Gene Therapy Technologies, Applications and Regulations: From Laboratory to Clinic

427 Pages·1999·3.972 MB·English

GeneTherapyTechnologies,ApplicationsandRegulations.EditedbyAnthonyMeager
Copyright©1999JohnWiley&SonsLtd
PrintISBN0-471-976709-2ElectronicISBN0-470-84238-5
Gene Therapy
Technologies,
Applications and
Regulations
GeneTherapyTechnologies,ApplicationsandRegulations.EditedbyAnthonyMeager
Copyright©1999JohnWiley&SonsLtd
PrintISBN0-471-976709-2ElectronicISBN0-470-84238-5
Gene Therapy
Tecnologies,
Applications and
Regulations
FROM LABORATORY TO CLINIC
Editedby
ANTHONYMEAGER
DivisionofImmunobiology,TheNationalInstituteforBiologicalStandardsandControl,
SouthMimms,UK
JOHNWILEY&SONSLTD
Chichester·NewYork·Weinheim·Brisbane·Singapore·Toronto
GeneTherapyTechnologies,ApplicationsandRegulations.EditedbyAnthonyMeager
Copyright©1999JohnWiley&SonsLtd
PrintISBN0-471-976709-2ElectronicISBN0-470-84238-5
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LibraryofCongressCataloging-in-PublicationData
Genetherapytechnologies,applications,andregulations:fromlaboratorytoclinic/editedby
AnthonyMeager.
p. cm.
Includesbibliographicalreferencesandindex.
ISBN0-471-96709-2(alk.paper)
1.Genetherapy. I.Meager,Anthony.
[DNLM:1.GeneTherapy–methods. QZ50 G3216 1999]
RB155.8.G467 1999
616'.042–dc21
DNLM/DLC 99-15301
forLibraryofCongress CIP
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AcataloguerecordforthisbookisavailablefromtheBritishLibrary
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GeneTherapyTechnologies,ApplicationsandRegulations.EditedbyAnthonyMeager
Copyright©1999JohnWiley&SonsLtd
PrintISBN0-471-976709-2ElectronicISBN0-470-84238-5
Contents
Listofcontributors xv
Preface xxi
1 CationicLiposomesforGeneTherapyApplications 1
J.P.ClancyandEricS.Sorscher
1.1 Introduction 1
1.2 Mechanismofactionofcationicliposomes 1
1.3 Lipid-mediatedgenetransfertopolarizedepithelium 3
1.4 Cationiclipiddrugdiscovery 3
1.5 Lipidretargeting 4
1.6 Plasmidmodification 5
1.7 Preclinicalandclinicaltrials 6
1.8 Regulatoryissuesregardinglipid–DNAcomplexes 7
1.9 Summary 9
2 DNACondensationandReceptor-mediatedGeneTransfer 13
AssemZiadyandThomasFerkol
2.1 Introduction 13
2.2 Receptor-mediatedgenetransfer 14
2.2.1 Targetingligand 16
2.2.1.1 Asialoglycoproteinreceptor 16
2.2.1.2 Transferrinreceptor 20
2.2.1.3 Polymericimmunoglobulinreceptor 21
2.2.1.4 Mannosereceptor 22
2.2.2 DNAcondensationandcomplexformation 23
2.2.3 Endosomaltraffickingandescape 25
2.2.4 Nucleartargetingandtranslocation 27
2.3 Conclusions 28
3 RetroviralVectors 35
WalterH.Gu¨nzburgandBrianSalmons
3.1 Introduction 35
3.2 Theretroviralreplicationcycle 36
3.2.1 Earlyevents 36
3.2.2 IntegrationofviralDNAintohostgenomicDNA 36
3.2.3 Transcription,translationandassembly 38
vi CONTENTS
3.3 Retroviralvectordevelopment 39
3.3.1 Principles 40
3.3.2 Improvements 41
3.4 Infectiontargeting 43
3.5 Geneexpressionfromretroviralvectors 45
3.5.1 Generalconsiderations 45
3.5.2 Expressiontargeting 48
3.5.3 Inducibleexpression 48
3.6 Retoviralvectortitresandstability 49
3.7 Lentiviralvectors 52
3.8 Conclusionsandperspectives 53
4 LentiviralVectors 61
AndrewM.L.Lever
4.1 Introduction 61
4.2 Geneticstructureoflentiviruses 62
4.2.1 Advantagesoflentiviralvectors 67
4.2.2 Disavantagesoflentiviralvectors 67
4.3 Lentivirus-basedvectors 67
4.3.1 Otherinfluencesonpackaging 68
4.3.2 Directgenetransfer 70
4.3.3 Helpervirusmediated 70
4.3.4 Co-transfectionsystems 71
4.3.4.1 Envelopecomplementation 71
4.3.4.2 Co-transfectionusingindependentvectorand
packagingconstructs 71
4.3.4.3 Three-plasmidco-transfections 76
4.3.5 Packagingcelllines 78
4.3.5.1 Problemproteins 79
4.3.5.2 Inducibleconstructs 80
4.3.6 Envelopepseudotyping 80
4.3.7 Proteindelivery 81
4.3.8 Viraltitres 81
4.4 Rangeofapplications 82
4.5 Safety 82
5 AdenoviralVectors 87
SheilaConnelly
5.1 Introduction 87
5.2 Structureandgenomicorganizationofhumanadenoviruses 88
5.3 Designandconstructionofreplication-defectivehuman
adenoviralvectors 90
CONTENTS vii
5.4 Propagationandpurificationofadenoviralvectors 94
5.5 Invivoadenovirus-mediatedgenetransfer 95
5.6 Circumventingthehostimmuneresponsetoinvivo
adenoviralgenetransfer 97
5.7 Summary 99
6 Adeno-associatedViralVectors 109
TerenceR.FlotteandBarrieJ.Carter
6.1 Introduction 109
6.2 BiologyofAAV 109
6.2.1 AAVtaxonomyandnaturalhistory 109
6.2.2 ThestructureofAAVanditsgenome 110
6.2.3 TheAAVlifecycle 112
6.2.4 Site-specificityofAAVintegration 113
6.3 AAV-derivedrecombinantvectors 114
6.3.1 StructureofrecombinantAAVvectors 114
6.3.2 StrategiesforpackagingAAVrecombinantvectors 114
6.3.3 PersistenceofvectorDNAintargetcells 116
6.3.4 HostcellfactorsaffectingAAVvector
transduction 116
6.3.5 Summaryofadvantagesanddisadvantagesof
AAVtransducingvectors 117
6.4 ApplicationsofAAVvectors 117
6.4.1 Invitroapplications 118
6.4.2 Invivoapplications 120
6.5 Safetyissues 120
6.5.1 Subjectsafety 120
6.5.2 Environmentalsafety 121
7 AdvancesinEngineeringHSVVectorsforGeneTransfer
totheNervousSystem 127
M.KarinaSoares,WilliamF.Goins,JosephC.Gloriosoand
DavidJ.Fink
7.1 Introduction 127
7.2 HSVbiology 129
7.3 DevelopmentofHSVvectorsforthenervoussystem 131
7.3.1 Deletionofaccessoryfunctionstoincreasethecapacity
forforeigngenes 132
7.3.2 Vector-associatedcytotoxicity 133
7.3.3 Promotersystemsfortransgeneexpression 136
7.3.3.1 Transientexpression 137
7.3.3.2 Long-termexpression 138
7.3.3.3 Regulatedtransgeneexpression 142
viii CONTENTS
7.3.4 HSVamplicons 143
7.3.5 NovelhybridHSV–AAVvectors 144
7.4 Summaryandfuturedirections 144
8 MammalianArtificialChromosomes:Prospectsfor
GeneTherapy 165
TomA.EbersoleandChristineJ.Farr
8.1 Introduction 165
8.2 WhybuildaMAC? 165
8.3 TheidealMAC 166
8.4 StrategiesforgeneratingaMAC 167
8.4.1 Thetop-downapproach 168
8.4.2 Thebottom-upapproach 171
8.5 Practicalproblemsandunknowns 173
8.6 Concludingremarks 174
9 GeneTherapyforSevereCombinedImmunodeficiency 179
AdrianJ.Thrasher,HubertB.Gasparand
ChristineKinnon
9.1 Introduction 179
9.2 MolecularpathologyofSCID 179
9.2.1 X-linkedseverecombinedimmunodeficiency 180
9.2.2 JAK-3defects 180
9.2.3 Adenosinedeaminaseandpurinenucleoside
phosphorylasedeficiencies 181
9.2.4 Recombinantactivatinggenes(RAG1andRAG2)
defects 181
9.2.5 ZAP70defects 181
9.2.6 MHCclassIdeficiency(type1barelymphocyte
syndrome) 181
9.2.7 MHCclassIIdeficiency(type2barelymphocyte
syndrome) 182
9.2.8 TCR-CD3abnormalities 182
9.3 SomaticgenetherapyforSCID 182
9.3.1 ClinicalgenetherapyforADA-SCID 183
9.3.2 TlymphocytegenetherapyforADA-SCID 184
9.3.3 StemcellgenetherapyforADA-SCID 185
9.3.4 Limitingfactorsforstemcellgenetherapy 186
9.4 Alternativevectorsystems 186
9.5 Pre-clinicalassessmentofhaematopoieticstemcell
genetransfer 187
9.6 Conclusions 187
CONTENTS ix
10 GeneTherapyforHaemophilia 195
RobC.Hoeben,FrederikH.E.Schagen,MarjolijnM.vanderEb,
FritsJ.Fallaux,AlexJ.vanderEbandHansvanOrmondt
10.1 Introduction 195
10.2 GenetherapyforhaemophiliaA 196
10.2.1 PropertiesoffactorVIII 196
10.2.2 Exvivogenetherapy:problemswithretroviralvectors 196
10.2.3 Implantationofretrovirally-transducedcells 199
10.2.4 Invivogenetherapy:encouragingresultswith
adenoviralvectors 200
10.3 GenetherapyforhaemophiliaB 201
10.4 Wheredowegofromhere? 202
11 CysticFibrosis:GeneTherapyApproaches 207
NatashaJ.Caplen
11.1 Introduction 207
11.2 Thegeneticsofcysticfibrosis 207
11.3 CFTRproteinanddiseasepathology 208
11.4 Treatmentforcysticfibrosis 209
11.5 Genetransfersystemsandcysticfibrosis 209
11.5.1 Background 209
11.5.2 Retroviral-mediatedgenetransfer 210
11.5.3 Adenoviral-mediatedgenetransfer 211
11.5.4 Adeno-associated-viral-mediatedgenetransfer 214
11.5.5 Cationiclipid-mediatedgenetransfer 215
11.5.6 Othergenetransfersystems 217
11.6 GenetansferandCF:willitwork? 218
12 TherapeuticApproachestoHaemoglobinopathies 227
YvesBeuzard
12.1 Introduction 227
12.2 Globinretoviralvector 229
12.3 Adeno-associatedviralvectors 231
12.4 Homologousrecombinationandrepair 232
12.5 Indirectgenetherapiesfor(cid:1)thalassaemia 232
12.5.1 Correctionofabnormalsplicing 233
12.5.2 Activationofcompensatinggenes 233
12.5.3 Erythropoietingenetransfer 233
12.5.4 Reductionof(cid:2)globingeneexpression 234
12.5.5 Othertherapeuticgenes 235
12.6 Sicklecelldisease 236
12.7 Futureprospects 236
x CONTENTS
13 GeneTherapyApproachestoDuchenneMuscularDystrophy 243
StephenMurphyandGeorgeDickson
13.1 Introduction 243
13.2 Clinicalandpathologicalfeatures 243
13.3 Thedystrophingeneanditsproducts 244
13.4 Thelocalisationandfunctionofdystrophin 247
13.5 ModelsystemsofDMD 250
13.6 TherapeuticapproachestowardsthetreatmentofDMD 251
13.7 CelltherapyforDMD:myoblasttransfer 252
13.8 GenetherapiesforDMD 253
13.8.1 DirectDNAinjection 254
13.8.2 Retrovirusvectors 255
13.8.3 Adenovirusvectors 257
13.9 Alternativetherapeuticstrategies 259
13.10 Conclusions 260
14 LysosomalStorageDiseases 267
LindaS.Lashford,LeslieJ.FairbairnandJ.E.Wraith
14.1 Introduction 267
14.2 Definingthepatientpopulation 269
14.2.1 Therelationshipbetweengenotypeandphenotype 269
14.3 Standardand‘experimental’treatments 271
14.3.1 Supportivecare 271
14.3.2 Enzymereplacement 271
14.3.3 Bonemarrowtransplant 273
14.4 Tissuetargetsforgenetherapy 275
14.4.1 Transplantsof‘neo-organs’ 275
14.4.2 Manipulationofprimarylymphocytes 277
14.4.3 Autologousbonemarrow 278
14.4.4 DirecttargetingofCNS 281
14.5 Summary 284
15 ProspectsforGeneTherapyofHIVInfectionsandAIDS 291
CarolineG.L.Lee,MichaelM.GottesmanandKuan-TehJeang
15.1 Introduction 291
15.2 LifecycleofHIV 292
15.2.1 Receptors 293
15.2.2 Intracellularevents 296
15.3 Strategiesforantiviraltherapy 296
15.3.1 InterferencewithHIV-1replication 297
15.3.1.1 Interferingwithvirusentry 297
15.3.1.2 Interferingwithtranscription/translation
and/orvirusassembly 297
CONTENTS xi
15.3.2 Inductionofcelldeath 301
15.3.3 Immunizationandaugmentationofimmunefunction 302
15.4 Deliveryandselectionstrategiesforgeneticantiviral
intervention 303
16 TheDevelopmentoftheRegulatoryProcessinEuropefor
BiologicalMedicines:howitAffectsGeneTherapyProducts 319
AnthonyMeager,TobiasVockeandGerdZimmermann
16.1 RegulationofbiologicsinEurope 319
16.1.1 Historicalintroduction 319
16.1.2 Classificationandcharacteristicsofbiologics 322
16.1.3 Theemergenceofgeneticmedicines:arethey
biologics? 323
16.2 Guidanceformanufacturersandregulatoryprocedures
applyingtobiologicalmedicinesinEurope 325
16.3 Developmentsinqualityassuranceforbiologics:
applicationtogenetherapyproducts 330
16.4 Qualityassuranceissues 335
16.4.1 Stabilityoftheexpressionvector 335
16.4.2 Producercell-andvector-DNA 336
16.4.3 Themanufacturingprocess 336
16.4.3.1 Cellbankingsystem 337
16.4.3.2 Fermentation 337
16.4.3.3 Purification 338
16.4.4 Specificationsandqualitycontrol 339
16.4.4.1 Safetyandpurity 339
16.4.4.2 Biologicalactivity(potency) 340
16.4.4.3 Regulatoryaspects,standardisation,and
batchrelease 341
16.5 Safetyissues 342
17 DevelopmentandRegulationofGeneTherapyDrugsin
Germany 347
KlausCichutek
17.1 Introductoryremarks 347
17.2 Definition 348
17.3 Preclinicalresearchanddevelopment 350
17.4 Manufactureofdrugsandingredientsforclinicaluse 352
17.5 Clinicaltrialsofgenetherapydrugs 353
17.6 On-goingorplannedgenetherapytrialsinGermany 354
17.7 InvolvementofthePaul-Ehrlich-Institutingenetherapy 355