . . . . . . . . . . . . 374
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . 374
References . . . . . . . . . . . . . . . . . . . . . . . . . . . 374

Index 379

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