Ad5 for systemic vector delivery: studies on non-target interactions of Ad5 with non-cellular and cellular host blood components
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| 1. Verfasser: | |
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| Format: | Abschlussarbeit Buch |
| Sprache: | English |
| Veröffentlicht: |
Ulm
2016
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| Online-Zugang: | Inhaltsverzeichnis |
| Beschreibung: | 188 Blätter Illustrationen, Diagramme |
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| 100 | 1 | |a Krutzke, Lea |e Verfasser |0 (DE-588)1122116675 |4 aut | |
| 245 | 1 | 0 | |a Ad5 for systemic vector delivery |b studies on non-target interactions of Ad5 with non-cellular and cellular host blood components |c Lea Krutzke |
| 264 | 1 | |a Ulm |c 2016 | |
| 300 | |a 188 Blätter |b Illustrationen, Diagramme | ||
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| 337 | |b n |2 rdamedia | ||
| 338 | |b nc |2 rdacarrier | ||
| 502 | |b Dissertation |c Universität Ulm |d 2016 | ||
| 650 | 0 | 7 | |a Adenovirus 5 |0 (DE-588)4566151-0 |2 gnd |9 rswk-swf |
| 653 | |a Genetic therapy | ||
| 653 | |a Adenoviridae | ||
| 655 | 7 | |0 (DE-588)4113937-9 |a Hochschulschrift |2 gnd-content | |
| 689 | 0 | 0 | |a Adenovirus 5 |0 (DE-588)4566151-0 |D s |
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Datensatz im Suchindex
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|---|---|
| adam_text | ULM UNIVERSITY
UNIVERSITAET
SITAET
I
ULM
DEPARTMENT OF GENE THERAPY
PROF. DR. STEFAN KOCHANEK
ULM UNIVERSITY
AD5 FOR SYSTEMIC VECTOR DELIVERY
STUDIES ON NON-TARGET INTERACTIONS OF AD5 WITH
NON-CELLULAR AND CELLULAR HOST BLOOD COMPONENTS
DISSERTATION SUBMITTED IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR
THE DEGREE OF
*DOCTOR RERUM NATURALIUM* (DR. RER. NAT.)
OF THE INTERNATIONAL GRADUATE SCHOOL IN MOLECULAR MEDICINE ULM.
LEA KRUTZKE
HEILBRONN-NECKARGARTACH
2016
TABLE OF CONTENTS
1 A
BBREVIATIONS___________________________________________________________________
1
2
INTRODUCTION____________________________________________________________________
5
2.1 GENE THERAPY
_______________________________________________________________
5
2.1.1 VIROTHERAPY FOR CANCER TREATM
ENT____________________________________________________________6
2.2 ADENOVIRUSES FOR VIROTHERAPY
___________________________________________________
7
2.2.1
TAXONOMY________________________________________________________________________________
8
2.2.2 STRUCTURE_______________________________________ 8
2.2.3
GENOME_________________________________________________________________________________
10
2.2.4 LIFE C Y C LE
_______________________________________________________________________________
12
2.2.5 TURNING A VIRUS INTO A VECTOR
_
_______________________________________________________________ 13
2.3
BARRIERS___________________________________________________________________
15
2.3.1 CELLULAR INTERACTIONS O F A D 5
_______________________________________________________________ 15
2.3.2 NON-CELLULAR INTERACTIONS O F
AD5____________________________________________________________ 17
2.3.3 THE INTERPLAY O F CELLULAR AND NON-CELLULAR INTERACTIONS O F A D 5
__________________________________18
2.3.4 THE INNATE AND ADAPTIVE IMMUNE RESPONSE AGAINST A D
5________________________________________19
2.4 STRATEGIES TO OVERCOME
BARRIERS________________________________________________ 20
2.4.1
TARGETING________________________________________________________________________________
20
2.4.2
DETARGETING______________________________________________________________________________21
2.5 CONCEPT OF GENETI-CHEMICAL
MODIFICATION_________________________________________ 23
2.5.1 POSITION-SPECIFIC
PEGYLATION______________________________________________________________
25
2.6 AIMS OF THIS THESIS
___________________________________________________________ 27
3 M
ATERIAL_______________________________________________________________________
28
3.1 CHEMICALS AND
REAGENTS_______________________________________________________ 28
3.2
ANTIBIOTICS__________________________________________________________________
32
3.3
ENZYMES___________________________________________________________________
32
3.4
ANTIBODIES__________________________________________________________________
33
3.5 CELL CULTURE
CHEMICALS________________________________________________________ 33
3.6 PCR
PRIMERS________________________________________________________________
34
3.6.1 PRIMERS FOR HOMOLOGOUS
RECOMBINATION_____________________________________________________ 34
3.6.2 PRIMERS FOR QUANTITATIVE REAL TIME
PCR______________________________________________________ 36
3.7 BUFFERS AND
SOLUTIONS_________________________________________________________ 36
3.8 BACTERIAL
STRAINS_____________________________________________________________ 42
3.9 VIRUS VECTORS 42
3.10 ANIMALS 43
3.11 PLASMA
____________________________________________________________________
44
3.12 CELL LINES
__________________________________________________________________
44
3.13 PRIMARY CELLS
_______________________________________________________________
44
3.14 CONSUMABLES
_______________________________________________________________
44
3.15 K ITS
______________________________________________________________________
47
3.16 EQUIPMENT
________________________________________________________________
48
4 M
ETHODS______________________________________________________________________
51
4.1 NUCLEIC ACID METHODS
________________________________________________________
51
4.1.1 PRECIPITATION O F D N A
___________________________
51
4.1.2 DNA CONCENTRATION DETERMINATION BY OPTICAL DENSITY MEASUREMENT
_____________________________
51
4.1.3 POLYMERASE CHAIN REACTION
(PCR)___________________________________________________________52
4.1.4 RESTRICTION ENZYME DIGESTION O F D N A
______________________________________________________
55
4.1.5 RESTRICTION SITE BLIN D IN G
__________________________________________________________________
56
4.1.6 REMOVAL O F 5* PHOSPHATE GROUPS (*CIPING*)
________________________________________________
56
4.1.7 DNA FRAGMENT
LIGATION____________________________________________________________________57
4.1.8 AGAROSE GEL EXTRACTION AND PHENOL/CHLOROFORM PURIFICATION
____________________________________
57
4.1.9 QUANTITATIVE REAL TIME POLYMERASE CHAIN REACTION (QPC R
)_____________________________________ 58
4.1.10 DNA ISOLATION FROM C E L L S
________________________________________________________________
58
4.1.11 VIRUS VECTOR DNA ISO LA TIO N
______________________________________________________________ 59
4.2 BACTERIA-BASED METHODS
_______________________________________________________
59
4.2.1 TRANSFORMATION O F BACTERIA
________________________________________________________________
59
4.2.2 PLASMID PREPARATION
______________________________________________________________________
59
4.2.3 BACMID PREPARATION (SM ALL-SCALE)
__________________________________________________________
60
4.2.4 BACMID PREPARATION (LARGE-SCALE)
__________________________________________________________
60
4.2.5 HOMOLOGOUS
RECOMBINATION_______________________________________________________________
61
4.2.6
CLONING_________________________________________________________________________________
65
4.2.7 SEQUENCING
____________________________________________________________________________
65
4.3 PROTEIN
METHODS_____________________________________________________________ 66
4.3.1
SDS-PAGE______________________________________________________________________________66
4.3.2 VISUALIZATION O F PROTEINS BY SILVER STAINING AFTER
SDS-PAGE___________________________________66
4.3.3 ELISA FOR THE DETECTION O F COMPLEMENT PROTEIN C
3B__________________________________________66
4.3.4 ELISA TO DETERMINE THE IL-6 CONCENTRATION IN MURINE
BLOOD___________________________________67
4.4 ADENOVIRUS VECTOR METHODS
________________________________________________
67
4.4.1 ADENOVIRUS VECTOR
AMPLIFICATION____________________________________________________________67
4.4.2 ADENOVIRUS VECTOR
PURIFICATION_____________________________________________________________
68
4.4.3 PEGYLATION O F VECTOR
PARTICLES_____________________________________________________________
69
4.4.4 TOTAL VECTOR PARTICLE TITRATION BY OPTICAL DENSITY
MEASUREMENT__________________________________ 70
4.4.5 TOTAL VECTOR PARTICLE TITRATION BY SLOT BLOT
ANALYSIS____________________________________________ 70
4.4.6 ALEXA488-LABELING O F AD5
_________________________________________________________________
71
4.4.7 SURFACE PLASMON RESONANCE ANALYSIS
________________________________________________________
72
4.4.8 ZETASIZER
MEASUREMENT____________________________________________________________________73
4.4.9 PARTICLE SIZE MEASUREMENTS
________________________________________________________________
73
4.5 CELL CULTURE METHODS
________________________________________________________
74
4.5.1 CELL
LINES________________________________________________________________________________
74
4.5.2 PEI-TRANSFECTION O F N52.E6
CELLS____________________________________________________________ 75
4.5.3 CELL
COUNTING_____________________________________________________________________________75
4.5.4 CELL TRANSDUCTION BY AD5
_________________________________________________________________
76
4.5.5 NEUTRALIZATION O F A D 5
_____________________________________________________________________ 76
4.5.6 FLOW CYTOMETRY
__________________________________________________________________________
77
4.5.7 ANALYSIS O F AD5-BINDING TO HUMAN ERYTHROCYTES
_____________________________________________
77
4.5.8 BLOOD COAGULATION FACTOR-MEDIATED CELL
TRANSDUCTION__________________________________________78
4.5.9 ISOLATION AND DIFFERENTIATION O F HUMAN PRIMARY MACROPHAGES
__________________________________ 78
4.5.10 UPTAKE O F AD5 BY
MACROPHAGES__________________________________________________________ 79
4.5.11 SEPARATION O F HUMAN BLOOD CELLS
__________________________________________________________
79
4.5.12 ISOLATION O F HUMAN LEUKOCYTES
___________________________________________________________
80
4.5.13 HUMAN LEUKOCYTE STAINING
________________________________________________________________
81
4.5.14 ANALYSIS O F AD5-BINDING TO HUMAN
LEUKOCYTES______________________________________________81
4.5.15 ANALYSIS O F AD5-BINDING TO HUMAN
PLATELETS________________________________________________ 81
4.5.16 HUMAN PLATELET ACTIVATION BY
AD5_________________________________________________________ 82
4.6
IN VIVO
EXPERIMENTS__________________________________________________________ 82
4.6.1 AD5 PHARMACOKINETICS IN MURINE B LO O D
_____________________________________________________ 82
4.6.2 FLUOROMETRIC ANALYSIS O F MURINE LIVER HOMOGENATES
__________________________________________
83
4.6.3 FLUORESCENCE MICROSCOPY O F MURINE LIVER AND SPLEEN
SECTIONS__________________________________ 84
4.7
STATISTICS___________________________________________________________________
84
5
RESULTS_______________________________________________________________________
85
5.1 GENETICALLY MODIFIED AD5 PARTICLES GREW TO NORMAL
TITERS___________________________ 85
5.2 VECTOR INFECTIVITY WAS MAINTAINED AFTER INTRODUCTION OF CYSTEINE
RESIDUE AND AFX MUTATION
88
5.3 CYSTEINE-BEARING HEXON PROTEINS WERE NEAR-QUANTITATIVELY
PEGYLATED________________88
5.4 PEGYLATION WITH SMALL PEG MOIETIES DID NOT INTERFERE WITH VECTOR
INFECTIVITY
_________
90
5.5 POSITION-SPECIFIC PEGYLATION INCREASED THE HYDRODYNAMIC DIAMETER OF
VECTOR PARTICLES _ 91
5.6 POSITION-SPECIFIC PEGYLATION REDUCED THE NEGATIVE SURFACE CHARGE OF
VECTOR PARTICLES
___
91
5.7 POSITION-SPECIFIC PEGYLATION ABROGATED BINDING TO FX IN COMBINATION
WITH AFX MUTATION
________________________________
93
5.8 POSITION-SPECIFIC PEGYLATION ABROGATED FX-MEDIATED ENHANCEMENT OF
CELL TRANSDUCTION IN
VITRO IN COMBINATION WITH AFX MUTATION
____________________________________________
95
5.9 PEGYLATED VECTORS EXHIBITED FX-INDEPENDENT HEPATOCYTE TRANSDUCTION
IN V IV O
_________
98
5.10 SUBSTANTIAL HEPATOCYTE TRANSDUCTION BY AFX VECTOR PARTICLES IN
ANTIBODY-DEFICIENT J
H
D
MICE_____________________________________________________________ 101
5.11 FX SHIELDED VECTOR PARTICLES FROM COMPLEMENT-DEPENDENT
NEUTRALIZATION BY MURINE
NATURAL ANTIBODIES
____________________________________________________________
102
5.12 PEGYLATION SUBSTITUTED THE FX SHIELD AND PREVENTED NEUTRALIZATION
OF AFX PARTICLES IN
AD-NAI VE MURINE PLASMA
_______________________________________________________
104
5.13 PEGYLATION OF HVR1 SUBSTITUTED FX AND REDUCED OPSONIZATION OF
VECTOR PARTICLES BY
COMPLEMENT__________________________________________________________________
105
5.14 PEGYLATED AFX VECTOR PARTICLES EXHIBITED IMPROVED PHARMACOKINETICS
IN MURINE BLOOD
107
5.15 POSITION-SPECIFIC PEGYLATION DID NOT INCREASE VECTOR TOXICITY
_____________________
109
5.16 INCREASED COMPLEMENT- AND ANTIBODY-DEPENDENT UPTAKE OF AFX VECTORS
BY MURINE
MACROPHAGES IN VITRO
__________________________________________________________
110
5.17 POSITION-SPECIFIC PEGYLATION PREVENTED PLASMA-DEPENDENT UPTAKE OF
AFX VECTORS BY
MURINE MACROPHAGES IN VITRO
____________________________________________________
112
5.18 POSITION-SPECIFIC PEGYLATION INHIBITED SCAVENGER RECEPTOR-MEDIATED
UPTAKE OF AD5 BY
MACROPHAGES IN VITRO
__________________________________________________________
113
5.19 POSITION-SPECIFIC PEGYLATION INTERFERED WITH FIX-MEDIATED CELL
TRANSDUCTION
_______
114
5.20 FX SHIELDED FROM COMPLEMENT-DEPENDENT NEUTRALIZATION OF PARTICLES
IN AD-NAI VE HUMAN
PLASMA
______________________________________________________________________
115
5.21 FX SHIELDED VECTOR PARTICLES FROM UPTAKE BY HUMAN PRIMARY
MACROPHAGES IN AD-NAIVE
PLASMA______________________________________________________________________
117
5.22 PEGYLATION DID NOT PREVENT PLASMA-DEPENDENT UPTAKE OF AFX VECTORS
BY HUMAN PRIMARY
MACROPHAGES_________________________________________________________________
118
5.23 AD5 VECTOR PARTICLES ATTACHED TO HUMAN ERYTHROCYTES
__________________________
120
5.24 AD5 VECTOR PARTICLES NEITHER BOUND TO HUMAN LEUKOCYTES NOR HUMAN
PLATELETS IN VITRO 121
5.25 AD5 VECTOR PARTICLES DID NOT ACTIVATE HUMAN PLATELETS IN VITRO
_____________________
123
5.26 INHIBITION OF FX-BINDING INCREASED COMPLEMENT-DEPENDENT BINDING OF
VECTOR PARTICLES TO
HUMAN ERYTHROCYTES
___________________________________________________________
125
5.27 PEGYLATION OF HVR1 ONLY PARTIALLY PREVENTED BINDING OF AD5
PARTICLES TO HUMAN
ERYTHROCYTES_________________________________________________________________
127
5.28 PEGYLATION OF HVR1 PARTIALLY SHIELDED VECTOR PARTICLES FROM
NEUTRALIZATION BY HUMAN
UAD I G G
____________________________________________________________________
129
5.29 PEGYLATION OF HVR1 PARTIALLY PREVENTED NEUTRALIZATION OF AFX VECTOR
PARTICLES IN AD-
NAI VE HUMAN PLASMA
__________________________________________________________
130
6
DISCUSSION____________________________________________________________________
132
6.1 GENETI-CHEMICAL MODIFICATION AS A PROPOSAL FOR SOLUTION OF AD5
VECTOR SEQUESTRATION
__
132
6.2 CHARACTERIZATION OF GENETI-CHEMICALLY MODIFIED VECTOR PARTICLES
___________________
133
6.3 SUBSTITUTION OF THE MURINE FX SHIELD BY POSITION-SPECIFIC PEGYLATION
_______________
135
6.4 PEGYLATION PREVENTED UPTAKE OF AD5 PARTICLES BY MURINE MACROPHAGES
____________
140
6.5 POSITION-SPECIFIC PEGYLATION SIGNIFICANTLY IMPROVED VECTOR
PHARMACOKINETICS
________
144
6.6 FX*S SHIELDING FUNCTION CONFIRMED FOR THE HUMAN SYSTEM
_________________________
146
6.7 INSUFFICIENT SUBSTITUTION OF THE FX SHIELD IN HUMAN BLOOD BY
PEGYLATION OF HVR1
____
148
6.8 PEGYLATION OF HVR1 ONLY PARTIALLY SHIELDED AD5 FROM IGG-ANTIBODIES
_____________
150
6.9 INTERACTION OF AD5 VECTOR PARTICLES WITH HUMAN BLOOD CELLS
_______________________
151
6.10 FROM MICE TO M EN
________________________________________________________
154
6.11 PROSPECTS ON USING HVR1-PEGYLATED AD5 PARTICLES AS GENE THERAPEUTIC
VECTORS
_____
155
6.12 PROSPECTS ON USING POSITION-SPECIFIC POLYMER-SHIELDED AD5 VECTORS
IN RESEARCH
______
157
7
SUMMARY_____________________________________________________________________
160
8
BIBLIOGRAPHY__________________________________________________________________161
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| institution | BVB |
| language | English |
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| spelling | Krutzke, Lea Verfasser (DE-588)1122116675 aut Ad5 for systemic vector delivery studies on non-target interactions of Ad5 with non-cellular and cellular host blood components Lea Krutzke Ulm 2016 188 Blätter Illustrationen, Diagramme txt rdacontent n rdamedia nc rdacarrier Dissertation Universität Ulm 2016 Adenovirus 5 (DE-588)4566151-0 gnd rswk-swf Genetic therapy Adenoviridae (DE-588)4113937-9 Hochschulschrift gnd-content Adenovirus 5 (DE-588)4566151-0 s DE-604 DNB Datenaustausch application/pdf http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=029643589&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA Inhaltsverzeichnis |
| spellingShingle | Krutzke, Lea Ad5 for systemic vector delivery studies on non-target interactions of Ad5 with non-cellular and cellular host blood components Adenovirus 5 (DE-588)4566151-0 gnd |
| subject_GND | (DE-588)4566151-0 (DE-588)4113937-9 |
| title | Ad5 for systemic vector delivery studies on non-target interactions of Ad5 with non-cellular and cellular host blood components |
| title_auth | Ad5 for systemic vector delivery studies on non-target interactions of Ad5 with non-cellular and cellular host blood components |
| title_exact_search | Ad5 for systemic vector delivery studies on non-target interactions of Ad5 with non-cellular and cellular host blood components |
| title_full | Ad5 for systemic vector delivery studies on non-target interactions of Ad5 with non-cellular and cellular host blood components Lea Krutzke |
| title_fullStr | Ad5 for systemic vector delivery studies on non-target interactions of Ad5 with non-cellular and cellular host blood components Lea Krutzke |
| title_full_unstemmed | Ad5 for systemic vector delivery studies on non-target interactions of Ad5 with non-cellular and cellular host blood components Lea Krutzke |
| title_short | Ad5 for systemic vector delivery |
| title_sort | ad5 for systemic vector delivery studies on non target interactions of ad5 with non cellular and cellular host blood components |
| title_sub | studies on non-target interactions of Ad5 with non-cellular and cellular host blood components |
| topic | Adenovirus 5 (DE-588)4566151-0 gnd |
| topic_facet | Adenovirus 5 Hochschulschrift |
| url | http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&local_base=BVB01&doc_number=029643589&sequence=000001&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA |
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