Autologous And Cancer Stem Cell Gene Therapy (Progress in Gene Therapy) (Progress in Gene Therapy)

I. From pioneering clinical retroviral gene therapy to experimental site-specific integrative gene therapy......Page 8
Preface Roger Bertolotti & Keiya Ozawa......Page 6
List of Contributors......Page 12
Introduction Toward a Universal Platform for Autologous Stem Cell Gene Therapy Roger Bertolotti......Page 22
1. Therapeutic Homing as the Very Drive of Both Long-term and Transient-Regenerative Stem Cell Gene Therapy......Page 23
2.1. Autologous Stem/Progenitor Cells as Tissue-Homing Vectors forTargetedTransient Regenerative GeneTherapy......Page 25
2.2. Autologous and Immortalized Stem/Progenitor Cells as Tumor-homing Vectors forTargeted Cancer GeneTherapy......Page 26
2.3. Cancer Stem Cells as BreakthroughTargets for Stem Cell-mediated GeneTherapy and Other CancerTherapies......Page 27
3. Therapeutic Homing and Autologous Stem Cells as the Main Drive of Our Stem Cell Gene Therapy Platform......Page 28
4. Autologous Pluripotent Stem Cells: Toward a Universal Stem Cell Gene Therapy Platform......Page 30
4.1.1. Endonuclease-boosted gene targeting......Page 31
4.1.3. Genomic homeostasis and hazard-free custom site-specific integrative gene therapy......Page 33
4.3. Emerging Pluripotent Stem Cells as Potential Universal Drives for Tissue-Specific and Multisystemic GeneTherapy......Page 34
References......Page 35
1 Stem Cell Gene Therapy for ADA-Deficiency without Myelopreparative Conditioning Makoto Otsu and Tadashi Ariga......Page 44
1. Introduction......Page 45
2. Severe Combined Immunodeficiency due to ADA-deficiency......Page 46
3.3. Second Generation of Stem Cell Gene Therapy Trials for ADA-deficiency......Page 47
4. Stem Cell Gene Therapy for ADA-deficiency without Myelopreparative Conditioning......Page 48
5.2. Transduction Procedures......Page 51
5.4. Use of PEG-ADA......Page 52
6.1. Concept of Myelopreparation......Page 53
6.2. Conditioning in SCGT: comparison between ADA-SCID and X-SCID......Page 55
7. Future of SCGT for ADA-deficiency......Page 56
References......Page 57
2 Targeted Insertion of Transgene into a Specific Site on Chromosome 19 by Using Adeno-Associated Virus Integration Machinery Masashi Urabe, Yoko Obara, Takayuki Ito, Hiroaki Mizukami, Akihiro Kume and Keiya Ozawa......Page 62
1. Introduction......Page 63
2. Overview of AAV......Page 64
3. Mechanism of AAVS1-Targeted Integration of the AAV Genome......Page 67
4. AAVTarget Site: AAVS1 Locus (19q13.4)......Page 69
5. Multifunctional Rep Protein......Page 71
6. The Use of the AAV Integration Machinery to Achieve Site-Specific Integration......Page 73
7. How to Regulate Rep Expression......Page 77
8. Vehicles to Deliver the Rep Gene into Cells......Page 79
References......Page 80
3 Herpes Simplex Virus Type 1/Adeno-Associated Virus Hybrids as Site-Specific Integrating Vectors Cornel Fraefel, Daniel L. Glauser, Thomas Heister and Mathias Ackermann......Page 90
1. Introduction......Page 91
2.1. HSV-1:Virion, Genome, and Life Cycle......Page 92
2.3. HSV-1 Amplicon......Page 96
3.1. AAV:Virion, Genome, and Life Cycle......Page 100
3.2. Recombinant AAV Vectors......Page 102
4.1. Rationale and Design......Page 103
4.2. Biological Properties......Page 104
5. Molecular Mechanisms of AAV-Mediated Inhibition of HSV/AAV Hybrid Vector Production......Page 106
6. Perspectives and Considerations for the Design of Novel HSV/AAV Hybrid Amplicons......Page 109
References......Page 112
I. Cancer stem cells as breakthrough targets of cancer gene therapy......Page 9
4 Endonuclease-Boosted Gene Targeting and Cybridization for Long-Term Stem Cell Gene Therapy Roger Bertolotti......Page 124
1. Introduction: Pioneering Clinical Retroviral Gene Therapy is Hampered by Random-Integration Oncogenic Hazards......Page 125
2.1. From Conventional to Endonuclease-Boosted Gene Targeting......Page 127
2.2. Double-strand Break (DSB) inTarget Chromosomal DNA as a Dramatic Stimulator of Gene Targeting......Page 128
3.1. Genesis of Sequence-specific DSBs with Designed Zinc-finger Nucleases......Page 129
3.3. Zinc Finger Nuclease-boosted Gene Targeting: Pioneering Single-base Correction Achievement......Page 130
3.4. From Single-base Correction to Multi-base Modification......Page 131
4. Customized Homing Endonucleases: New Impulse to Endonuclease-Boosted Gene Targeting......Page 133
5.1. Chimeric Zinc-finger Nucleases: Polydactyl Assembly of the DNA-binding Domain as the Critical Point of ZFN Customization......Page 134
5.2. Emerging Customized Homing Endonucleases......Page 136
5.3. Engineered Group II Intron Ribonucleoproteins as Potential Site-specific Endonucleases or Site-specific Integrating Vectors......Page 137
5.4. Custom Site-specific Endonucleases as the Ultimate Personalized Tools......Page 138
6. Ex vivo and in vivo Stem Cell Gene Therapy: Transfection (Plasmid dsDNA) or Transduction (AAV ssDNA and HD-Ad dsDNA)......Page 139
7. Endonuclease-Boosted Stem Cell Gene Targeting: From Highly Personalized Single-Base Correction to Broad Selective Gene Therapy......Page 140
8.1. Mitochondrial Genome (mtDNA) Mutants: From Human Diseases to Transmitochondrial Mouse Models......Page 141
8.2. Homoplasmic Embryonic Stem (ES) Cybrids as BasicTools for the Production of Transmitochondrial Animals......Page 142
8.3.2. Therapeutic autologous cybrid stem cells......Page 143
8.4. Toward Transmitochondrial Stem Cell Gene Therapy for mtDNA diseases......Page 145
9. Endonuclease-Boosted Gene Targeting and Cybridization as the Long-Term Gene Therapy Arm of our Stem Cell Gene Therapy Platform......Page 146
References......Page 148
5 Cell-Free Protein-Evolution Systems for Engineering of Novel Sequence-Specific DNA-Binding and -Modifying Activities Armin Sepp, Farid Ghadessy and Yen Choo......Page 158
1.2. Designed Zinc Finger Proteins......Page 159
1.3.1. Phage display......Page 160
1.3.2. In vitro mRNA-based libraries: ribosome- and RNA-displays......Page 161
2. In Vitro Compartmentalization......Page 162
3. Selection of Zinc Finger Proteins and Zinc Finger Fusion Proteins by IVC......Page 165
4. Selection of DNA-Modifying Enzymes......Page 167
5. New Developments and Perspectives......Page 170
6. Conclusion......Page 171
References......Page 172
6 Advances in Engineering Homing Endonucleases for Gene Targeting: Ten Years After Structures Barry L. Stoddard, Andrew M. Scharenberg and Raymond J. Monnat, Jr......Page 178
1.1. Monogenic Disorders:A Case for Targeted Gene Repair......Page 179
1.2. Genome Engineering: A Targeted Approach......Page 180
2. Double Strand Break-Induced Gene Conversion and Gene-Specific Nucleases......Page 182
3. LAGLIDADG Homing Endonuclease Proteins are Well-Suited for Protein Engineering and Genomic Targeting Applications......Page 187
3.1. The Structure, Specificity and Catalytic Activity of LAGLIDADG Endonucleases......Page 189
3.2. Engineering and Selection of LAGLIDADG Homing Endonucleases with Altered Structures and Specificities......Page 192
3.3. Redesign of Homing Endonuclease Domain Architecture and Oligomery......Page 194
3.4. Redesign of Homing Endonuclease DNA Contacts and Specificity......Page 196
3.4.1. Redesign of specificity at individual DNA base pairs......Page 199
3.4.2. High-throughput screening and targeting of genomic loci......Page 200
4. Concluding Remarks......Page 202
References......Page 204
1. Introduction......Page 212
2.1. Chromosomal Integration of E1-deleted AdVs......Page 213
2.2. Gene Targeting with Replication-competent or E1-deleted AdVs......Page 215
3.1. Development of Helper-dependent Adenoviral Vector System......Page 216
3.2. Attempts for Gene Targeting in Human Glioblastoma Cells......Page 217
3.3. Gene Targeting with HDAdVs in Mouse ES Cells......Page 218
3.4. Targeted Integration Mediated by Chromatin Tethering......Page 220
3.5. Integration Sites of HDAdVs......Page 221
4. Toward Endonuclease-boosted HDAdV Gene Targeting......Page 222
5.1.1. HDAdV transduction or conventional gene targeting......Page 223
5.2.1. From ex vivo to in vivo gene targeting......Page 224
5.2.2. Promises of endonuclease-boosted HDAdVs......Page 225
References......Page 226
1. Introduction......Page 230
2. Methods Used for Genetic Modification......Page 231
3. Hematopoietic Stem Cells in Gene Therapy Approaches......Page 233
4. Adult Stem Cells with Greater Potency......Page 235
5. What are Multipotent Adult Progenitor Cells......Page 236
6. Are Adult Stem Cells with Greater Potential Good Candidates for Cellular Gene Therapy?......Page 238
References......Page 240
9 Leukemia Stem Cells, A Pioneering Paradigmatic Model Daniel J. Pearce and Dominique Bonnet......Page 246
2. Normal Hematopoietic Stem Cell......Page 247
2.1. Characterization of the Hematopoietic Stem Cell......Page 249
2.2. Identification/Isolation of Hematopoietic Stem Cells......Page 252
3.1. Concept of the Leukemia-Initiating Cell......Page 256
3.3. Identification/Isolation of the Leukemia-Initiating Cell......Page 257
4.1. The Hematopoietic Stem Cell Niche......Page 258
4.2.1. Cell cycle regulators......Page 260
4.2.2. Polycomb genes......Page 262
4.2.3. Other master regulators of HSC self-renewal......Page 263
4.3.1. SCL/TAL......Page 264
4.3.2. Homeobox genes: Hox B3, B4 and A9......Page 265
4.3.3. Mesodermal inducing factors in the regulation of HSC fate......Page 266
4.4. Differentiation Control......Page 267
4.5. Epigenetic Factors......Page 270
4.5.1. Methylation and histone modifications......Page 271
4.5.2. Micro-RNAs and hematopoietic regulation......Page 272
5. Dysregulation of Key Processes inAML......Page 273
6. The cell of Origin in Leukemia......Page 276
7. The Heterogeneity of Leukemia-Initiating Cells......Page 281
8. Cytokines and AML......Page 282
9. Competition Between Normal and Leukemia Cells......Page 283
10. Conclusive Remarks......Page 284
References......Page 286
10 Mammary Stem Cells Mark Shackleton, Marie-Liesse Asselin-Labat, François Vaillant, Geoffrey J. Lindeman and Jane E. Visvader......Page 304
2.1. Mammary Gland Structure and Function......Page 305
2.2. Mammary Development in the Mouse......Page 306
3. Mammary Epithelial Cell Lineages......Page 308
4. Evidence for the Existence of Mammary Stem Cells......Page 310
5. Identification of Mouse Mammary Stem Cells......Page 312
6. Multi-Lineage Differentiation and Self-Renewal of Mammary Stem Cells......Page 314
7.1. Cell Markers Enabling Enrichment of Mammary Stem Cells......Page 316
7.2. Expression of Hormone Receptors in Mammary Stem Cells......Page 318
7.3. Expression of Lineage-Associated Markers in Mammary Stem Cells......Page 319
8. Identification of Progenitor Populations in Mammary Epithelium......Page 320
9. The Mammary Stem Cell Niche......Page 321
10. Molecular Regulation of Mammary Stem Cells......Page 323
11. Mammary Stem Cells and Breast Cancer......Page 324
11.2. The Origins of Breast Cancer......Page 325
11.3. Breast Cancer Stem Cells......Page 328
12. Conclusions......Page 329
References......Page 331
11 Human Brain Tumor Stem Cells Sara G. M. Piccirillo and Angelo L. Vescovi......Page 342
2. Stem Cells and Malignant Transformation......Page 343
3. Cancer Stem Cells and Brain Tumors......Page 344
4.1. Neurosphere Assay......Page 345
4.2. Discriminating True Cancer Stem Cells From Short-term Proliferating Progenitors......Page 347
4.3. Identification of Brain Tumor Stem Cells: Multipotency and Tumor-initiating Ability of Neurosphere-forming Cells......Page 348
4.5. Establishment of Cancer Stem Cell Lines and Pitfalls of the Neurosphere Assay......Page 349
5.1. Differentiation Inhibits the Tumour-initiating Ability of the Cancer Stem Cell Population......Page 350
5.2. Differentiation as an Alternate to Drug-Targeting/Sensitization of CSCs......Page 352
6. Conclusions......Page 355
References......Page 357
1. Introduction......Page 360
2. The CD44 Family......Page 361
4.1. Leukemic Stem Cells......Page 362
4.2. Breast Cancer Stem Cells......Page 364
4.3. Prostate Cancer Stem Cells......Page 365
4.4. Pancreatic and Head/Neck Cancer Stem Cells......Page 369
5. CD44-expressing CSCs asTherapeutic Targets......Page 370
References......Page 372
II. Armed stem cells as tumor-homing vectors for cancer gene therapy......Page 10
13 Neural Stem Cell-mediated Therapy of Primary and Metastatic Solid Tumors Joseph Najbauer, Mary K. Danks, Nils-Ole Schmidt, Seung U. Kim and Karen S. Aboody......Page 378
1.1. The Challenges of Effective CancerTreatment......Page 379
1.2. Stem Cell-mediated Gene Therapy: A Tumor-selective Therapeutic Approach......Page 380
1.3.1. Advantages of clonal NSC Lines......Page 382
1.3.2. Disadvantages of primary (non-immortalized/clonal) NSC pools......Page 386
1.3.4. HB1.F3 NSCs as potential off-the-shelf human tumor-homing cell line......Page 387
3. Generation of Immortalized Human HB1.F3 Neural Stem Cells......Page 388
4. Introduction of Therapeutic Genes into Neural Stem Cells......Page 389
4.1. Cytosine Deaminase......Page 390
4.2. Carboxylesterase......Page 391
4.3.2. TRAIL......Page 393
4.3.3. PEX......Page 394
5.1. HB1.F3 NSCs Migrate to Tumor-conditioned Medium......Page 395
5.2. Neural Stem CellsTransduced with Therapeutic or Reporter Genes Retain Their Tumor-tropic Properties......Page 396
6.1.1. Glioma......Page 397
6.1.3. Solid tumor metastases to brain: melanoma......Page 401
6.2. Disseminated Solid Tumor Models: Neuroblastoma......Page 403
6.2.3. Neural stem/progenitor cell-directed enzyme pro-drug therapy (NDEPT)......Page 404
7. Factors Involved in NSC Tumor Tropism......Page 406
8. NSC-mediated Therapeutic Applications to Invasive and MetastaticTumors: Future Directions......Page 408
References......Page 409
14 Antitumor Activity of Adenovirally Transduced CD34+ Cells Expressing Membrane-bound TRAIL Carmelo Carlo-Stella, Cristiana Lavazza, Antonino Carbone and Alessandro M. Gianni......Page 416
1. Introduction......Page 417
2.1. TRAIL-induced Apoptosis Signaling......Page 418
2.2. TRAIL Resistance......Page 419
2.3. Pharmacological Approaches for Targeting TRAIL Agonistic Receptors......Page 420
2.4. Gene Therapy Approaches for Targeting TRAIL Agonistic Receptors......Page 421
3.1. Ad-TRAIL Transduction of CD34+ Cells......Page 422
3.2. In Vitro Antitumor Activity of CD34-TRAIL+ Cells......Page 423
3.4. In Vivo Toxicity of CD34-TRAIL+ Cells......Page 425
3.5. Mechanism(s) of Action of CD34-TRAIL+ Cells......Page 426
4.1. CD34+ CellsTarget Disseminated Lympho-hematopoietic Tumors......Page 428
4.2. Hemorrhagic Necrosis/Apoptosis of TRAIL-Sensitive/Resistant Tumors......Page 429
References......Page 430
1. Introduction: Cells as Vectors for Therapeutic Delivery......Page 436
2.1. Definition: Mesenchymal Stem Cells or Multipotent Mesenchymal Stromal Cells?......Page 437
2.2. Methods of Isolation and Culturing......Page 439
2.3. MSC Markers......Page 440
2.4. Subtypes......Page 441
2.5. Species Variations......Page 442
3. MSC as a Delivery Platform: Biodistribution, Homing and Engraftment......Page 443
3.1. Detection and Quantification of Transplanted MSCs......Page 444
3.2. Mode of Cell Introduction: Local Versus Systemic Injection and LungTrapping......Page 446
3.3.1. Unconditioned models......Page 450
3.3.2. Injury models......Page 452
3.3.3. Cancer models......Page 457
4. MSC-based Delivery of Anti-Cancer Therapeutics......Page 458
5.1. Problems Related to Direct Virus Introduction......Page 461
5.2. Requirements for Cell-based Virus Delivery......Page 462
5.3.1. Immune cells (primary T lymphocytes, CIK cells)......Page 465
5.3.2. Tumor cell lines......Page 467
5.3.3. Progenitor/stem cells......Page 468
5.4. Carrier Cell Immune Evasion......Page 469
6. Mesenchymal Stromal Cells as Carriers for Oncolytic Adenoviruses......Page 471
References......Page 474
Index......Page 488