Gene Therapy - technologies, markets and companies

Table of Contents

0. 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 β-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-β
• 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-G™ 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
• β-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-1α 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)-β 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