Holdings: Adenoviral vectors for gene therapy

Adenoviral vectors for gene therapy:

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Bibliographic Details
Other Authors:	Curiel, David 19XX- (Editor)
Format:	Book
Language:	English
Published:	Amsterdam [u.a.] Acad. Press 2002
Subjects:	Adenoviridae Adenovírus Adénovirus Genes virais Thérapie génique Vecteurs de clonage Vírus de dna Adenoviruses Gene Therapy > methods Gene therapy Genetic Vectors > therapeutic use Gentherapie Adenoviren
Online Access:	Inhaltsverzeichnis
Item Description:	Includes bibliographical references
Physical Description:	XXVIII, 677 S. Ill., graph. Darst.
ISBN:	0121995046

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adam_text	Contents Contributors xxiii Preface xxvii CHAPTER 1 Adenovirus Structure Phoebe L. Stewart I. Introduction 1 II. Molecular Composition 2 III. Structure of the Intact Virion 3 IV. Structure of the Capsid Components 4 A. Hexon, Polypeptide II 4 B. Penton Base, Polypeptide III 6 C. Fiber, Polypeptide IV 8 D. Polypeptide Ilia 10 E. Polypeptide VI 10 F. Polypeptide VIII 11 G. Polypeptide IX 11 v vi Contents V. Core Structure 12 VI. Adenovirus Protease 12 VII. Summary 13 References 14 CHAPTER 2 Biology of Adenovirus Cell Entry Glen R. Nemerow I. Pathway of Adenovirus Cell Entry 19 II. Cell Receptors Involved in Attachment 21 A. CAR 21 B. Other Adenovirus Receptors 23 III. Adenovirus Internalization Receptors 24 A. Role of av Integrins as Coreceptors 24 B. Structural Features of Penton Base av Integrin Association 26 C. Signaling Events Associated with Adenovirus Internalization 26 IV. Virus Mediated Endosome Disruption and Uncoating 29 A. Role of Penton Base and av Integrins 29 B. Role of the Adenovirus Cysteine Protease 30 V. Beyond the Endosome: Trafficking of Viral Capsids and Import of Viral DNA into the Nucleus 30 A. Intracytoplasmic Transport of Viral Capsids 30 B. Docking at the Nuclear Pore and Translocation of Viral DNA 31 VI. Conclusions 31 References 32 CHAPTER 3 Adenovirus Replication Jared D. Evans and Patrick Hearing I. Introduction 39 II. Classification 40 Contents vjj III. Genome Organization 40 IV. Virus Infection 42 V. Early Gene Expression 42 VI. Early Region 1A(E1A) 43 VII. Early Region 1B(E1B) 46 VIII. Early Region 2 (E2) 47 IX. Early Region 3 (E3) 49 X. Early Region 4 (E4) 52 XI. Viral DNA Replication 55 XII. VA RNA Genes 59 XIII. Late Gene Expression and Virus Assembly 59 XIV. Vector Design 62 XV. Conclusion 63 References 64 CHAPTER 4 Adenoviral Vector Construction I: Mammalian Systems Philip Ng and Frank L. Graham I. Introduction 71 A. Adenovirus Biology 71 B. Adenovirus Vectors 73 C. Early Methods of Constructing Recombinant Adenoviruses 73 II. The Two Plasmid Rescue System 75 A. Development of the Two Plasmid Rescue System 77 B. Refinements to the Two Plasmid Rescue Method 79 C. The Ad Genomic Plasmid 82 D. The Shuttle Plasmid 82 III. Protocols for the Two Plasmid Rescue System 85 A. Preparation of Plasmid DNA 85 B. Cell Culture 88 C. Cotransfection 89 D. Analysis of Recombinant Vectors and Preparation of Working Vector Stocks 93 viii Contents E. Titration of Adenovirus 94 F. Preparation of High Titer Viral Stocks (Crude Lysate) 95 G. Purification of Adenovirus by CsCl Banding 97 H. Characterization of Adenoviral Vector Preparations 99 I. Alternative Procedures to Expedite Vector Production 101 References 101 CHAPTER 5 Adenoviral Vector Construction II: Bacterial Systems M. Lusky, E. Degryse, M. Mehtali, and C. Chartier I. Introduction 105 II. Generation of Ad: Traditional Approaches 106 III. Generation of Ad: Bacterial Systems 107 IV. Homologous Recombination in £. coli 108 V. Homologous Recombination with Linear Ad Vector Genome Plasmids 109 VI. Homologous Recombination with Circular Ad Vector Genome Plasmids 116 VII. Ad Vector Construction by Transposon Mediated Recombination 118 VIII. Ad Vector Construction by in Vitro Ligation 119 IX. Conclusion 121 References 123 CHAPTER 6 Propagation of Adenoviral Vectors: Use ofPER.C6 Cells W. W. Nichols, R. Lardenoije, B. J. Ledwith, K. Brouwer, S. Manam, R. Vogels, D. Kaslow, D. Zuidgeest, A. J. Beft, L. Chen, M. van der Kaaden, S. M. Galloway, R. B. Hill, S. V. Machotka, C. A. Anderson, J. Lewis, D. Martinez, J. Lebron, C. Russo, D. Valerio, and A. Bout I. Introduction 129 Contents jx A. Scope of the Chapter 129 B. Adenoviruses 130 C. Adenovirus Replication 131 II. Cells Expressing El of Adenovirus 134 A. Transformation of Cells by El of Adenovirus 134 B. El Expressing Cell Lines for Adenoviral Vector Production 135 III. PER.C6 Prevents RCA during Vector Production 136 A. RCA 136 B. PER.C6: Absence of Sequence Overlap Eliminates RCA Generation 137 C. Frequency of RCA Occurrence 139 IV. Production of Adenoviral Vectors 141 A. Vector Stability 141 B. The Production Process 143 C. Yields of Adenoviral Vectors 145 D. Scale of Adenoviral Vector Production 145 V. Safety Considerations of PER.C6 146 A. QC Testing of PER.C6 Cells for Use in the Manufacture of Biologicals and Vaccines 146 B. Tumorigenicity 150 C. Prion Related Issues 156 D. Genetic Characterization of PER.C6 Cells 157 VI. Conclusions 159 References 160 CHAPTER 7 Purification of Adenovirus Paul Shabram, Gary Vellekamp and Carl Scandella I. Introduction 167 A. The Physical Characteristics of the Adenovirus Particle in Solution 167 X Contents B. Features of the Milieu 170 C. Summary of Characteristics 173 II. Recovery and Purification of Adenoviral Particles 173 A. Harvest Methods 173 B. Lysis Methods 175 C. Clarification 179 D. Purification 181 E. Buffer Exchange 189 III. Analytical Methods for Process Development and Process Tracking 190 A. Plaque Forming Titer Assays 190 B. Adenovirus 96 Well Titer Plate Assay 191 C. Flow Cytometry 194 D. Particle Concentration Determination by Ultraviolet Absorbance 194 E. Analytical Reverse Phase HPLC 195 F. Analytical Anion Exchange HPLC 196 IV. Formulation and Stability 196 V. Conclusions 200 References 200 CHAPTER 8 Targeted Adenoviral Vectors I: Transductional Targeting Victor Krasnykh and Joanne T. Douglas I. Introduction 205 II. The Pathway of Adenoviral Infection 206 III. Strategies and Considerations 207 IV. Conjugate Based Targeting 209 A. Bispecific Chemical Conjugates 209 B. Bispecific Recombinant Fusion Proteins 213 C. Bispecific Peptides 215 D. Polymer Mediated Coupling of Ligands to Ad Capsid Proteins 215 Contents xj E. Biotinylated Ad/Avidin Bridge/Biotinylated Ligand 216 V. Genetic Targeting 216 A. Ad Targeting Strategies Involving Genetic Manipulations of the Fiber Protein 217 B. Ad Targeting Strategies Involving Genetic Manipulations of the Hexon and Penton Base Proteins 231 VI. Transductionally Targeted Ad Vectors for Clinical Gene Therapy Applications 232 VII. Conclusion 235 References 236 CHAPTER 9 Targeted Adenoviral Vectors II: Transcriptional Targeting Sudhanshu P. Raikwar, Chinghai H. Kao, and Thomas A. Gardner I. Introduction: Rationale of Transcriptional Targeting 247 II. Regulation of Transcription in Eukaryotes 248 A. Molecular Organization of DNA 248 B. The Central Dogma 248 C. Transcription 249 D. Mechanism of Transcription 251 E. Structural Motifs 253 F. Regulation of Adenoviral DNA Transcription Process 256 III. Approaches of Transcriptional Regulation 256 A. Prior Rationale Universal Promoters 256 B. Current Rationale of Tissue Specific Promoters 257 C. MN/CA9 Promoter 268 D. Inducible Transcription 269 IV. Enhanced Control of Transgene Expression 271 A. Safety Improvements 271 B. Potency Concerns 272 V. Future Directions 272 A. Enhancement of Weak But Specific Promoters 272 xii Contents B. Improving Specificity with Multiple Promoter Segments 274 C. Tumor Specific Oncolysis 274 D. Combined Targeting Approaches 274 VI. Summary 274 References 275 CHAPTER 10 Development of Attenuated Replication Competent Adenoviruses (ARCAs) for the Treatment of Prostate Cancer Daniel R. Henderson and De Chao Yu I. Introduction 287 II. ARCAs for Prostate Cancer: CV706 and CV787 290 A. Adenovirus: Gene Expression and Regulation 290 B. Tissue Specificity of ARCA 291 C. Antitumoral Efficacy of ARCA 295 D. Mechanism for Cell Killing of ARCA 296 III. Synergy of ARCA and Conventional Therapy 298 A. Synergy of CV706 and Irradiation 299 B. Synergy of CV787 and Chemotherapy 302 IV. Toxicity of Intravenously Administered ARCAs in the Absence or Presence of Docetaxel 305 V. Effects of Preexisting Adenovirus Antibody on Antitumor Activity and Immunoapheresis for Human Therapy 308 A. Preexisting Adenovirus Antibodies Inhibit Systemic Toxicity and Antitumor Activity 309 B. SIAPA: Screening and Immunoapheresis of Preexistent Antibody for Monitoring and Removing Preexistent Ad5 Antibodies from Blood 313 VI. Clinical Development of CV706 and CV787 314 A. CV706 Phase I/II Trial for Locally Recurrent Prostate Cancer 314 B. Factors Impacting Clinical Efficacy and Safety 317 Contents xiii VII. Summary 318 References 319 CHAPTER 1 1 Replication Selective Oncolytic Adenovirus El Region Mutants: Virotherapy for Cancer David Kirn I. Introduction 329 II. Attributes of Replication Selective Adenoviruses for Cancer Treatment 332 III. Biology of Human Adenovirus 332 IV. Mechanisms of Adenovirus Mediated Cell Killing 333 V. Approaches to Optimizing Tumor Selective Adenovirus Replication 333 VI. E1A CR2 Region Deletion Mutants 334 VII. El B 55 kDa Gene Deletion Mutant: d/1 520 335 VIII. Clinical Trial Results with Replication Competent Adenoviruses in Cancer Patients 337 A. Clinical Trial Results with Wild Type Adenovirus 337 B. A Novel Staged Approach to Clinical Research with Replication Selective Viruses: The Example of J/1520 (Onyx 015) 338 IX. Results from Clinical Trials with d/1520 (Onyx 015 or Cl 1042) 340 A. Toxicity 340 B. Viral Replication 340 C. Immune Response 342 X. Clinical Trial Results with d/1520 (Onyx 015): Summary 343 XI. Future Directions: Why Has d/1520 (Onyx 015) Failed to Date as a Single Agent? 344 XII. Improving the Efficacy of Replication Selective Oncolytic Adenoviral Agents 345 XIII. Summary 345 References 346 xiv Contents CHAPTER 12 Innate Immune Responses to in Vivo Adenovirus Infection Bruce C. Trapnell and Thomas P. Shanley I. Overview: Components of Innate Immunity 349 II. Distribution and Clearance of Adenovirus from the Respiratory Tract 354 A. Clinical Aspects of Natural Adenoviral Infection in Humans 354 B. Distribution of Recombinant, Replication Deficient Adenoviral Vectors 355 C. Kinetics and Mechanisms of Clearance of Adenovirus 356 III. Molecular Mediators of Inflammation 359 A. Clinical Adenovirus Infections in Humans 360 B. Adenovirus Infections in Animal Models 361 C. Acute Cytokine Responses 362 D. Intermediate Cytokine Responses 363 E. Late Cytokine Responses 364 IV. Inflammatory Cell Recruitment 364 V. Innate Immunity and Programming of Adaptive Responses 367 VI. Innate Immunity and in Vivo Gene Therapy 368 VII. Future Directions 369 References 369 CHAPTER 13 Humoral Immune Response Catherine O Riordan I. Introduction 375 II. Adenovirus Structure and Serotype 376 A. Classification of Adenoviruses 376 B. Adenoviral Structural Proteins and Type Specific Epitopes 376 C. Chimeric Adenovirus Vectors 379 Contents XV D. Influence of Serotypic Variations on Adenoviral Cell Interactions 380 III. Host Response to Gene Therapy Vectors 381 A. Innate Immune Response 381 B. Adaptive Immune Response: B T Cell Interactions 382 IV. Strategies to Overcome the Humoral Immune Response 384 A. General Immunosuppression 384 B. Transient Selective Immunosuppression 386 C. Oral Tolerance 387 D. Serotype Switching 388 E. Masking Neutralizing Epitopes 389 F. Immunoapheresis 390 V. Factors Modulating Host Responses to Gene Transfer Vectors 390 A. Viral Vector Backbone 390 B. Species and Strain 393 C. Route of Delivery 395 VI. Immune Response to Adenoviral based Vectors in Humans 396 VII. Conclusion 398 References 399 CHAPTER 14 Novel Methods to Eliminate the Immune Response to Adenovirus Gene Therapy Huang Ge Zhang, Hui Chen Hsu, and John D. Mountz I. Introduction 409 II. Immune Suppression 410 III. Immune Modulation 411 IV. Treatment with Soluble TNFR1 to Eliminate Ad Inflammation in Lung and Liver 414 V. Inhibition of Cell Cytolysis Which Combines Treatment with Soluble DR5, Soluble Fas, and Soluble TNFR1 415 VI. Immune Privilege 417 xvi Contents VII. APC AdFasL Prolongs Transgene Expression and Specifically Minimizes T Cell Response 419 VIII. Production of AdsTACI Prolongs Gene Expression and Minimizes B Cell Response 421 IX. Summary 423 References 424 CHAPTER 15 High Capacity Gutless Adenoviral Vectors: Technical Aspects and Applications Gudrun Schiedner, Paula R. Clemens, Christoph Volpers, and Stefan Kochanek I. Introduction 429 II. Technical Aspects 430 A. Vector Production 430 B. Sniffer DNA 432 C. Vector Capsid Modification 434 III. Applications 435 A. Liver Gene Transfer 435 B. Gene Transfer into Skeletal Muscle 439 C. Gene Transfer into the Eye and into the CNS 440 IV. Conclusion 442 References 442 CHAPTER 16 Xenogenic Adenoviral Vectors Gerald W. Both I. Impetus and Rationale 447 II. Classification of Adenoviruses 447 III. Factors Affecting Vector Design and Utility 448 A. Host Range and Pathogenicity 448 B. Neutralization 450 C. Genome Structure and Function 450 Contents xvii D. Transforming Ability 454 E. Cell Lines 456 F. Strategies for Vector Construction and Rescue 458 IV. Utility of Xenogenic Vectors 460 A. Veterinary Studies 460 B. Vector Biology 462 C. Gene Therapy Studies 466 V. Biosafety 466 A. Complementation and Recombination 466 B. Oncogenes in Viral and Cellular DNA 468 C. Virus/Cell Interactions 468 D. Replication Competent Viruses 469 VI. Vector Production and Purification 469 References 470 CHAPTER 17 Hybrid Adenoviral Vectors Stephen J. Murphy and Richard G. Vile I. Introduction 481 A. Retroviral Vectors 483 B. Adenoviral Vectors 487 C. Adeno associated Viruses 487 D. Herpes Simplex Viruses 488 E. Lentiviral Vectors 488 F. The Choice of Gene Therapy Vector 489 G. How to Maintain Stable Transgene Expression 491 II. Hybrid Viral Vectors 492 A. Are Hybrid Vectors Truly New Technology? 493 III. Hybrid Adenoviral Vector Systems 494 A. Pseudotyping and Retargeting Adenoviral Vectors 494 B. Adenoviral/Retroviral Hybrid Vector Technologies 496 xviii Contents C. Adenoviral/Epstein Barr Virus Hybrid Vectors 508 D. Hybrid Retro viruses Trafficking to the Nucleus 511 E. Hybrid Adenoviral/Adeno Associated Virus Vectors 512 IV. Conclusion 518 References 524 CHAPTER 18 Utility of Adenoviral Vectors in Animal Models of Human Disease I: Cancer Raj K. Batra, Sherven Sharma, and Lily Wu I. Introduction 533 II. Animal Models of Lung Cancer 535 A. Human Lung Cancer 535 B. Animal Models of Human Lung Cancer 537 C. Gene Therapy of Lung Cancer Using Adenoviral Vectors 543 III. Animal Models of Human Prostate Cancer 547 A. Human Prostate Cancer 547 B. Spontaneous and Transgenic Models of Human Prostate Cancer 547 C. Xenograft Models of Human Prostate Cancer 548 D. Gene Therapy Approaches with Adenovectors in Prostate Cancer 550 IV. Summary and Discussion 551 References 553 CHAPTER 19 Utility of Adenoviral Vectors in Animal Models of Human Disease II: Genetic Disease Raymond John Pickles I. Introduction 565 II. Pathophysiology of Cystic Fibrosis (CF) Lung Disease 566 Contents xix III. Trials and Tribulations with Adenoviral Vectors for CF Lung Disease 567 IV. The Airway Epithelium: Cellular Targets for CF Gene Therapy 568 V. Adenoviral Vectors as Gene Transfer Vectors in the Lung 570 A. Animal Models for CF Airway Gene Transfer Studies 570 B. Success and Limitations of Ad 571 C. Overcoming the Limitations of Ad 577 VI. Other Vectors 585 VII. Conclusion 586 References 586 CHAPTER 2 0 Utility of Adenoviral Vectors in Animal Models of Human Disease III: Acquired Diseases Erik Lubberts and Jay K. Kolls I. Adenoviral Vectors for Infectious Disease 595 A. Tuberculosis 596 B. Pneumonia 598 C. Opportunistic Infections 601 D. Viral Hepatitis 603 II. Chronic Inflammatory Diseases 603 A. Inflammatory Bowel Disease 603 B. Arthritis 604 C. Fibrotic Lung Disease 607 III. Conclusions 608 References 608 CHAPTER 2 1 Testing of Adenoviral Vector Gene Transfer Products: FDA Expectations Steven R. Bauer, Anne M. Pilaro, and Karen D. Weiss I. Introduction 615 XX Contents II. Manufacturing Control and Product Characterization 616 A. Purity, Safety, and Potency 616 B. Regulation of Process as Well as Product 617 C. Current Good Manufacturing Practices 617 III. Development of Recommendations for the Manufacture and Characterization of Adenoviral Vectors 618 IV. Considerations in Manufacturing Adenoviral Vectors 620 A. Components and Characterization 620 B. Protocols 621 V. Process Controls 621 A. Standard Operating Procedures 621 B. Quality Assurance and Quality Control Programs 622 VI. Characterization of Adenoviral Vector Production Intermediates 623 A. Master Cell Bank 623 B. Working Cell Bank 626 C. Master Virus Bank 626 VII. Characterization of Adenoviral Vector Final Products 628 VIII. Preclinical Testing of Adenoviral Vectors 630 A. Pharmacologic Activity 631 IX. Toxicology Testing 632 A. Scope of Toxicity Testing 632 B. Species Selection 633 C. Route of Administration 634 D. Selection of Dose 634 X. Biodistribution 636 A. Good Laboratory Practices 637 XI. Introduction to Clinical Testing 637 A. Phases of Clinical Development 638 XII. Good Clinical Practices 639 A. Responsibilities of a Sponsor and Investigators 639 B. Adverse Event Reporting 639 Contents xxi C. Consent and Vulnerable Populations 640 D. Monitoring and Auditing 641 XIII. Clinical Safety of Adenoviral Vector Products 642 XIV. Bioactivily of Adenoviral Vector Products 643 XV. Clinical Efficacy of Adenoviral Vector Products 644 A. Choice of Control 645 B. Endpoint Selection 645 XVI. How the Role of FDA Regulators Has Changed Since September 1999 646 A. Safety Symposia in Conjunction with OBA 647 B. Results of FDA s Directed Inspections 648 C. Description of the March 6, 2000, Letter and Summary of Responses 649 D. Results of Additional Inspections 650 E. Sponsor Outreach and Education 651 XVI. Summary 651 References 652 CHAPTER 2 2 Imaging Adenovirus Mediated Gene Transfer Kurt R. Zinn and Tandra R. Chaudhuri I. Introduction 655 II. What Information Is Provided by Imaging? 656 III. Scientific Basis for Imaging 657 A. Electromagnetic Energy 657 B. Contrast 657 C. Gamma Rays and Detection 657 D. Light Based Imaging and Detection 661 E. Magnetic Resonance Imaging and Spectroscopy 662 IV. Imaging and Gene Therapy Vectors 663 A. Gamma Ray Imaging 663 B. Light Based Imaging 666 C. Magnetic Resonance Technologies 668 xxii Contents V. Gene Therapy Vectors May Advance Molecular Imaging 669 VI. Conclusion 671 References 671
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isbn	0121995046
language	English
lccn	2001098272
oai_aleph_id	oai:aleph.bib-bvb.de:BVB01-009891754
oclc_num	49780706
open_access_boolean
owner	DE-355 DE-BY-UBR DE-11
owner_facet	DE-355 DE-BY-UBR DE-11
physical	XXVIII, 677 S. Ill., graph. Darst.
publishDate	2002
publishDateSearch	2002
publishDateSort	2002
publisher	Acad. Press
record_format	marc
spelling	Adenoviral vectors for gene therapy ed. by David T. Curiel ... Amsterdam [u.a.] Acad. Press 2002 XXVIII, 677 S. Ill., graph. Darst. txt rdacontent n rdamedia nc rdacarrier Includes bibliographical references Adenoviridae ram Adenovírus larpcal Adénovirus Genes virais larpcal Thérapie génique Thérapie génique ram Vecteurs de clonage ram Vírus de dna larpcal Adenoviridae Adenoviruses Gene Therapy methods Gene therapy Genetic Vectors therapeutic use Gentherapie (DE-588)4296957-8 gnd rswk-swf Adenoviren (DE-588)4141412-3 gnd rswk-swf Adenoviren (DE-588)4141412-3 s Gentherapie (DE-588)4296957-8 s DE-604 Curiel, David 19XX- (DE-588)122647828X edt HBZ Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=009891754&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis
spellingShingle	Adenoviral vectors for gene therapy Adenoviridae ram Adenovírus larpcal Adénovirus Genes virais larpcal Thérapie génique Thérapie génique ram Vecteurs de clonage ram Vírus de dna larpcal Adenoviridae Adenoviruses Gene Therapy methods Gene therapy Genetic Vectors therapeutic use Gentherapie (DE-588)4296957-8 gnd Adenoviren (DE-588)4141412-3 gnd
subject_GND	(DE-588)4296957-8 (DE-588)4141412-3
title	Adenoviral vectors for gene therapy
title_auth	Adenoviral vectors for gene therapy
title_exact_search	Adenoviral vectors for gene therapy
title_full	Adenoviral vectors for gene therapy ed. by David T. Curiel ...
title_fullStr	Adenoviral vectors for gene therapy ed. by David T. Curiel ...
title_full_unstemmed	Adenoviral vectors for gene therapy ed. by David T. Curiel ...
title_short	Adenoviral vectors for gene therapy
title_sort	adenoviral vectors for gene therapy
topic	Adenoviridae ram Adenovírus larpcal Adénovirus Genes virais larpcal Thérapie génique Thérapie génique ram Vecteurs de clonage ram Vírus de dna larpcal Adenoviridae Adenoviruses Gene Therapy methods Gene therapy Genetic Vectors therapeutic use Gentherapie (DE-588)4296957-8 gnd Adenoviren (DE-588)4141412-3 gnd
topic_facet	Adenoviridae Adenovírus Adénovirus Genes virais Thérapie génique Vecteurs de clonage Vírus de dna Adenoviruses Gene Therapy methods Gene therapy Genetic Vectors therapeutic use Gentherapie Adenoviren
url	http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=009891754&sequence=000002&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA
work_keys_str_mv	AT curieldavid adenoviralvectorsforgenetherapy

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