Pharmaceutical perspectives of nucleic acid-based therapeutics

Book Cover......Page 1
Half-Title......Page 2
Title......Page 3
Copyright......Page 4
Dedication......Page 5
Contents......Page 6
Color plates......Page 9
Figures......Page 10
Tables......Page 17
Contributors......Page 18
Foreword......Page 28
Preface......Page 29
ESSENTIAL ELEMENTS OF EXPRESSION PLASMID VECTORS......Page 31
TRANSCRIPTIONAL REGULATORY ELEMENTS......Page 32
RNA PROCESSING......Page 34
TRANSCRIPTIONAL TERMINATION SEQUENCES......Page 35
TRANSLATION CONTROL......Page 36
MULTIPLE GENE PRODUCTS FROM A SINGLE mRNA......Page 37
MULTIPLE CLONING SITE OR POLYLINKER......Page 38
PERSISTENCE OF GENE EXPRESSION......Page 39
REFERENCES......Page 40
GENERAL APPROACHES......Page 43
STRESS INDUCIBLE PROMOTERS......Page 45
HEAT SHOCK PROMOTERS......Page 46
IONIZING RADIATION INDUCIBLE PROMOTERS......Page 48
Metabolic genes......Page 49
Metallothionein......Page 50
Tetracycline/Doxycycline ‘gene switches’......Page 51
COMBINATION STRATEGIES......Page 52
LEAKY VERSUS TIGHTLY CONTROLLED EXPRESSION......Page 53
ACKNOWLEDGMENT......Page 54
REFERENCES......Page 55
INTRODUCTION......Page 60
Cleavage of target sequences......Page 62
Microinjection of in vitro transcribed RNA......Page 63
Oligonucleotide analogs with backbone modifications......Page 64
Uptake of antisense oligonucleotides......Page 65
Random ‘sequence-walking’ approach......Page 66
Computer-aided target selection: computer folding of mRNA......Page 67
Pharmacological evaluation of antisense oligonucleotides......Page 68
MDM2 as a target for cancer therapy......Page 69
Design of anti-MDM2 oligonucleotides......Page 71
Optimization of anti-MDM2 oligos......Page 72
In vitro and in vivo activities......Page 73
REFERENCES......Page 75
INTRODUCTION......Page 79
CATALYTIC MOTIFS......Page 80
RIBOZYME APPLICATIONS......Page 83
OPTIMIZING INTRACELLULAR FUNCTION OF RIBOZYMES......Page 84
RIBOZYME DELIVERY......Page 86
TRANSGENIC ANIMALS EXPRESSING RIBOZYMES......Page 87
OTHER CONSIDERATIONS......Page 88
FUTURE PROSPECTS......Page 89
REFERENCES......Page 91
INTRODUCTION......Page 96
DETECTION OF PNA BINDING-INDUCED TRANSCRIPTION IN VITRO......Page 98
DETERMINATION OF TRANSCRIPTION INITIATION SITES OF PNA BINDING-INDUCED TRANSCRIPTION......Page 100
PNA-INDUCED ENDOGENOUS -GLOBIN GENE EXPRESSION IN HUMAN CELLS......Page 101
CORRELATION BETWEEN PNA BINDING GENERATED D-LOOPS AND NATURAL PROMOTER IN TARGET GENE TRANSCRIPTION......Page 102
PNA LENGTH REQUIREMENT FOR INDUCING TRANSCRIPTION FROM PNA BINDING SITES......Page 104
TRANSCRIPTION COMPONENTS INVOLVED IN PNA BINDING-INDUCED TRANSCRIPTION......Page 106
CONCLUDING REMARKS......Page 107
REFERENCES......Page 108
INTRODUCTION......Page 110
SELECTING THE SHAPE......Page 111
APTAMERS TO NUCLEIC ACID-BINDING PROTEINS......Page 113
Polymerases......Page 114
Nucleases......Page 116
Translation and splicing factors......Page 117
Control of gene expression by aptamer-protein complexes......Page 119
APTAMERS TO NUCLEIC ACIDS......Page 121
CHEMICALLY-MODIFIED APTAMERS......Page 125
CONCLUDING REMARKS......Page 130
REFERENCES......Page 131
DNA BREAKAGE AND REPAIR......Page 139
Flap endonuclease-1 (FEN-1)......Page 140
DNA polymerases and DNA ligases......Page 143
POLY(ADP-RIBOSE) POLYMERASE-1 (PARP-1)......Page 144
Architecture of PARP-1......Page 145
PARP-1 and DNA breaks......Page 146
Cell death and PARP-1......Page 147
CONCLUDING REMARKS......Page 148
REFERENCES......Page 149
INTRODUCTION......Page 153
SWITCHING ON THE CONFORMATION OF DNA......Page 154
COMPACTION BY MULTI-VALENT CATIONS......Page 156
COMPACTION BY POLYMER......Page 159
COMPACTION BY CATIONIC LIPIDS AND SURFACTANTS......Page 161
MORPHOLOGICAL VARIATION IN COMPACT DNA......Page 163
SINGLE CHAIN COMPACTION AND MULTI-CHAIN ASSEMBLING......Page 165
GENERATION OF LARGE SCALE COOPERATION BY NON-SPECIFIC INTERACTION......Page 167
MANIPULATING INDIVIDUAL DNA......Page 168
CONCLUDING REMARKS......Page 169
REFERENCES......Page 170
POLYCATIONS USED FOR PREPARATION OF POLYPLEXES......Page 178
Polyion coupling reaction......Page 181
Composition of the complex......Page 183
Disproportionation......Page 184
A core-shell model for positively charged complexes......Page 185
Block ionomer complexes......Page 186
Effect of proteins......Page 187
Morphology and conformation in DNA/polycation complexes......Page 188
Stabilization of DNA secondary structures by polycations......Page 189
Polyion interchange reactions in DNA containing complexes......Page 191
Recognition of DNA topology by cationic copolymers......Page 193
REFERENCES......Page 195
INTRODUCTION......Page 202
LAMELLAR  PHASE OF CL/DNA COMPLEXES......Page 203
THE INVERTED HEXAGONAL PHASE OF CATIONIC LIPOSOM/DNA COMPLEXES: PATHWAYS FROM LAMELLAR PHASE......Page 208
INTERACTIONS BETWEEN LAMELLAR  AND INVERTED HEXAGONAL  PHASE OF CL/DNA COMPLEXES AND ANIONIC GIANT LIPOSOMES MIMICKING THE CELL PLASMA MEMBRANE......Page 212
INTERACTIONS BETWEEN LAMELLAR  AND INVERTED HEXAGONAL  PHASE OF CL/DNA COMPLEXES AND MOUSE FIBROBLAST CELLS......Page 214
CONCLUDING REMARKS......Page 216
REFERENCES......Page 217
INTRODUCTION......Page 220
INTERNALIZATION AND ENTRAPMENT IN ENDO-LYSOSOMAL COMPARTMENT......Page 221
Diffusional constraint of plasmid mobility in cytoplasm......Page 223
Metabolic instability of plasmid in cytoplasm......Page 225
NUCLEAR UPTAKE OF PLASMID......Page 228
NUCLEOCYTOPLASMIC TRAFFICKING OF OLIGONUCLEOTIDES......Page 229
Virus trafficking in cytoplasm......Page 230
CONCLUDING REMARKS......Page 231
REFERENCES......Page 232
Mechanisms of nuclear transport......Page 237
Nuclear envelope......Page 240
Cell cycle......Page 241
Sequence specific nuclear uptake......Page 242
Nuclear import in permeabilized cells......Page 245
Effect of nuclear import sequences on transfection......Page 248
Sequence-specific nuclear import of plasmids in vivo......Page 249
Nuclear import of exogenous DNA/protein complexes......Page 251
Alternative pathways of DNA nuclear uptake......Page 254
Non-covalent attachment of proteins......Page 256
Covalent attachment of peptides to DNA......Page 257
Peptide nucleic acids and their use......Page 258
OTHER OBSTACLES IN TRANSPORT TO NUCLEUS......Page 259
REFERENCES......Page 260
FUNDAMENTALS OF RNA EXPORT......Page 276
hnRNPs......Page 277
TRANSPORT RECEPTORS......Page 279
NUCLEAR PORE COMPLEXES (NPC)......Page 280
MULTIPLE RNA EXPORT PATHWAYS......Page 281
REV-MEDIATED EXPORT OF VIRAL RNA......Page 282
CTE-MEDIATED EXPORT OF VIRAL RNAs......Page 283
NUCLEAR EXPORT OF INTRONLESS VIRAL MESSAGES......Page 285
NUCLEAR EXPORT OF mRNAs......Page 286
ROLE OF RNA EXPORT IN GENE THERAPY......Page 289
REFERENCES......Page 291
IN VIVO TRANSFECTION OF MUSCLE USING NAKED pDNA......Page 298
MECHANISM OF pDNA ENTRY INTO MUSCLE TISSUE......Page 299
IN VIVO TRANSFECTION OF OTHER TISSUES BY NAKED pDNA......Page 300
Biological activity of naked pDNA......Page 301
pDNA therapy of autoimmune diseases......Page 302
pDNA therapy of cancer......Page 304
Electroporation......Page 306
Preclinical safety studies......Page 307
CONCLUDING REMARKS......Page 308
REFERENCES......Page 309
INTRODUCTION......Page 313
STRUCTURE AND SYNTHESIS OF COMMONLY USED CATIONIC LIPIDS......Page 314
Quaternary ammonium salt lipids......Page 315
Lipopolyamines......Page 316
Amidinium salts cationic lipids......Page 324
Imidazole, phosphonium, arsonium salts and miscellaneous cationic entities......Page 325
Targeted cationic lipids......Page 329
Biodegradable cationic lipids......Page 331
Non electrostatic DNA-groove binding lipids......Page 335
ACKNOWLEDGMENTS......Page 338
REFERENCES......Page 339
INTRODUCTION......Page 344
POLY(L-LYSINE)-BASED GENE DELIVERY SYSTEMS......Page 346
Chloroquine......Page 347
Glutamic acid-rich peptides......Page 348
H5WYG peptide......Page 350
Histidylated polylysines (HpK)......Page 351
MEMBRANE PERMEABILIZATION......Page 353
SMALL MOLECULAR WEIGHT PEPTIDE-BASED GENE DELIVERY......Page 354
PEPTIDES WITH THIOL GROUPS......Page 357
Integrin targeting......Page 358
RGD......Page 359
Sugars......Page 360
PEPTIDES CONTAINING NUCLEAR LOCALIZATION SIGNAL DOMAINS......Page 361
DNA UNPACKAGING......Page 363
PEPTIDE FROM ANTI-DNA ANTIBODIES......Page 365
Viral protein R (Vpr)......Page 366
RECOMBINANT PROTEIN-BASED GENE DELIVERY SYSTEMS......Page 367
CONCLUDING REMARKS......Page 368
REFERENCES......Page 369
DNA CONDENSATION......Page 376
CELLULAR TRAFFICKING......Page 377
POLYETHYLENIMINE......Page 378
POLYAMIDOAMINES......Page 384
POLYAMINOMETHACRYLATES......Page 387
NON-CONDENSING POLYMERS......Page 389
CONCLUDING REMARKS......Page 390
REFERENCES......Page 392
INTRODUCTION......Page 396
PMGT principles......Page 397
Advantages of PMGT......Page 399
IN VIVO APPLICATIONS OF PMGT APPROACH......Page 400
Generation of tumor vaccines in vitro and ex vivo......Page 401
DNA vaccination in vivo......Page 402
Cytokine gene therapy......Page 404
Electroporation for ex vivo gene therapy......Page 405
Use of electroporation for DNA vaccination......Page 406
JET DEVICE-MEDIATED NUCLEIC ACID DELIVERY......Page 407
REFERENCES......Page 408
INTRODUCTION......Page 415
WHOLE BODY PHARMACOKINETICS AFTER SYSTEMIC ADMINISTRATION......Page 416
pDNA......Page 419
Oligonucleotides......Page 420
Nonviral vector complex......Page 421
Bolus injection......Page 424
Constant infusion......Page 426
Isolated perfused kidney......Page 428
Tissue-isolated perfused tumor......Page 429
REFERENCES......Page 433
INTERSTITIAL TRANSPORT OF MACROMOLECULES IN SOLID TUMORS......Page 438
Convection......Page 439
Hydraulic conductivity......Page 441
Retardation coefficient......Page 443
Diffusion......Page 444
Binding......Page 446
Effects of the microenvironment on interstitial transport in tumors......Page 447
Diffusion of nucleic acids in solutions......Page 449
Diffusion of nucleic acids in polymeric gels......Page 450
CONCLUDING REMARKS......Page 452
REFERENCES......Page 453
INTRODUCTION......Page 458
EFFECT OF VOLUME AND INJECTION SPEED ON DNA DELIVERY TO HEPATOCYTES......Page 460
TOXICITY EVALUATION ON HYDRODYNAMICS-BASED PROCEDURE......Page 461
EFFICIENCY OF HYDRODYNAMICS-BASED DNA DELIVERY......Page 462
INTRODUCTION AND EXPRESSION OF MULTIPLE GENES BY HYDRODYNAMICS-BASED PROCEDURE......Page 464
PERSISTENCE OF GENE EXPRESSION......Page 465
GENE FUNCTION ANALYSIS USING HYDRODYNAMICS-BASED DNA DELIVERY......Page 467
REFERENCES......Page 469
INTRODUCTION......Page 472
Cellular stimulation......Page 473
Signal transduction......Page 474
Therapeutic vaccines......Page 477
PREVENTION AND TREATMENT OF ATOPIC DISEASES......Page 478
CpG ODN as a stand-alone therapy......Page 479
Cancer vaccines......Page 480
Neutralizing CpG motifs and gene therapy......Page 481
CONCLUDING REMARKS......Page 482
REFERENCES......Page 483
INTRODUCTION......Page 488
INTRAVASCULAR DELIVERY......Page 490
STENTS......Page 491
VEGFs AS THERAPEUTIC GENES......Page 492
CONCLUDING REMARKS......Page 494
REFERENCES......Page 495
GENE THERAPY CLINICAL TRIALS......Page 500
ISCHEMIC HEART DISEASE (IHD)......Page 501
CARDIAC TRANSPLANTATION......Page 502
GENE DELIVERY SYSTEMS......Page 503
ROUTE OF ADMINISTRATION......Page 504
CONCLUDING REMARKS......Page 505
REFERENCES......Page 506
PATHOGENESIS OF AUTOIMMUNE DIABETES......Page 508
Autoantigen-related gene therapy for the prevention of autoimmune diabetes......Page 510
CYTOKINES IN AUTOIMMUNE DIABETES......Page 511
Systemic delivery of cytokine expression plasmids......Page 512
Delivery of tissue-specific or glucose responsive expression plasmid......Page 513
OTHER TRIALS FOR AUTOIMMUNE DIABETES......Page 514
REFERENCES......Page 515
Index......Page 519