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Gene Therapy - Technologies, Markets and Companies
Jain PharmaBiotech, Nov 2009, Pages: 659
Executive Summary
1. Introduction
Definitions
Historical evolution of gene therapy
Relation of gene therapy to other biotechnologies
Molecular biological basics for gene therapy
Genome
DNA
RNA
Alternative RNA splicing
Genes
Gene regulation
Gene expression
Chromosomes
Telomeres
Mitochondrial DNA
Proteins
2. Gene Therapy Technologies
Classification of gene therapy techniques
Ex vivo and in vivo gene therapy
Ex vivo gene therapy
In vivo gene therapy
Physical methods of gene transfer
Electroporation
Applications of electroporation
Clinical applications of electroporation
Advantages of electroporation
Limitations of electroporation
Hydrodynamic
Microinjection
Particle bombardment
Ultrasound-mediated transfection
Molecular vibration
Application of pulsed magnetic field and superparamagnetic nanoparticles
Gene transfection using laser irradiation
Photochemical transfection
Chemical methods of gene transfer
Gene repair and replacement
Gene repair by single-stranded oligonucleotides
History and current status of chimeraplasty
mRNA gene therapy
Spliceosome mediated RNA trans-splicing
Vectors for gene therapy
Basic considerations
Use of genes as pharmaceuticals
The ideal vector for gene therapy
Viral vectors
Adenovirus vectors
Adeno-associated virus vectors
Alphavirus vectors
Baculovirus vectors
Foamy virus vectors
Herpes simplex virus vectors
Lentiviral vectors
Multicistronic retroviral vectors
Retroviral vectors
Oncognic potential of retroviral vectors
Future prospects of viral vectors
Companies using viral vectors
Nonviral vectors for gene therapy
Effects of shape of DNA molecules on delivery with nonviral vectors
Anionic lipid-DNA complexes
Cationic lipid-DNA complexes
Liposomes for gene therapy
Liposome-nucleic acid complexes
Liposome-HVJ complex
Polycation-DNA complexes (polyplexes)
Plasmid DNA vector for treatment of chronic inflammatory disease
Polymer molecules
Synthetic peptide complexes
Future prospects of nonviral vs viral vectors
Nanobiotechnology for gene transfer
Nanoparticles as nonviral vectors for gene therapy
Dendrimers
Cochleates
Calcium phosphate nanoparticles as non-viral vectors
Lipid nanoparticles for nucleic acid delivery
Silica nanoparticles as a nonviral vector for gene delivery
Gelatin nanoparticles for gene delivery
Nonionic polymeric micelles for oral gene delivery
Biological nanoparticle technology
Nanoparticles with virus-like function as gene therapy vectors
Receptor-mediated endocytosis
Artificial viral vectors
Directed evolution of AAV to create efficient gene delivery vectors
Bacterial ghosts as DNA delivery systems
Bacteria plus nanoparticles for gene delivery into cells
Chromosome-based vectors for gene therapy
Companies using nonviral vectors
Concluding remarks about vectors
Cell-mediated gene therapy
Fibroblasts
Skeletal muscle cells
Vascular smooth muscle cells
Keratinocytes
Hepatocytes
Lymphocytes
Regulating protein delivery by genetically encoded lymphocytes
Implantation of microencapulated genetically modified cells
Stem cell gene therapy
Therapeutic applications for hematopoietic stem cell gene transfer
Improving delivery of genes to stem cells
Lentiviral vectors for gene transfer to marrow stem cells
Use of mesenchymal stem cells for gene therapy
In utero gene therapy using stem cells
Gene delivery to stem cells by artificial chromosome expression
Linker based sperm-mediated gene transfer technology
Combination of gene therapy with therapeutic cloning
Expansion of transduced HSCs in vivo
The future of hematopoietic stem cell gene therapy
Routes of administration for gene therapy
Direct injection of naked DNA
Intramuscular injection
Intravenous DNA injection
Intraarterial delivery
Companies with gene delivery devices/ technologies
Targeted gene therapy
Targeted integration
Bacteriophage integrase system for site-specific gene delivery
Controlled-release delivery of DNA
Controlled gene therapy
Controlled delivery of genetic material
Controlled induction of gene expression
Drug-inducible systems for control of gene expression
Timed activation of gene therapy by a circuit based on signaling network
Small molecules for post-transcriptional regulation of gene expression
Engineered zinc finger DNA binding proteins for gene correction
Light Activated Gene Therapy
Spatial control of gene expression via local hyperthermia
Companies with regulated /targeted gene therapy
Gene marking
Germline gene therapy
Potential applications of human germline genome modification
Pros and cons of human germline genome modification
Role of gene transfer in antibody therapy
Genetically engineered vaccines
DNA vaccines
DNA inoculation technology
Methods for enhancing the potency of DNA vaccines
Advantages of DNA vaccines
Vaccine vectors
Challenges and limitations of genetically engineered vaccines
Vaccines based on reverse genetics
Technologies for gene suppression
Antisense oligonucleotides
Transcription factor decoys
Aptamers
Ribozymes
Peptide nucleic acid
Intracellular delivery of PNAs
Locked nucleic acid
Zorro-LNA
Gene silencing
Post-transcriptional gene silencing
Definitions and terminology of RNAi
RNAi mechanisms
Inhibition of gene expression by antigene RNA
RNAi gene therapy
Application of molecular diagnostic methods in gene therapy
Use of PCR to study biodistribution of gene therapy vector
PCR for verification of the transcription of DNA
In situ PCR for direct quantification of gene transfer into cells
Detection of retroviruses by reverse transcriptase (RT)-PCR
Confirmation of viral vector integration
Monitoring of gene expression
Monitoring of gene expression by green fluorescent protein
Monitoring in vivo gene expression by molecular imaging
Advantages of gene therapy compared with protein therapy
3. Clinical Applications of Gene Therapy
Introduction
Bone and joint disorders
Bone fractures
Gene therapy for intervertebral disc degeneration
Spinal fusion
Osteogenesis imperfecta
Rheumatoid arthritis
Local or systemic treatment
In vivo or ex vivo gene therapy of RA
Clinical trials
Gene therapy for osteoarthritis
Sports injuries
Repair of articular cartilage defects
Regeneration and replacement of bone by gene therapy
Bacterial infections
Antisense approach to bacterial infections
Dentistry
Tissue engineering in dental implant defects
Endocrine disorders
Introduction
Diabetes mellitus
Methods of gene therapy of diabetes mellitus
Viral vector-mediated gene transfer in diabetes
Gene delivery with ultrasonic microbubble destruction technology
Genetically engineered cells for diabetes mellitus
Genetically altered liver cells
Genetically modified stem cells
Genetically engineered dendritic cells
Insertion of gene encoding for IL-4
Concluding remarks about cell and gene therapy of diabetes
Gene therapy of growth-hormone deficiency
Gene therapy of obesity
Ad viral vector-mediated transfer of leptin gene
AAV vector-mediated delivery of GDNF for obesity
Gastrointestinal disorders
Introduction
Methods of gene transfer to the gastrointestinal tract
Direct delivery of genes
Naked plasmid DNA into the submucosa
Viral vectors
Receptor-mediated endocytosis
Indications for gastrointestinal gene therapy
Gene therapy for inflammatory disorders of the bowel
Gene transfer to the salivary glands
Potential clinical applications of salivary gene therapy
Hematology
Hemophilias
Gene therapy of hemophilia
Hemophilia A
Hemophilia B
Concluding remarks about gene therapy of hemophilias
Hemoglobinopathies
Stem cell-based gene therapy and RNAi for sickle cell disease
Gene therapy for b-thalassemia
Gene therapy of Fanconi's anemia
Acquired hematopoietic disorders
Chronic acquired anemias
Neutropenia
Thrombocytopenia
Concluding remarks about gene therapy of hemoglobinopathies
Companies involved in gene thery of hematological disorders
In utero gene therapy
Fetal gene transfer techniques
Animal models of fetal gene therapy
Potential applications of fetal gene therapy
Fetal gene therapy for cystic fibrosis
Fetal intestinal gene therapy
Hearing disorders
Potential of gene therapy
Vectors for gene therapy of hearing disorders
Auditory hair cell replacement and hearing improvement by gene therapy
Kidney diseases
End-stage renal disease
Methods of gene delivery to the kidney
Gene transfer into kidney by adenoviral vectors
Non-viral gene transfer to the kidneys
Gene transfer into the glomerulus by HVJ-liposome
Bone marrow stem cells for renal disease
Mesangial cell therapy
Liposome-mediated gene transfer into the tubules
Gene transfer to tubules with cationic polymer polyethylenimine
Gene therapy in animal experimental models of renal disease
Genetic manipulations of the embryonic kidney
Antisense intervention in glomerulonephritis
Gene therapy for renal fibrosis
Use of genetically engineered cells for uremia due to renal failure
Concluding remarks
Liver disorders
Techniques of gene delivery to liver
Direct injection of DNA into liver
Local gene delivery by isolated organ perfusion
Liposome-mediated direct gene transfer
Retroviral vector for gene transfer to liver
Adenoviral vectors for gene transfer to liver
Receptor-mediated approach
Cell therapy for liver disorders
Transplantation of genetically modified hepatocytes
Genetically modified hematopoietic stem cells
Gene therapy by ex vivo transduced liver progenitor cells
Gene therapy of genetic diseases affecting the liver
Crigler-Najjar syndrome
Hereditary tyrosinemia type I (HT1)
Hereditary tyrosinemia type 3
Gene therapy of acquired diseases affecting the liver
Cirrhosis of liver
Ophthalmic disorders
Introduction to gene therapy of ophthalmic disorders
Degenerative retinal disorders
Inherited retinal degenerations
Leber congenital amaurosis
X-linked juvenile retinoschisis
Retinitis pigmentosa
Age-related macular degeneration
Proliferative retinopathies
Methods of gene transfer to retinal cells
DNA nanoparticles for nonviral gene transfer to the eye
Prevention of complications associated with eye surgery
Prevention of proliferative retinopathy by gene therapy
DNA nanoparticles for gene therapy of retinal degenerative disorders
Posterior capsule opacification after cataract surgery
Autoimmune uveitis
Retinal ischemic injury
Corneal disorders
Glaucoma
Disorders of hearing
Gene therapy for hearing loss
Organ transplantation
Introduction
Veto cells and transplant tolerance
Gene therapy for prolonging allograft survival
Gene therapy in lung transplantation
Role of gene therapy in liver transplantation
Gene therapy in kidney transplantation
Pulmonary disorders
Techniques of gene delivery to the lungs
Adenoviral vectors
Non-viral vectors
Aerosolization as an aid to gene transfer to lungs
Cystic fibrosis
Genetics and clinical features
Gene therapy for CF
CFTR gene transfer in CF
Concluding remarks about gene therapy of CF
Miscellaneous pulmonary disorders
Gene therapy for pulmonary arterial hypertension
Gene therapy for bleomycin-induced pulmonary fibrosis
Pulmonary complications of a1-antitrypsin deficiency
Gene therapy for asthma
Gene therapy for adult respiratory distress syndrome
Gene therapy for lung injury
Gene therapy for bronchopulmonary dysplasia
Concluding remarks about gene therapy of lungs
Companies involved in pulmonary gene therapy
Skin and soft tissue disorders
Gene transfer to the skin
Electroporation for transdermal delivery of DNA vaccines
Ultrasound and topical gene therapy
Gene therapy in skin disorders
Gene therapy of hair loss
Gene therapy for xeroderma pigmentosa
Gene therapy for lamellar ichthyosis
Gene therapy for epidermolysis bullosa
Gene transfer techniques for wound healing
Urogenital disorders
Gene therapy for urinary tract dysfunction
Gene therapy for erectile dysfunction
NOS gene transfer for erectile dysfunction
Clinical trial of hMaxi-K Gene transfer in erectile dysfunction
Gene therapy for erectile dysfunction due to nerve injury
Concluding remarks on gene therapy for erectile dysfunction
Veterinary gene therapy
Gene therapy for mucopolysaccharidosis VII in dogs
Gene therapy to increase disease resistance
Gene therapy for infections
Gene therapy for chronic anemia
Gene therapy for endocrine disorders
Gene therapy for arthritis
Cancer gene therapy
Brain tumors in cats and dogs
Breast cancer in dogs
Canine hemangiosarcoma
Canine melanoma
Canine soft tissue sarcoma
Melanoma in horses
4. Gene Therapy of Genetic Disorders
Introduction
Primary immunodeficiency disorders
Severe combined immune deficiency
Chronic granulomatous disease
Wiskott-Aldrich syndrome
Purine nucleoside phosphorylase deficiency
Major histocompatibility class II deficiency
Future prospects of gene therapy of inherited immunodeficiencies
Metabolic disorders
Adrenoleukodystrophy
Canavan disease
Lesch-Nyhan syndrome
Ornithine transcarbamylase deficiency
Phenylketonuria
Porphyrias
Tetrahydrobiopterin deficiency
Lysosomal storage disorders
Batten disease
Fabry's disease
Gaucher disease
Animals models of Gaucher's disease
Gene therapy of Gaucher's disease
Hunter syndrome
Combination of cell and gene therapy for Krabbe's disease
Metachromatic leukodystrophy
Mucopolysaccharidosis type 1 (Hurler syndrome)
Niemann-Pick type A disease
Pompe disease
Sanfilippo A syndrome
Sly syndrome
Tay-Sachs disease
Future prospects of gene therapy of lysosomal storage disorders
Trinucleotide repeat disorders
Muscular dystrophies
Duchenne muscular dystrophy (DMD)
Animal models for gene therapy of DMD
Types of dystrophin constructs
Antisense approach to DMD
Post-transcriptional modulation of gene expression in DMD
Myoblast-based gene transfer in DMD
Plasmid-mediated gene therapy
Liposome-mediated gene transfer
Viral vectors for DMD
Routes of administration of gene therapy in DMD
Conclusions and future prospects of gene therapy of DMD
Limb-girdle muscular dystrophy
Myotonic dystrophy
Spinal muscular atrophy
Antisense gene therapy of SMA
Hereditary neuropathies
Charcot-Marie-Tooth disease
Hereditary axonal neuropathies of the peripheral nerves
Gene therapy of mitochondrial disorders
Companies involved in gene therapy of genetic disorders
5. Gene Therapy of Cancer
Strategies for cancer gene therapy
Direct gene delivery to the tumor
Injection into tumor
Direct injection of adenoviral vectors
Direct injection of a plasmid DNA-liposome complex
A polymer approach to local gene therapy for cancer
Electroporation for cancer gene therapy
Control of gene expression in tumor by local heat
Radiation-guided gene therapy of cancer
Nanoparticles to facilitate combination of hyperthermia and gene therapy
Cell-based cancer gene therapy
Adoptive cell therapy
Cytokine gene therapy
Genetic modification of human hematopoietic stem cells
Immunogene therapy
Cancer vaccines
Genetically modified cancer cell vaccines
GVAX cancer vaccines
Genetically modified dendritic cells
Nucleic acid-based cancer vaccines
DNA cancer vaccines
RNA vaccines
Viral vector-based cancer vaccines
Intradermal delivery of cancer vaccines by Ad vectors
Future prospects of cancer vaccines
Companies involved in nucleic acid-based cancer vaccines
Monoclonal antibody gene transfer for cancer
Transfer and expression of intracellular adhesion-1 molecules
Other gene-based techniques of immunotherapy of cancer
Fas (Apo-1)
Chemokines
Major Histocompatibility Complex (MHC) Class I
IGF (Insulin-Like Growth Factor)
Inhibition of immunosuppressive function in cancer
Delivery of toxic genes to tumor cells for eradication
Gene-directed enzyme prodrug therapy
Combination of gene therapy with radiotherapy
Correction of genetic defects in cancer cells
Targeted gene therapy for cancer
Bacteria as novel anticancer gene vectors
Cancer-specific gene expression
Cancer-specific transcription
Delivery of retroviral particles hitchhiking on T cells
Electrogene and electrochemotherapy
Epidermal growth factor-mediated DNA delivery
Gene-based targeted drug delivery to tumors
Gene expression in hypoxic tumor cells
Genetically modified T cells for targeting tumors
Genetically engineered stem cells for targeting tumors
Hematopoietic stem cells for targeted cancer gene therapy
Immunolipoplex for delivery of p53 gene
Nanomagnets for targeted cell-based cancer gene therapy
Nanoparticles for targeted site-specific delivery of anticancer genes
Targeted cancer therapy using a dendrimer-based synthetic vector
Tumor-targeted gene therapy by receptor-mediated endocytosis
Virus-mediated oncolysis
Targeted cancer treatments based on oncolytic viruses
Oncolytic HSV
Oncolytic adenoviruses
Oncolytic vesicular stomatitis virus
Oncolytic paramyxovirus
Oncolytic vaccinia virus
Cancer terminator virus
Cytokine-induced killer cells for delivery of an oncolytic virus
Monitoring of viral-mediated oncolysis by PET
Oncolytic gene therapy
Companies developing oncolytic viruses
Apoptotic approach to improve cancer gene therapy
Tumor suppressor gene therapy
P53 gene therapy
BRIT1 gene therapy
Nitric oxide-based cancer gene therapy
Nitric oxide synthase II DNA injection
Gene therapy for radiosensitization of cancer
Gene therapy of cancer of selected organs
Gene therapy for bladder cancer
Gene therapy for glioblastoma multiforme
Targeted adenoviral vectors
Genetically engineered MSCs for gene delivery to intracranial gliomas
Targeting normal brain cells with an AAV vector encoding interferon-b
Viral oncolysis of brain tumors
Autophagy induced by conditionally replicating adenoviruses
Oncolytic virus targeted to brain tumor stem cells
Antiangiogenic gene therapy
Baculovirus vector for diphtheria toxin gene therapy
Intravenous gene delivery with nanoparticles into brain tumors
Gene therapy targeting hepatocyte growth factor
RNAi gene therapy of brain cancer
Ligand-directed delivery of dsRNA molecules targeted to EGFR
Gene therapy for breast cancer
Intratumoral injection of Ad5CMV-p53 (Advexin)
Gene vaccine for breast cancer
Recombinant adenoviral ErbB-2/neu vaccine
Gene Therapy for ovarian cancer
Gene therapy for malignant melanoma
Gene therapy of lung cancer
Intravenous nanoparticle formulation for delivery of FUS1 gene
Aerosol gene delivery for lung cancer
Gene therapy for cancer of prostate
Experimental studies
Nanoparticle-based gene therapy for prostate cancer
Tumor suppressor gene therapy in prostate cancer
Vaccine for prostate cancer
Clinical trials
Gene therapy of head and neck cancer
Adenoviral vector based P53 gene therapy
Gene therapy of pancreatic cancer
Adenovirus-mediated transfer of vasostatin gene
Rexin-GÔ for targeted gene delivery in cancer
Targeted Expression of BikDD gene
Cancer gene therapy companies
6. Gene Therapy of Neurological Disorders
Indications
Gene transfer techniques for the nervous system
Methods of gene transfer to the nervous system
Ideal vector for gene therapy of neurological disorders
Promoters of gene transfer
Lentivirus-mediated gene transfer to the CNS
AAV vector mediated gene therapy for neurogenetic disorders
Gene transfer to the CNS using recombinant SV40-derived vectors
Routes of delivery of genes to the CNS
Direct injection into CNS
Introduction of the genes into cerebral circulation
Introduction of genes into cerebrospinal fluid
Intravenous administration of vectors
Delivery of gene therapy to the peripheral nervous system
Cell-mediated gene therapy of neurological disorders
Neuronal cells
Neural stem cells and progenitor cells
Astrocytes
Cerebral endothelial cells
Implantation of genetically modified encapsulated cells into the brain
Gene therapy of neurodegenerative disorders
Gene therapy for Parkinson disease
Rationale
Techniques of gene therapy for PD
Delivery of neurotrophic factors by gene therapy
Delivery of parkin gene
Introduction of functional genes into the brain of patients with PD
Nanoparticle-based gene therapy for PD
Mitochondrial gene therapy for PD
RNAi approach to PD
Prospects of gene therapy for PD
Companies developing gene therapy for PD
Gene therapy for Alzheimer disease
Rationale
NGF gene therapy for AD
Neprilysin gene therapy
Targeting plasminogen activator inhibitor type-1 gene
Gene vaccination
Combination of gene therapy with other treatments for AD
Gene therapy of Huntington disease
Encapsulated genetically engineered cellular implants
Viral vector mediated administration of neurotrophic factors
RNAi gene therapy
Gene therapy of amyotrophic lateral sclerosis
Rationale
Technique of gene therapy of ALS
Gene therapy of cerebrovascular diseases
Preclinical research in gene therapy for cerebrovascular disease
Animal models of stroke relevant to gene therapy
Transgenic mice as models for stroke
Animal models for gene therapy of arteriovenous malformations
Gene transfer to cerebral blood vessels
Gene therapy for vasospasm following subarachnoid hemorrhage
NOS gene therapy for cerebral vasospasm
Gene therapy for stroke
Gene therapy for stroke using neurotrophic factors
Gene therapy of strokes with a genetic component
Gene therapy for intracranial aneurysms
Concluding remarks about gene therapy for stroke
Gene therapy of injuries to the nervous system
Traumatic brain injury
Spinal cord injury
Gene therapy of epilepsy
Gene therapy for control of seizures
Gene therapy for neuroprotection in epilepsy
Gene therapy for genetic forms of epilepsy
Gene therapy for multiple sclerosis
Gene therapy for relief of pain
Rationale of gene therapy for pain
Vectors for gene therapy of pain
Methods of gene delivery for pain
Endogenous analgesic production for cranial neuralgias
Gene delivery by intrathecal route
Gene transfer for delivery of analgesics to the spinal nerve roots
Gene therapy of peripheral neuropathic pain
Gene transfer by injections into the brain substance
Targets for gene therapy of pain
Zinc finger DNA-binding protein therapeutic for chronic pain
Gene therapy for producing enkephalin to block pain signals
Targeting nuclear factor-kB
Gene therapy targeted to neuroimmune component of chronic pain
Potential applications of gene therapy for management of pain
Concluding remarks on gene therapy for pain
Gene therapy for psychiatric disorders
Gene therapy for depression
Gene therapy for enhancing cognition after stress
Companies involved in gene therapy of neurological disorders
7. Gene Therapy of Cardiovascular Disorders
Introduction
Techniques of gene transfer to the cardiovascular system
Direct plasmid injection into the myocardium
Catheter-based systems for vector delivery
Ultrasound microbubbles for cardiovascular gene delivery
Vectors for cardiovascular gene therapy
Adenoviral vectors for cardiovascular diseases
Plasmid DNA-based delivery in cardiovascular disorders
Intravenous rAAV vectors for targeted delivery to the heart
Hypoxia-regulated gene therapy for myocardial ischemia
Angiogenesis and gene therapy of ischemic disorders
Therapeutic angiogenesis vs vascular growth factor therapy
Gene painting for delivery of targeted gene therapy to the heart
Gene delivery to vascular endothelium
Targeted plasmid DNA delivery to the cardiovascular system with nanoparticles
Vascular stents for gene delivery
Gene therapy for genetic cardiovascular disorders
Genetic disorders predisposing to atherosclerosis
Familial hypercholesterolemia (FH)
Apolipoprotein E (apoE) deficiency
Hypertension
Genetic factors for myocardial infarction
Acquired cardiovascular diseases
Coronary artery disease with angina pectoris
Ad5FGF-4
Ischemic heart disease with myocardial infarction
Myocardial repair with IGF-1 therapy
Metalloproteinase-2 inhibitor gene therapy
Congestive heart failure
Rationale of gene therapy in CHF
b-ARKct gene therapy
Intracoronary adenovirus-mediated gene therapy for CHF
AAV-mediated gene transfer for CHF
AngioCell gene therapy for CHF
nNOS gene transfer in CHF
Cardiomyopathies
Cardiac conduction disturbances
Gene transfer approaches for biological pacemakers
Genetically engineered biological pacemakers
Gene therapy and heart transplantation
Peripheral arterial disease
Incidence and clinical features
Current management
Gene therapy for peripheral arterial disease
Angiogenesis by gene therapy
HIF-1a gene therapy for peripheral arterial disease
HGF gene therapy for peripheral arterial disease
Ischemic neuropathy secondary to peripheral arterial disease
Prevention of restenosis after angioplasty
Antisense approaches
Gene therapy to prevent restenosis after angioplasty
Techniques of gene therapy for restenosis
NOS gene therapy for restenosis
hTIMP-1 gene therapy to prevent intimal hyperplasia
Maintaining vascular patency after surgery
Companies involved in gene therapy of cardiovascular diseases
Future prospects of gene therapy of cardiovascular disorders
8. Gene therapy of viral infections
Introduction
Acquired Immunodeficiency Syndrome (AIDS)
Current management of AIDS
Gene therapy strategies in HIV/AIDS
HIV/AIDS vaccines
Insertion of protective genes into target cells
Cell/gene therapies for HIV/AIDS
Transplantation of genetically modified T-cells
Transplantation of genetically modified hematopoietic cells
Anti-HIV ribozyme delivered in hematopoietic progenitor cells
Inhibition of HIV-1 replication by lentiviral vectors
VRX496
Intracellular immunization
Engineered cellular proteins such as soluble CD4s
Intracellular antibodies
Anti-rev single chain antibody fragment
Use of genes to chemosensitize HIV-1 infected cells
Autocrine interferon (INF)-b production by somatic cell gene therapy
Antisense approaches to AIDS
RNA decoys
Antisense oligodeoxynucleotides
RNA decoys
Ribozymes
RNAi applications in HIV/AIDS
siRNA-directed inhibition of HIV-1 infection
Role of the nef gene during HIV-1 infection and RNAi
Bispecific siRNA constructs
Targeting CXCR4 with siRNAs
Targeting CCR5 with siRNAs
Companies involved in developing gene therapy for HIV/AIDS
Conclusions regarding gene therapy of HIV/AIDS
Genetic vaccines for other viral infections
Cytomegalic virus infections
Viral hepatitis
Vaccine for hepatitis B virus
Vaccine for hepatitis C virus
Vaccine for herpes simplex virus
DNA vaccine against rabies
DNA vaccine for Ebola
Vaccines for avian influenza
Future prospects of DNA vaccines for avian influenza
Human trial of a DNA vaccine for avian influenza
Companies developing genetic vaccines for infections other than AIDS
9. Research, Development and Future of Gene Therapy
Basic research in gene therapy
R & D in gene therapy
Animal models of human diseases for gene therapy research
Lentiviral transgenesis
Financing research and development
Role of the NIH in gene therapy research
National Gene Vector Laboratories
Financing by the industry
Clinical trials in gene therapy
Clinical trials worldwide
Clinical trials in cancer gene therapy
Clinical trials in cardiovascular gene therapy
Clinical trials in inherited monogenic diseases
Clinical trials for other indications
Clinical trials in the US
Vectors used in gene therapy clinical trials
Future prospects for the gene therapy
How to improve gene therapy
Promising areas of application of gene therapy
Neurological disorders
Gene therapy of cardiovascular disorders
Cancer gene therapy
Personalized gene therapy
10. Regulatory, Safety and Ethical Issues of Gene Therapy
Regulation of gene therapy in the United States
US Federal guidelines for research involving recombinant DNA molecules
Regulation of gene therapy in US
Office of Biotechnology Activities
Implantation of genetically manipulated cells
Clinical trials in gene therapy
Cell and gene therapy INDs placed on hold by the FDA
Regulation of gene therapy in Germany
Preclinical research
Clinical Trials
Marketing authorization
Regulation of gene therapy in the United Kingdom
Regulation of gene therapy in France
Regulation of gene therapy in the Netherlands
Regulation of gene therapy in Australia
Regulation of gene therapy in Japan
Regulation of gene therapy in China
Safety issues of gene transfer
Adverse effects of retroviral vectors
Insertional mutagenesis
Adverse effects of HSV vectors
Neurotoxicity of HSV vectors
Hepatotoxicity of HSV-tk/ganciclovir approach
Adverse effects of adenoviral vectors
Inflammatory effects of adenoviruses in lungs
Inflammatory effects involving the liver
Induction of immune response by adenoviral vectors
Impairment of adrenocortical steroidogenesis
Adverse effects of AAV vectors
Toxicity associated with cationic lipid-mediated gene transfer
Toxicity of lipopolysaccharides
Potential side effects of RNAi gene therapy
Role of molecular diagnostics in safety of gene therapy
Quality control of vectors
Testing for retroviruses
Adenoviral vectors
Replication competent viruses
Genetic characteristics of viral vectors
Concluding remarks about safety of viral vectors
Ethical aspects of gene therapy
The lay consumer's view of somatic gene therapy ethics
Ethical aspects of clinical trials
Ethical aspects of germline gene therapy
Germline gene therapy for genetic enhancement
Athletic enhancement by genetic engineering
Gene doping in sports
Gene transfer methods used for enhancing physical performance
Adverse effect of genetic engineering
Problems in detecting genetic manipulations in athletes
Ethical dilemma
11. Markets for Gene Therapy
Introduction
Gene therapy markets in various regions of the world
Gene therapy markets according to therapeutic areas
Cancer gene therapy market
Markets for gene therapy of genetic disorders
Markets for DNA vaccines
DNA vaccines markets according to technologies
DNA vaccines markets according to therapeutic indications
DNA vaccines markets according to geographical areas
Competing treatments
Antisense
RNAi
Cell therapy
Strategies for developing gene therapy markets
Collaboration with pharmaceutical companies
Collaboration with companies developing cell-based therapies
Overcoming obstructions to the development of gene therapy
Collaboration with academic gene therapy centers
Developing safer and cost-effective gene medicines
Unmet needs in gene therapy
Promising areas for the development of gene therapy
12. References
Tables
Table 1-1: Landmarks in development of gene therapy
Table 2-1: Classification of methods of gene therapy
Table 2-2: A comparison of various physical methods of gene transfer
Table 2-3: Experimental applications of gene transfer by electroporation
Table 2-4: An overview of characteristics of commonly used viral vectors
Table 2-5: Companies using viral vectors
Table 2-6: Companies using nonviral vectors
Table 2-7: Target organs for non-viral gene therapy methods
Table 2-8: Potential routes for administration of DNA
Table 2-9: Companies with gene delivery devices/ technologies
Table 2-10: Strategies for targeted gene therapy
Table 2-11: In vivo animal experimental studies of gene delivery with polymeric systems
Table 2-12: Approaches to controlling gene expression in gene therapy
Table 2-13: Companies with regulated / targeted gene therapy and special techniques
Table 2-14: Potential applications of human germline genome modification
Table 2-15: Applications of molecular diagnostics in gene therapy
Table 2-16: Advantages of gene therapy compared with protein therapy
Table 3-1: Experimental approaches to gene therapy of rheumatoid arthritis
Table 3-2: Gene therapy strategies for osteoarthritis
Table 3-3: Cell and gene therapy approaches for type 1 diabetes mellitus
Table 3-4: Indications for gastrointestinal gene therapy
Table 3-5: Hematological disorders that can be potentially treated by gene therapy
Table 3-6: Companies involved in gene therapy of hematological disorders
Table 3-7: Techniques of gene transfer to the kidneys
Table 3-8: Gene therapy in animal experimental models of renal disease
Table 3-9: Applications of gene therapy in ophthalmological disorders
Table 3-10: Strategies for gene delivery to the lungs
Table 3-11: Companies developing gene therapy for pulmonary disorders
Table 4-1: Genetic disorders that are being investigated for gene therapy
Table 4-2: X-linked immunodeficiency disorders
Table 4-3: Examples of inherited metabolic disorders amenable to gene therapy
Table 4-4: Gene therapy approaches to Duchenne muscular dystrophy
Table 4-5: Companies involved in gene therapy of genetic/metabolic disorders
Table 5-1: Strategies for cancer gene therapy
Table 5-2: Cell-based gene therapy for cancer
Table 5-3: Companies with nucleic acids/genetically modified cell cancer vaccines
Table 5-4: Enzyme/prodrug combinations employed in suicide gene therapy
Table 5-5: Mutation compensation strategies used clinically
Table 5-6: Companies developing oncolytic viruses
Table 5-7: Strategies for gene therapy of malignant brain tumors
Table 5-8: Clinical trials of gene therapy in ovarian cancer
Table 5-9: Gene therapy for malignant melanoma
Table 5-10: Clinical trials in gene therapy for prostate cancer
Table 5-11: Companies involved in cancer gene therapy
Table 6-1: Example of potential indications for gene therapy of neurologic disorder
Table 6-2: Methods of gene transfer as applied to neurologic disorders
Table 6-3: Gene therapy techniques applicable to Parkinson disease
Table 6-4: Companies developing gene therapy for Parkinson's disease
Table 6-5: Gene transfer in animal models of carotid artery restenosis
Table 6-6: Gene therapy strategies for vasospasm
Table 6-7: Neuroprotective gene therapy in animal stroke models
Table 6-8: Experimental gene therapy approaches for relief of pain
Table 6-9: Companies involved in gene therapy of neurological disorders
Table 7-1: Cardiovascular disorders for which gene therapy is being considered
Table 7-2: Catheter-based systems for vector delivery to the cardiovascular system
Table 7-3: Companies involved in gene therapy of cardiovascular diseases
Table 8-1: Strategies for gene therapy of AIDS
Table 8-2: Companies involved in developing gene therapy for HIV/AIDS
Table 8-3: Companies developing genetic vaccines for infections other than AIDS
Table 9-1: Clinical trials of gene therapy in the US according to applications
Table 9-2: Potential future applications of gene therapy in disorders of the nervous system
Table 10-1: Genes that may be used for performance enhancement
Table 11-1: Gene therapy market according to regions/countries - 2008 to 2018
Table 11-2: Gene therapy markets according to therapeutic areas - 2008 to 2018
Table 11-3: Cancer gene therapy market according to type of cancer - 2008 to 2018
Table 11-4: Gene therapy market for selected genetic disorders - 2008 to 2018
Table 11-5: DNA vaccines markets according to technologies - 2008 to 2018
Table 11-6: DNA vaccines markets according to therapeutic indications - 2008 to 2018
Table 11-7: DNA vaccines markets according to geographical areas - 2008 to 2018
Figures
Figure 1-1: Relation of gene therapy to other biotechnologies
Figure 1-2: Relationship of DNA, RNA and protein in the cell
Figure 2-1: Ex vivo and in vivo techniques of gene therapy
Figure 2-2: Structure of the Helios gene gun
Figure 2-3: Cochleate-mediated gene therapy
Figure 2-4: Bacteria plus nanoparticles for drug delivery into cells
Figure 2-5: Schematic of suppression of gene expression by RNAi
Figure 6-1: Effect of tyrosine hydroxylase gene delivery on dopamine levels
Figure 6-2: Role of cell and gene therapy in stroke according to pathology and stage
Figure 9-1: Product development cycle in gene therapy
Figure 9-2: Proportions of therapeutic areas in clinical trials of gene therapy in the US
Figure 9-4: Proportions of various vectors used in gene therapy trials
Figure 11-1: Unmet needs in gene therapy
13. Companies involved in Gene Therapy
History of commercial development of gene therapy
Selection of companies and information
Supporting services for gene therapy
Profiles of Companies
Collaborations
Tables
Table 13-1: Major players in gene therapy
Table 13-2: Companies with supporting services for gene therapy
Table 13-3: Product pipeline of Medegene AG
Table 13-4: Product pipeline of Valentis
Table 13-5: Collaborations of gene therapy companies
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