Reportlinker Adds Gene Therapy - Technologies, Markets and Companies
NEW YORK, Oct. 5 /PRNewswire/ -- Reportlinker.com announces that a new market research report is available in its catalogue:
Gene Therapy - technologies, markets and companies
http://www.reportlinker.com/p0203543/Gene-Therapy---technologies-markets-and-companies.html
Benefits of this report
* Up-to-date on-stop information on gene therapy with 72 tables and 13 figures
* Evaluation of gene therapy technologies
* 700 selected references from the literature
* Estimates of gene therapy markets from 2009-2019
* Profiles of 189 companies involved and collaborations in this area
Who should read this report?
* Biotechnology companies developing gene therapy
* Academic institutions doing research in gene therapy
* Drug delivery companies
* Pharmaceutical companies interested in gene therapy
* Gene therapy companies
* Venture capital and investment companies
Summary
Gene therapy can be broadly defined as the transfer of defined genetic material to specific target cells of a patient for the ultimate purpose of preventing or altering a particular disease state. Genes and DNA are now being introduced without the use of vectors and various techniques are being used to modify the function of genes in vivo without gene transfer. If one adds to this the cell therapy particularly with use of genetically modified cells, the scope of gene therapy becomes much broader. Gene therapy can now combined with antisense techniques such as RNA interference (RNAi), further increasing the therapeutic applications. This report takes broad overview of gene therapy and is the most up-to-date presentation from the author on this topic built-up from a series of gene therapy report written by him during the past decade including a textbook of gene therapy and a book on gene therapy companies. This report describes the setbacks of gene therapy and renewed interest in the topic
Gene therapy technologies are described in detail including viral vectors, nonviral vectors and cell therapy with genetically modified vectors. Gene therapy is an excellent method of drug delivery and various routes of administration as well as targeted gene therapy are described. There is an introduction to technologies for gene suppression as well as molecular diagnostics to detect and monitor gene expression.
Clinical applications of gene therapy are extensive and cover most systems and their disorders. Full chapters are devoted to genetic syndromes, cancer, cardiovascular diseases, neurological disorders and viral infections with emphasis on AIDS. Applications of gene therapy in veterinary medicine, particularly for treating cats and dogs, are included.
Research and development is in progress in both the academic and the industrial sectors. The National Institutes of Health (NIH) of the US is playing an important part. As of January 2010, over 2024 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide. A breakdown of these trials is shown according to the areas of application.
Since the death of Jesse Gelsinger in the US following a gene therapy treatment, the FDA has further tightened the regulatory control on gene therapy. A further setback was the reports of leukemia following use of retroviral vectors in successful gene therapy for adenosine deaminase deficiency. Several clinical trials were put on hold and many have resumed now. The report also discusses the adverse effects of various vectors, safety regulations and ethical aspects of gene therapy including germline gene therapy.
The markets for gene therapy are difficult to estimate as there is only one approved gene therapy product and it is marketed in China since 2004. Gene therapy markets are estimated for the years 2009-2019. The estimates are based on epidemiology of diseases to be treated with gene therapy, the portion of those who will be eligible for these treatments, competing technologies and the technical developments anticipated in the next decades. In spite of some setbacks, the future for gene therapy is bright. The markets for DNA vaccines are calculated separately as only genetically modified vaccines and those using viral vectors are included in the gene therapy markets
The voluminous literature on gene therapy was reviewed and selected 700 references are appended in the bibliography. The references are constantly updated. The text is supplemented with 72 tables and 13 figures.
Profiles of 189 companies involved in developing gene therapy are presented along with 210 collaborations. There were only 44 companies involved in this area in 1995. In spite of some failures and mergers, the number of companies has increased more than 4-fold within a decade. These companies have been followed up since they were the topic of a book on gene therapy companies by the author of this report. John Wiley & Sons published the book in 2000 and from 2001 to 2003, updated versions of these companies (approximately 160 at mid-2003) were available on Wiley's web site. Since that free service was discontinued and the rights reverted to the author, this report remains the only authorized continuously updated version on gene therapy companies.
TABLE OF CONTENTS
0. Executive Summary 20
1. Introduction . 22
Definitions . 22
Historical evolution of gene therapy 22
Relation of gene therapy to other biotechnologies. 24
Molecular biological basics for gene therapy . 24
Genome 24
DNA . 25
RNA . 25
Alternative RNA splicing . 26
Genes . 27
Gene regulation . 27
Gene expression 29
Chromosomes . 29
Telomeres . 30
Mitochondrial DNA . 30
Proteins 31
2. Gene Therapy Technologies 32
Classification of gene therapy techniques 32
Ex vivo and in vivo gene therapy . 33
Ex vivo gene therapy 33
In vivo gene therapy 34
Physical methods of gene transfer . 34
Electroporation 34
Applications of electroporation . 35
Clinical applications of electroporation . 36
Advantages of electroporation 36
Limitations of electroporation . 37
Hydrodynamic . 37
Microinjection 37
Particle bombardment 38
Ultrasound-mediated transfection 40
Molecular vibration . 41
Application of pulsed magnetic field and superparamagnetic nanoparticles 41
Gene transfection using laser irradiation . 41
Photochemical transfection 42
Chemical methods of gene transfer . 42
Gene repair and replacement . 42
Gene repair by single-stranded oligonucleotides. 43
History and current status of chimeraplasty 43
mRNA gene therapy . 43
Spliceosome mediated RNA trans-splicing . 44
Vectors for gene therapy . 45
Basic considerations . 45
Use of genes as pharmaceuticals . 45
The ideal vector for gene therapy . 46
Viral vectors 46
Adenovirus vectors 47
Adeno-associated virus vectors . 49
Alphavirus vectors. 51
Baculovirus vectors . 51
Foamy virus vectors 52
Herpes simplex virus vectors 52
Lentiviral vectors 54
Multicistronic retroviral vectors . 55
Retroviral vectors 56
Oncogenic potential of retroviral vectors 57
Future prospects of viral vectors . 58
Companies using viral vectors 58
Nonviral vectors for gene therapy 60
Anionic lipid-DNA complexes 60
Cationic lipid-DNA complexes . 61
Effects of shape of DNA molecules on delivery with nonviral vectors 61
Electrostatic modifications of surface to improve gene delivery . 61
Liposomes for gene therapy . 62 - 4 -
Liposome-nucleic acid complexes 63
Liposome-HVJ complex 64
Transposons DNA vectors. 64
Polycation-DNA complexes (polyplexes) . 65
Plasmid DNA vector for treatment of chronic inflammatory disease . 66
Polymer molecules 66
Synthetic peptide complexes 66
Future prospects of nonviral vs viral vectors . 66
Nanobiotechnology for gene transfer 67
Nanoparticles as nonviral vectors for gene therapy 67
Dendrimers 67
Cochleates . 68
Calcium phosphate nanoparticles as non-viral vectors . 68
Lipid nanoparticles for nucleic acid delivery 69
Silica nanoparticles as a nonviral vector for gene delivery 69
Gelatin nanoparticles for gene delivery 70
Nonionic polymeric micelles for oral gene delivery . 70
Biological nanoparticle technology . 70
Nanoparticles with virus-like function as gene therapy vectors 70
Receptor-mediated endocytosis . 71
Artificial viral vectors 72
Directed evolution of AAV to create efficient gene delivery vectors . 72
Bacterial ghosts as DNA delivery systems . 73
Bacteria plus nanoparticles for gene delivery into cells 73
Chromosome-based vectors for gene therapy 74
Companies using nonviral vectors 75
Concluding remarks about vectors . 76
Cell-mediated gene therapy . 77
Fibroblasts 78
Skeletal muscle cells 79
Vascular smooth muscle cells 79
Keratinocytes 79
Hepatocytes 80
Lymphocytes . 80
Regulating protein delivery by genetically encoded lymphocytes . 80
Implantation of microencapulated genetically modified cells 80
Stem cell gene therapy . 81
Therapeutic applications for hematopoietic stem cell gene transfer 82
Improving delivery of genes to stem cells 82
Lentiviral vectors for gene transfer to marrow stem cells . 82
Use of mesenchymal stem cells for gene therapy 82
Microporation for transfection of MSCs . 82
In utero gene therapy using stem cells 83
Gene delivery to stem cells by artificial chromosome expression . 83
Linker based sperm-mediated gene transfer technology . 83
Combination of gene therapy with therapeutic cloning . 84
Expansion of transduced HSCs in vivo . 84
The future of hematopoietic stem cell gene therapy 84
Routes of administration for gene therapy 84
Direct injection of naked DNA 85
Intramuscular injection . 85
Intravenous DNA injection 86
Intraarterial delivery 86
Companies with gene delivery devices/ technologies 86
Targeted gene therapy . 87
Targeted integration . 88
Bacteriophage integrase system for site-specific gene delivery 88
Controlled-release delivery of DNA . 88
Controlled gene therapy 89
Controlled delivery of genetic material 89
Controlled induction of gene expression 89
Drug-inducible systems for control of gene expression 90
Timed activation of gene therapy by a circuit based on signaling network 90
Small molecules for post-transcriptional regulation of gene expression . 91
Engineered zinc finger DNA binding proteins for gene correction 91
Light Activated Gene Therapy 91
Spatial control of gene expression via local hyperthermia 92
Companies with regulated /targeted gene therapy . 92
Gene marking 93
Germline gene therapy 93
Potential applications of human germline genome modification 94 - 5 -
Pros and cons of human germline genome modification 94
Role of gene transfer in antibody therapy 95
Genetically engineered vaccines 96
DNA vaccines 96
DNA inoculation technology 96
Methods for enhancing the potency of DNA vaccines . 97
Advantages of DNA vaccines 97
Vaccine vectors . 98
Challenges and limitations of genetically engineered vaccines 99
Vaccines based on reverse genetics 99
Technologies for gene suppression 99
Antisense oligonucleotides 100
Transcription factor decoys . 100
Aptamers 101
Ribozymes 101
Peptide nucleic acid 101
Intracellular delivery of PNAs 102
Locked nucleic acid 102
Zorro-LNA 102
Gene silencing . 103
Post-transcriptional gene silencing . 103
Definitions and terminology of RNAi . 103
RNAi mechanisms 103
Inhibition of gene expression by antigene RNA 104
RNAi gene therapy . 105
Application of molecular diagnostic methods in gene therapy . 105
Use of PCR to study biodistribution of gene therapy vector 106
PCR for verification of the transcription of DNA 106
In situ PCR for direct quantification of gene transfer into cells . 106
Detection of retroviruses by reverse transcriptase (RT)-PCR 106
Confirmation of viral vector integration . 106
Monitoring of gene expression . 107
Monitoring of gene expression by green fluorescent protein 107
Monitoring in vivo gene expression by molecular imaging . 107
Advantages of gene therapy compared with protein therapy . 108
3. Clinical Applications of Gene Therapy . 110
Introduction 110
Bone and joint disorders 110
Bone fractures . 110
Gene therapy for intervertebral disc degeneration 111
Spinal fusion . 111
Osteogenesis imperfecta . 112
Rheumatoid arthritis . 112
Local or systemic treatment . 113
In vivo or ex vivo gene therapy of RA 113
Clinical trials. 114
Gene therapy for osteoarthritis 115
Sports injuries . 116
Repair of articular cartilage defects . 116
Regeneration and replacement of bone by gene therapy . 117
Bacterial infections 118
Antisense approach to bacterial infections . 118
Dentistry 118
Tissue engineering in dental implant defects . 118
Endocrine and metabolic disorders 119
Introduction 119
Gene therapy of obesity 119
Ad viral vector-mediated transfer of leptin gene 119
AAV vector-mediated delivery of GDNF for obesity 120
Diabetes mellitus . 120
Methods of gene therapy of diabetes mellitus 120
Viral vector-mediated gene transfer in diabetes 121
Gene delivery with ultrasonic microbubble destruction technology . 122
Genetically engineered cells for diabetes mellitus 122
Genetically altered liver cells 122
Genetically modified stem cells . 123
Genetically engineered dendritic cells 123
Insertion of gene encoding for IL-4 . 123
Leptin gene therapy 124
Concluding remarks about cell and gene therapy of diabetes 124 - 6 -
Gene therapy of growth-hormone deficiency . 124
Gastrointestinal disorders 125
Introduction 125
Methods of gene transfer to the gastrointestinal tract . 126
Direct delivery of genes . 126
Naked plasmid DNA into the submucosa 126
Viral vectors . 126
Receptor-mediated endocytosis 126
Indications for gastrointestinal gene therapy . 127
Gene therapy for inflammatory disorders of the bowel . 127
Gene transfer to the salivary glands . 128
Potential clinical applications of salivary gene therapy . 128
Hematology . 129
Hemophilias 129
Gene therapy of hemophilia . 130
Hemophilia A 130
Hemophilia B 131
Concluding remarks about gene therapy of hemophilias . 132
Hemoglobinopathies . 132
Stem cell-based gene therapy and RNAi for sickle cell disease 132
Gene therapy for ?-thalassemia 133
Gene therapy of Fanconi's anemia . 134
Acquired hematopoietic disorders . 135
Chronic acquired anemias 135
Neutropenia . 136
Thrombocytopenia 136
Concluding remarks about gene therapy of hemoglobinopathies 137
Companies involved in gene theory of hematological disorders 138
In utero gene therapy 138
Fetal gene transfer techniques . 138
Animal models of fetal gene therapy 139
Potential applications of fetal gene therapy . 139
Fetal gene therapy for cystic fibrosis . 140
Fetal intestinal gene therapy 140
Hearing disorders 140
Potential of gene therapy 141
Vectors for gene therapy of hearing disorders 141
Auditory hair cell replacement and hearing improvement by gene therapy 142
Kidney diseases . 142
End-stage renal disease 142
Methods of gene delivery to the kidney . 143
Gene transfer into kidney by adenoviral vectors 143
Non-viral gene transfer to the kidneys . 143
Gene transfer into the glomerulus by HVJ-liposome . 144
Bone marrow stem cells for renal disease 144
Mesangial cell therapy . 144
Liposome-mediated gene transfer into the tubules 145
Gene transfer to tubules with cationic polymer polyethylenimine . 145
Gene therapy in animal experimental models of renal disease . 145
Genetic manipulations of the embryonic kidney . 146
Antisense intervention in glomerulonephritis . 146
Gene therapy for renal fibrosis 146
Use of genetically engineered cells for uremia due to renal failure 147
Concluding remarks . 147
Liver disorders . 147
Techniques of gene delivery to liver . 148
Direct injection of DNA into liver . 148
Local gene delivery by isolated organ perfusion 149
Liposome-mediated direct gene transfer 149
Retroviral vector for gene transfer to liver 149
Adenoviral vectors for gene transfer to liver . 149
Receptor-mediated approach 150
Cell therapy for liver disorders . 150
Transplantation of genetically modified hepatocytes 150
Genetically modified hematopoietic stem cells 151
Gene therapy by ex vivo transduced liver progenitor cells 151
Gene therapy of genetic diseases affecting the liver . 151
Crigler-Najjar syndrome 151
Hereditary tyrosinemia type I (HT1) 152
Hereditary tyrosinemia type 3 152
Gene therapy of acquired diseases affecting the liver . 152 - 7 -
Cirrhosis of liver . 152
Ophthalmic disorders . 153
Introduction to gene therapy of ophthalmic disorders . 153
Degenerative retinal disorders . 154
Age-related macular degeneration. 154
Inherited retinal degenerations . 155
Inherited disorders affecting vision . 156
Gene therapy for color blindness . 156
Leber congenital amaurosis 156
Retinitis pigmentosa 157
Stargardt disease 158
Usher syndrome . 158
X-linked juvenile retinoschisis . 159
Proliferative retinopathies . 159
Methods of gene transfer to retinal cells . 159
DNA nanoparticles for nonviral gene transfer to the eye . 160
Prevention of complications associated with eye surgery . 161
Prevention of proliferative retinopathy by gene therapy . 161
DNA nanoparticles for gene therapy of retinal degenerative disorders 161
Posterior capsule opacification after cataract surgery . 161
Autoimmune uveitis . 161
Retinal ischemic injury 162
Corneal disorders . 162
Glaucoma . 163
Disorders of hearing 163
Gene therapy for hearing loss 163
Organ transplantation 164
Introduction 164
DNA vaccines for transplantation . 164
Gene therapy for prolonging allograft survival . 164
Gene therapy in lung transplantation 165
Role of gene therapy in liver transplantation . 165
Gene therapy in kidney transplantation. 165
Veto cells and transplant tolerance . 166
Pulmonary disorders 166
Techniques of gene delivery to the lungs 167
Adenoviral vectors 167
Non-viral vectors 168
Aerosolization as an aid to gene transfer to lungs. 168
Cystic fibrosis 169
Genetics and clinical features . 169
Gene therapy for CF 169
CFTR gene transfer in CF . 169
Concluding remarks about gene therapy of CF 171
Miscellaneous pulmonary disorders 171
Gene therapy for pulmonary arterial hypertension . 171
Gene therapy for bleomycin-induced pulmonary fibrosis 172
Pulmonary complications of a1-antitrypsin deficiency 172
Gene therapy for asthma . 173
Gene therapy for adult respiratory distress syndrome 174
Gene therapy for lung injury 174
Gene therapy for bronchopulmonary dysplasia 174
Concluding remarks about gene therapy of lungs . 175
Companies involved in pulmonary gene therapy 175
Skin and soft tissue disorders 176
Gene transfer to the skin 176
Electroporation for transdermal delivery of plasmid DNA 176
Electroporation for transdermal delivery of DNA vaccines . 177
Liposomes for transdermal gene delivery . 177
Ultrasound and topical gene therapy . 177
Gene therapy in skin disorders 177
Gene therapy of hair loss . 178
Gene therapy for xeroderma pigmentosa . 178
Gene therapy for lamellar ichthyosis 178
Gene therapy for epidermolysis bullosa 179
Gene transfer techniques for wound healing 179
Urogenital disorders 180
Gene therapy for urinary tract dysfunction 180
Gene therapy for erectile dysfunction . 180
NOS gene transfer for erectile dysfunction . 180
Clinical trial of hMaxi-K Gene transfer in erectile dysfunction 181 - 8 -
Gene therapy for erectile dysfunction due to nerve injury. 181
Concluding remarks on gene therapy for erectile dysfunction 181
Veterinary gene therapy 182
Gene therapy for mucopolysaccharidosis VII in dogs 182
Gene therapy to increase disease resistance 182
Gene therapy for infections . 183
Gene therapy for chronic anemia . 183
Gene therapy for endocrine disorders . 184
Gene therapy for arthritis 184
Cancer gene therapy 184
Brain tumors in cats and dogs 184
Breast cancer in dogs 185
Canine hemangiosarcoma 186
Canine melanoma . 186
Canine soft tissue sarcoma . 186
Melanoma in horses . 187
4. Gene Therapy of Genetic Disorders . 188
Introduction 188
Primary immunodeficiency disorders . 189
Severe combined immune deficiency 190
Chronic granulomatous disease . 192
Wiskott-Aldrich syndrome . 192
Purine nucleoside phosphorylase deficiency . 193
Major histocompatibility class II deficiency 193
Future prospects of gene therapy of inherited immunodeficiencies . 194
Metabolic disorders 194
Adrenoleukodystrophy 195
Canavan disease 195
Lesch-Nyhan syndrome 196
Ornithine transcarbamylase deficiency 196
Phenylketonuria . 197
Porphyrias 197
Tetrahydrobiopterin deficiency . 198
Lysosomal storage disorders. 198
Batten disease . 199
Fabry's disease 200
Farber's disease . 200
Gaucher disease 201
Animals models of Gaucher's disease. 201
Gene therapy of Gaucher's disease 201
Hunter syndrome . 202
Combination of cell and gene therapy for Krabbe's disease 202
Metachromatic leukodystrophy 203
Mucopolysaccharidosis type 1 (Hurler syndrome) . 204
Niemann-Pick type A disease . 204
Pompe disease 204
Sanfilippo A syndrome 205
Sly syndrome 205
Tay-Sachs disease . 206
Future prospects of gene therapy of lysosomal storage disorders . 206
Trinucleotide repeat disorders . 206
Muscular dystrophies . 207
Duchenne muscular dystrophy (DMD) . 207
Animal models for gene therapy of DMD 207
Antisense approach to DMD 207
Liposome-mediated gene transfer . 208
Myoblast-based gene transfer in DMD 209
Plasmid-mediated gene therapy 209
Post-transcriptional modulation of gene expression in DMD 209
Repair of dystrophin gene 210
Routes of administration of gene therapy in DMD 210
Types of dystrophin constructs . 210
Viral vectors for DMD 211
Conclusions and future prospects of gene therapy of DMD 212
Limb-girdle muscular dystrophy . 213
Myotonic dystrophy 213
Spinal muscular atrophy . 214
Antisense gene therapy of SMA . 214
Hereditary neuropathies 214
Charcot-Marie-Tooth disease . 214 - 9 -
Hereditary axonal neuropathies of the peripheral nerves . 215
Gene therapy of mitochondrial disorders . 215
Companies involved in gene therapy of genetic disorders . 216
5. Gene Therapy of Cancer 218
Strategies for cancer gene therapy 218
Direct gene delivery to the tumor 219
Injection into tumor . 219
Direct injection of adenoviral vectors . 219
Direct injection of a plasmid DNA-liposome complex 220
A polymer approach to local gene therapy for cancer . 220
Electroporation for cancer gene therapy 220
Control of gene expression in tumor by local heat 221
Radiation-guided gene therapy of cancer 221
Nanoparticles to facilitate combination of hyperthermia and gene therapy . 222
Cell-based cancer gene therapy . 222
Adoptive cell therapy 222
Cytokine gene therapy 223
Genetic modification of human hematopoietic stem cells . 226
Immunogene therapy . 226
Cancer vaccines . 227
Genetically modified cancer cell vaccines 227
GVAX cancer vaccines . 227
Genetically modified dendritic cells 228
Nucleic acid-based cancer vaccines 228
DNA cancer vaccines . 229
RNA vaccines 229
Viral vector-based cancer vaccines . 229
Intradermal delivery of cancer vaccines by Ad vectors . 230
Future prospects of cancer vaccines . 230
Companies involved in nucleic acid-based cancer vaccines 230
Monoclonal antibody gene transfer for cancer . 231
Transfer and expression of intracellular adhesion-1 molecules . 232
Other gene-based techniques of immunotherapy of cancer . 232
Fas (Apo-1) . 232
Chemokines 232
Major Histocompatibility Complex (MHC) Class I 233
IGF (Insulin-Like Growth Factor) 233
Inhibition of immunosuppressive function in cancer . 233
Delivery of toxic genes to tumor cells for eradication 234
Gene-directed enzyme prodrug therapy 234
Combination of gene therapy with radiotherapy 234
Correction of genetic defects in cancer cells 235
Targeted gene therapy for cancer 235
Antiangiogenic therapy for cancer 235
Bacteria as novel anticancer gene vectors . 236
Cancer-specific gene expression 237
Cancer-specific transcription 237
Delivery of retroviral particles hitchhiking on T cells . 237
Electrogene and electrochemotherapy 238
Epidermal growth factor-mediated DNA delivery 238
Gene-based targeted drug delivery to tumors 238
Gene expression in hypoxic tumor cells 239
Genetically modified T cells for targeting tumors 239
Genetically engineered stem cells for targeting tumors . 240
Hematopoietic stem cells for targeted cancer gene therapy . 241
Immunolipoplex for delivery of p53 gene 241
Nanomagnets for targeted cell-based cancer gene therapy 242
Nanoparticles for targeted site-specific delivery of anticancer genes . 242
Targeted cancer therapy using a dendrimer-based synthetic vector 242
Tumor-targeted gene therapy by receptor-mediated endocytosis . 243
Virus-mediated oncolysis 243
Targeted cancer treatments based on oncolytic viruses 243
Oncolytic HSV . 243
Oncolytic adenoviruses 244
Oncolytic vesicular stomatitis virus 245
Oncolytic paramyxovirus 245
Oncolytic vaccinia virus 246
Cancer terminator virus . 246
Cytokine-induced killer cells for delivery of an oncolytic virus . 247
Monitoring of viral-mediated oncolysis by PET. 247 - 10 -
Oncolytic gene therapy 247
Companies developing oncolytic viruses . 248
Apoptotic approach to improve cancer gene therapy . 248
Tumor suppressor gene therapy 249
P53 gene therapy. 249
BRIT1 gene therapy . 249
Nitric oxide-based cancer gene therapy . 250
Nitric oxide synthase II DNA injection . 250
Gene therapy for radiosensitization of cancer 250
Gene therapy of cancer of selected organs 250
Gene therapy for bladder cancer 250
Gene therapy for glioblastoma multiforme. . 251
Targeted adenoviral vectors . 252
Genetically engineered MSCs for gene delivery to intracranial gliomas . 253
Targeting normal brain cells with an AAV vector encoding interferon-?. 253
Viral oncolysis of brain tumors 253
Autophagy induced by conditionally replicating adenoviruses 254
Oncolytic virus targeted to brain tumor stem cells . 254
Antiangiogenic gene therapy 255
Baculovirus vector for diphtheria toxin gene therapy . 255
Intravenous gene delivery with nanoparticles into brain tumors 255
Gene therapy targeting hepatocyte growth factor 256
RNAi gene therapy of brain cancer 256
Ligand-directed delivery of dsRNA molecules targeted to EGFR . 256
Gene therapy for breast cancer 257
Gene vaccine for breast cancer . 257
Recombinant adenoviral ErbB-2/neu vaccine 258
Gene Therapy for ovarian cancer . 258
Gene therapy for malignant melanoma . 259
Gene therapy of lung cancer 261
Intravenous nanoparticle formulation for delivery of FUS1 gene 261
Aerosol gene delivery for lung cancer 262
Gene therapy for cancer of prostate . 262
Experimental studies . 262
Nanoparticle-based gene therapy for prostate cancer 262
Tumor suppressor gene therapy in prostate cancer . 263
Vaccines for prostate cancer . 263
Clinical trials. 263
Gene therapy of head and neck cancer . 264
Adenoviral vector based P53 gene therapy . 264
Gene therapy of pancreatic cancer . 264
Rexin-G for targeted gene delivery in cancer 265
Targeted Expression of BikDD gene . 265
Concluding remarks on gene therapy of pancreatic cancer . 265
Cancer gene therapy companies 266
6. Gene Therapy of Neurological Disorders . 270
Indications 270
Gene transfer techniques for the nervous system 271
Methods of gene transfer to the nervous system 271
Ideal vector for gene therapy of neurological disorders . 271
Promoters of gene transfer 271
Lentivirus-mediated gene transfer to the CNS . 272
AAV vector mediated gene therapy for neurogenetic disorders . 272
Gene transfer to the CNS using recombinant SV40-derived vectors 273
Routes of delivery of genes to the CNS . 273
Direct injection into CNS 273
Introduction of the genes into cerebral circulation . 274
Introduction of genes into cerebrospinal fluid . 274
Intravenous administration of vectors 274
Delivery of gene therapy to the peripheral nervous system . 275
Cell-mediated gene therapy of neurological disorders . 275
Neuronal cells . 275
Neural stem cells and progenitor cells 275
Astrocytes 275
Cerebral endothelial cells . 276
Implantation of genetically modified encapsulated cells into the brain 276
Gene therapy of neurodegenerative disorders . 276
Gene therapy for Parkinson disease 276
Rationale 277
Techniques of gene therapy for PD 278 - 11 -
Delivery of neurotrophic factors by gene therapy 281
Delivery of parkin gene 282
Introduction of functional genes into the brain of patients with PD 282
Nanoparticle-based gene therapy for PD 282
Mitochondrial gene therapy for PD . 282
RNAi approach to PD . 283
Prospects of gene therapy for PD 283
Companies developing gene therapy for PD 284
Gene therapy for Alzheimer disease . 285
Rationale . 285
NGF gene therapy for AD . 285
Neprilysin gene therapy . 286
Targeting plasminogen activator inhibitor type-1 gene . 287
Gene vaccination 287
Combination of gene therapy with other treatments for AD 287
Gene therapy of Huntington disease . 287
Encapsulated genetically engineered cellular implants 287
Viral vector mediated administration of neurotrophic factors 288
RNAi gene therapy 288
Gene therapy of amyotrophic lateral sclerosis 288
Rationale . 288
Technique of gene therapy of ALS . 288
Gene therapy of cerebrovascular diseases . 290
Preclinical research in gene therapy for cerebrovascular disease 290
Animal models of stroke relevant to gene therapy 290
Transgenic mice as models for stroke 290
Animal models for gene therapy of arteriovenous malformations . 291
Gene transfer to cerebral blood vessels 291
Gene therapy for vasospasm following subarachnoid hemorrhage 292
NOS gene therapy for cerebral vasospasm . 293
Gene therapy for stroke 293
Gene therapy for stroke using neurotrophic factors . 294
Gene therapy of strokes with a genetic component . 295
Gene therapy for intracranial aneurysms 295
Concluding remarks about gene therapy for stroke. 295
Gene therapy of injuries to the nervous system . 296
Traumatic brain injury 296
Spinal cord injury 296
Gene therapy of epilepsy . 297
Gene therapy for control of seizures . 297
Gene therapy for neuroprotection in epilepsy 298
Gene therapy for genetic forms of epilepsy . 299
Gene therapy for multiple sclerosis . 299
Gene therapy for relief of pain . 300
Rationale of gene therapy for pain . 300
Vectors for gene therapy of pain 300
Methods of gene delivery for pain 300
Endogenous analgesic production for cranial neuralgias . 301
Gene delivery by intrathecal route 301
Gene transfer for delivery of analgesics to the spinal nerve roots 302
Gene therapy of peripheral neuropathic pain 303
Gene transfer by injections into the brain substance 303
Targets for gene therapy of pain 304
Zinc finger DNA-binding protein therapeutic for chronic pain 304
Gene therapy for producing enkephalin to block pain signals 304
Targeting nuclear factor-?B 304
Gene therapy targeted to neuroimmune component of chronic pain 304
Potential applications of gene therapy for management of pain 305
Concluding remarks on gene therapy for pain 305
Gene therapy for psychiatric disorders 306
Gene therapy for depression . 307
Gene therapy for enhancing cognition after stress 307
Gene therapy against fear disorders . 307
Companies involved in gene therapy of neurological disorders 308
7. Gene Therapy of Cardiovascular Disorders . 310
Introduction 310
Techniques of gene transfer to the cardiovascular system 310
Direct plasmid injection into the myocardium 311
Catheter-based systems for vector delivery . 311
Ultrasound microbubbles for cardiovascular gene delivery . 312 - 12 -
Vectors for cardiovascular gene therapy . 312
Adenoviral vectors for cardiovascular diseases 312
Plasmid DNA-based delivery in cardiovascular disorders . 312
Intravenous rAAV vectors for targeted delivery to the heart . 313
Hypoxia-regulated gene therapy for myocardial ischemia 313
Angiogenesis and gene therapy of ischemic disorders . 313
Therapeutic angiogenesis vs vascular growth factor therapy 314
Gene painting for delivery of targeted gene therapy to the heart . 314
Gene delivery to vascular endothelium . 315
Targeted plasmid DNA delivery to the cardiovascular system with nanoparticles 315
Vascular stents for gene delivery . 315
Gene therapy for genetic cardiovascular disorders 316
Genetic disorders predisposing to atherosclerosis . 316
Familial hypercholesterolemia (FH) 316
Apolipoprotein E (apoE) deficiency . 318
Hypertension . 318
Genetic factors for myocardial infarction . 319
Acquired cardiovascular diseases 319
Coronary artery disease with angina pectoris . 319
Ad5FGF-4. 319
Ischemic heart disease with myocardial infarction 320
Myocardial repair with IGF-1 therapy . 321
Metalloproteinase-2 inhibitor gene therapy . 321
Congestive heart failure 322
Rationale of gene therapy in CHF 322
?-ARKct gene therapy 322
Intracoronary adenovirus-mediated gene therapy for CHF 323
AAV-mediated gene transfer for CHF . 323
AngioCell gene therapy for CHF 324
nNOS gene transfer in CHF. 324
Cardiomyopathies 324
Cardiac conduction disturbances 325
Gene transfer approaches for biological pacemakers 325
Genetically engineered biological pacemakers . 325
Gene therapy and heart transplantation 326
Peripheral arterial disease . 326
Incidence and clinical features . 326
Current management . 327
Gene therapy for peripheral arterial disease 327
Angiogenesis by gene therapy 327
HIF-1? gene therapy for peripheral arterial disease . 327
HGF gene therapy for peripheral arterial disease . 328
Ischemic neuropathy secondary to peripheral arterial disease 328
Prevention of restenosis after angioplasty . 329
Antisense approaches 329
Gene therapy to prevent restenosis after angioplasty 329
Techniques of gene therapy for restenosis 331
NOS gene therapy for restenosis . 331
hTIMP-1 gene therapy to prevent intimal hyperplasia 332
Maintaining vascular patency after surgery . 332
Companies involved in gene therapy of cardiovascular diseases . 333
Future prospects of gene therapy of cardiovascular disorders 333
8. Gene therapy of viral infections 336
Introduction 336
Acquired Immunodeficiency Syndrome (AIDS) 336
Current management of AIDS 336
Gene therapy strategies in HIV/AIDS 337
HIV/AIDS vaccines 337
Insertion of protective genes into target cells. 338
Cell/gene therapies for HIV/AIDS . 339
Transplantation of genetically modified T-cells 339
Transplantation of genetically modified hematopoietic cells 339
Anti-HIV ribozyme delivered in hematopoietic progenitor cells 340
Inhibition of HIV-1 replication by lentiviral vectors . 340
VRX496 . 340
Intracellular immunization. 341
Engineered cellular proteins such as soluble CD4s 341
Intracellular antibodies . 341
Anti-rev single chain antibody fragment 341
Use of genes to chemosensitize HIV-1 infected cells . 342 - 13 -
Autocrine interferon (INF)-? production by somatic cell gene therapy . 342
Antisense approaches to AIDS . 342
RNA decoys 342
Antisense oligodeoxynucleotides . 342
RNA decoys 343
Ribozymes . 343
RNAi applications in HIV/AIDS . 344
siRNA-directed inhibition of HIV-1 infection 344
Role of the nef gene during HIV-1 infection and RNAi 344
Bispecific siRNA constructs . 345
Targeting CXCR4 with siRNAs . 345
Targeting CCR5 with siRNAs . 345
Companies involved in developing gene therapy for HIV/AIDS . 346
Conclusions regarding gene therapy of HIV/AIDS . 347
Ge
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