Учебники / Gene Therapy of Cochlear Deafness - Present Concepts and Future Aspects Ryan 2009

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Ryan · Mullen · Doherty

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64Taura A, Taura K, Choung YH, Masuda M, Pak K, Chavez E, Ryan AF: Histone deacetylase inhibition enhances adenoviral vector transduction in inner ear tissue. Submitted, 2009.

Adeno-associated virus (AAV) vectors advantages and limitations 29, 68 cellular tropism 68, 71, 95 endolymphatic system gene delivery 28 genome engineering 90, 91

inner ear targets 69, 93

perilymphatic system gene delivery 21, 27 purification 90

replication 69 serotypes 91

small interfering RNA delivery 31 transduction efficiency

overview 90 promoters 91, 93–96

Adenovirus vectors

advantages and limitations 29, 68 animal studies 40

cellular tropism 68, 71

delivery to inner ear 40–42, 54, 55 endolymphatic system gene delivery 28 gene transduction characteristics in inner

ear 39–42

genome modifications 39, 54, 69

hair cell regeneration gene therapy 45–47, 75

inner ear targets 69, 70

perilymphatic system gene delivery 27 protection of hair cells and neurons with

gene therapy 42–45, 75 receptor 41

small interfering RNA delivery 31 toxicity 88, 95

transduction efficiency cytomegalovirus promoter 88, 89 overview 87, 88

viral load 88, 90 vestibular regeneration

animal models 53 atoh1 gene therapy

delivery to aminoglycoside-treated macular organ cultures 56, 57

inner ear delivery efficiency 58–61

prospects 60 rationale 53, 54

balance disorder epidemiology 52 gene delivery to damaged macular

neuroepithelium, efficiency 55, 56 vestibular-ocular reflex and hair cell

loss 53

Antisense oligonucleotide (ASO) development 15, 16

principles of gene knockdown 15

Atoh1

adenovirus vector-mediated gene therapy overview 46, 47

vestibular regeneration

delivery to aminoglycoside-treated macular organ cultures 56, 57 inner ear delivery efficiency 58–61

prospects 60 rationale 53, 54

gene therapy and hair cell regeneration 10 regulatory elements 107

Balance disorders, see Vestibular regeneration Brain lipid-binding protein promoter, adeno-

associated virus vectors 94 Brain-derived neurotrophic factor (BDNF)

adenovirus vector-mediated gene therapy for protection of hair cells and neurons 43

spiral ganglion cell survival gene therapy 74

CAG promoter, adeno-associated virus vectors 92, 93

CDH23, gene therapy targeting 76 Challenges, gene therapy 7, 8 Ciliary-derived neurotrophic factor (CDNF),

adenovirus vector-mediated gene therapy for protection of hair cells and neurons 44

Cochleostomy, adenovirus vector delivery 40, 41

Cytomegalovirus promoter adeno-associated virus vectors 91, 93, 95 adenovirus vectors 88, 89

Deafness

etiology 64, 65

gene mutations 1, 9, 10 gene therapy targets 76, 77

Decoy oligodeoxynucleotides, gene

knockdown 15–17

DFNA5, mutations in deafness 14 DFNB1, gene therapy targeting 77 Distortion product otoacustic emission

(DPOAE), adenovirus vector toxicity 88, 89

DNA methylation, gene expression regulation 100, 101

Dominant negative mutation overview 3

phenotypes and deafness 14

Endolymphatic system, gene delivery 28 Enhancer, gene expression regulation 101,

102

Ethics, gene therapy 8, 9

Gene delivery, inner ear, see also Adenovirus vectors

advantages and limitations of approaches 28, 29, 66, 67

animal models 24–27 endolymphatic system 28 perilymphatic system

direct approaches 21, 27 indirect approaches 27

principles 65, 66 rationale 37, 38

route of delivery 38, 39

Gene regulatory elements, see Regulatory elements

Gene repair, strategy 6

Gene replacement, principles 6

Gene silencing approaches 15–21

dominant disorder management 6 GJB2

gene therapy targeting 77 mutations in deafness 9, 14 RNA interference 80

GLAST promoter, adeno-associated virus vectors 95

Glial fibrillary acid protein (GFAP), adenoassociated virus vectors 93, 94

Glial-derived neurotrophic factor (GDNF) adenovirus vector-mediated gene therapy

for protection of hair cells and neurons 43, 44

spiral ganglion cell survival gene therapy 74, 75

Hair cell

adenovirus vector-mediated gene therapy protection 42–45, 74

regeneration 10, 45–47, 75 Atoh1 gene therapy for vestibular

regeneration

delivery to aminoglycoside-treated macular organ cultures 56, 57 inner ear delivery efficiency 58–61

prospects 60 rationale 53, 54

gene regulatory elements 106–109 iron chelator protection 75 permanent loss in mammals 65

Hammerhead ribozyme, gene knockdown 17, 18

Hearing loss, see Deafness

Herpes simplex virus (HSV) vectors advantages and limitations 68 cellular tropism 68, 71, 72 engineering 71

inner ear targets 72, 73

Iron chelators, hair cell protection 75

KCNE1, gene therapy targeting 76, 77

KCNQ1, gene therapy targeting 76, 77 KCNQ4, mutations in deafness 14

Lentivirus vectors

advantages and limitations 68 cellular tropism 68, 72, 73 inner ear targets 73

Liposome vectors

advantages and limitations 68 cellular tropism 68 mechanisms 73, 74

Loss-of-function mutation definition 3

gene therapy 4

Math1, see Atoh1

MicroRNA, gene expression regulation 101 MYO6, gene therapy targeting 76

MYO7A

gene regulatory elements 106 gene therapy targeting 76

MYO15, gene therapy targeting 76

PCDH15, gene therapy targeting 76 Perilymphatic system, gene delivery

direct approaches 21, 27 indirect approaches 27 Polygenic disorders, heredity 4

Regulatory elements

gene expression regulation 101, 102 identification 104

inner ear gene therapy ganglion neurons 109, 110 hair cells 106–109 limitations 111

miscellaneous promoters 110, 111 overview 104–106

prospects for study 111, 112 spiral ligament 110

stria vascularis 110 supporting cells 109

Repressor, gene expression regulation 101, 102 RNA interference

disease models for gene therapy 22, 23 GJB2 80

mechanism 19–21

small interfering RNA 18, 19 vectors

expression vectors 30 liposomes 30

viral vectors 31

Round window membrane (RWM), gene delivery 21, 29

SANS, gene therapy targeting 76

Severe combined immunodeficiency disease (SCID), gene therapy 2, 6

Small interfering RNA, see RNA interference Spiral ganglion cell (SGC)

gene regulatory elements 109, 110 gene therapy for survival 74, 75

Spiral ligament, gene regulatory elements 110 Stem cell transplantation

adult cells 79

embryonic or neonatal cells 78, 79 inner ear delivery 79, 80 rationale 77, 78

Stria vascularis, gene regulatory elements 110

Transcription factors, gene expression regulation 101–103

Transforming growth factor-β (TGF-β), adenovirus vector-mediated gene therapy for protection of hair cells and neurons 43

Usher’s syndrome, gene therapy targets 77 USH1C, gene therapy targeting 76

Vaccinia virus, gene therapy vectors 73 Vestibular regeneration

adenovirus-mediated gene therapy atoh1 gene therapy

delivery to aminoglycoside-treated macular organ cultures 56, 57 inner ear delivery efficiency 58–61

prospects 60 rationale 53, 54

animal models 53

balance disorder epidemiology 52 gene delivery to damaged macular neuroepithelium, efficiency

55, 56

vestibular-ocular reflex and hair cell loss 53