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Gene Therapy - Technologies, Markets and Companies Product Image

Gene Therapy - Technologies, Markets and Companies

  • ID: 70434
  • October 2014
  • Region: Global
  • 676 Pages
  • Jain PharmaBiotech

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 READ MORE >

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
ENCODE
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
Genome editing
Gene editing by use of short synthetic oligonucleotides
Genome engineering by using TALENs
Genome editing by using CRISPR system
CRISPER system for creating animal models of human diseases
Targeted genome editing by artificial nucleases
Applications of CRISPR systems
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
Oncogenic potential of retroviral vectors
Future prospects of viral vectors
Companies using viral vectors
Nonviral vectors for gene therapy
Anionic lipid-DNA complexes
Cationic lipid-DNA complexes
Effects of shape of DNA molecules on delivery with nonviral vectors
Electrostatic modifications of surface to improve gene delivery
Liposomes for gene therapy
Liposome-nucleic acid complexes
Liposome-HVJ complex
Transposons DNA vectors
Polycation-DNA complexes (polyplexes)
Plasmid DNA vs minicircle DNA
Polymer vectors for gene therapy
Synthetic biology and DNA vectors
Synthetic peptide complexes
Future prospects of nonviral vs viral vectors
Nanobiotechnology for gene therapy
Antisense nanoparticles for gene regulation
Biological nanoparticle technology
Dendrimers
Cochleates
Calcium phosphate nanoparticles as nonviral vectors
DNA nanoparticles as nonviral vectors
Gelatin nanoparticles for gene delivery
Lipid nanoparticles for nucleic acid delivery
Nanoparticles as nonviral vectors for gene therapy
Nanoparticles with virus-like function as gene therapy vectors
Nanobiolistics for nucleic acid delivery
Nonionic polymeric micelles for oral gene delivery
Silica nanoparticles as a nonviral vector for gene delivery
Virus-like particles as nonviral vector
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
Mammalian artificial chromosomes (MACs)
Artificial Chromosome Expression (ACE)
Human artificial chromosomes (HACs)
FC31 integrase system
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
Microporation for transfection of MSCs
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
Role of genetically modified bacteria in 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
RNA vaccines
Nonviral delivery of self-amplifying RNA vaccine
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
microRNA 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
Aging research
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 and metabolic disorders
Introduction
Gene therapy of obesity
Ad viral vector-mediated transfer of leptin gene
AAV vector-mediated delivery of GDNF for obesity
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
Glucokinase and insulin co-expression
Leptin gene therapy
Concluding remarks about cell and gene therapy of diabetes
Gene therapy of growth-hormone deficiency
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 ß-thalassemia
Gene editing using ZFN as treatment for both SCD and ß-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/fetal 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
Methods of gene transfer to retinal cells
Delivery of gene therapy by intravitreal inection
DNA nanoparticles for nonviral gene transfer to the eye
Degenerative retinal disorders
Age-related macular degeneration
Inherited retinal degenerations
Inherited disorders affecting vision
Choroideremia
Color blindness
Leber congenital amaurosis
Retinitis pigmentosa
Stargardt disease
Usher syndrome
X-linked retinoschisis
Diabetic retinopathy
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
Companies developing gene therapy for eye disorders
Organ transplantation
Introduction
DNA vaccines for transplantation
Gene therapy for prolonging allograft survival
Gene therapy in lung transplantation
Role of gene therapy in liver transplantation
Gene therapy in kidney transplantation
Veto cells and transplant tolerance
Pulmonary disorders
Techniques of gene delivery to the lungs
Adenoviral vectors
Nonviral 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
Gene therapy of emphysema due to 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 plasmid DNA
Electroporation for transdermal delivery of DNA vaccines
Liposomes for transdermal gene delivery
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
Alpha1-antitrypsin deficiency
AAV mediated gene therapy for a1-antitrypsin deficiency
iPSCs for targeted gene correction of a1-antitrypsin deficiency
Adrenoleukodystrophy
Canavan disease
Lesch-Nyhan syndrome
Lipoprotein lipase deficiency
Alipogene tiparvovec
Ornithine transcarbamylase deficiency
Phenylketonuria
Porphyrias
Tetrahydrobiopterin deficiency
Lysosomal storage disorders.
Batten disease
Fabry's disease
Farber’s disease
Gaucher disease
Animals models of Gaucher's disease
Gene therapy of Gaucher's disease
Hunter syndrome
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
Antisense approach to DMD
Antisense oligonucleotide-induced exon-skipping for DMD
Liposome-mediated gene transfer
Myoblast-based gene transfer in DMD
Plasmid-mediated gene therapy
Post-transcriptional modulation of gene expression in DMD
Repair of dystrophin gene
Routes of administration of gene therapy in DMD
Types of dystrophin constructs
Viral vectors for DMD
Conclusions and future prospects of gene therapy of DMD
Limb-girdle muscular dystrophy
Myotonic dystrophy
Spinal muscular atrophy
Gene therapy for SMA
Antisense therapy of SMA
X-linked myotubular myopathy (XLMTM)
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
Radioprotective gene therapy
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
Antiangiogenic 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
Cytokine-induced killer cells for delivery of an oncolytic virus
Monitoring of viral-mediated oncolysis by PET
Oncolytic adenoviruses
Oncolytic HSV
Oncolytic measles viruses
Oncolytic vaccinia virus
Oncolytic vesicular stomatitis virus
Targeted cancer treatments based on oncolytic viruses
Concluding remarks on 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
Anticancer effect of nitric oxide synthase
Gene therapy for radiosensitization of cancer
Gene therapy of cancer of selected organs
Gene therapy for bladder cancer
Gene therapy for glioblastoma multiforme.
Adenoviral vectors for treatment of brain tumors
Antiangiogenic gene therapy
Autophagy induced by conditionally replicating adenoviruses
Baculovirus vector for diphtheria toxin gene therapy
Cerepro® (sitimagene ceradenovec)
Gene therapy targeting hepatocyte growth factor
Genetically engineered MSCs for gene delivery to intracranial gliomas
Intravenous gene delivery with nanoparticles into brain tumors
Ligand-directed delivery of dsRNA molecules targeted to EGFR
RNAi gene therapy of brain cancer
Targeting normal brain cells with an AAV vector encoding interferon-ß
Viral oncolysis of glioblastoma multiforme
Gene therapy for breast cancer
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
Vaccines for prostate cancer
Viral oncolysis for prostate cancer
Clinical trials
Gene therapy of head and neck cancer
Adenoviral vector based P53 gene therapy
Gene therapy as adjunct to 5-FU for nasopharangeal carcinoma
Gene therapy of pancreatic cancer
Correction of altered genes
Targeted gene therapy
Targeting in pancreatic adenocarcinoma with cell surface antigens
Targeted Expression of BikDD gene
Viral oncolysis in pancreatic cancer
Concluding remarks on gene therapy of pancreatic cancer
Gene therapy of renal cancer
Viral onclolytic therapy for renal cancer
Gene therapy of hematological malignancies
Genetically engineered T lymphocytes
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 transfer for neuromodulation
Gene therapy of neurodegenerative disorders
Gene therapy for Parkinson disease
Rationale
Techniques of gene therapy for PD
Augmenting CNS glucocerebrosidase activity
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
Concluding remarks about gene therapy of PD
Companies developing gene therapy for PD
Gene therapy for Alzheimer disease
Rationale
NGF gene therapy for AD
FGF2 gene transfer in 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
Other approaches to 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
RNAi-based gene silencing for neuroprotection in cerebral ischemia
Concluding remarks about gene therapy for stroke
Gene therapy of injuries to the nervous system
Traumatic brain injury
Spinal cord injury
Peripheral nerve injuries
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 impairment of special senses
Gene therapy for hearing loss
Gene therapy for olfactory impairment
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-?B
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
Gene therapy against fear disorders
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
AAV vectors for therapeutic delivery to the heart
Adenoviral vectors for cardiovascular diseases
Molecular cardiac surgery with recirculating delivery of AAV vectors
Plasmid DNA-based delivery in cardiovascular disorders
Gene therapy for counteracting hypoxia in myocardial ischemia
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
Apolipoprotein E deficiency
Hypertension
Genetic factors for myocardial infarction
Acquired cardiovascular diseases
Coronary artery disease with angina pectoris
Ad5FGF-4
Gene therapy for improving long-term CABG patency rates
Ischemic heart disease with myocardial infarction
Gene therapy and angiogenesis in ischemic heart disease
Induction of angiogenesis in myocardium by HEXIM1 re-expression
Myocardial repair with IGF-1 therapy
Metalloproteinase-2 inhibitor gene therapy
miRNA gene therapy for ischemic heart disease
Congestive heart failure
Rationale of gene therapy in CHF
AAV-mediated gene transfer for CHF
AngioCell gene therapy for CHF
ß-ARKct gene therapy
Elevating cardiac dATP by gene therapy to improve cardiac function
Intracoronary adenovirus-mediated gene therapy for CHF
nNOS gene transfer in CHF
Cardiomyopathies
Cardiac conduction disturbances
Gene transfer approaches for biological pacemakers
Genetically engineered biological pacemakers
Cholesterol reduction by genetic engineering of PCSK9 gene
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-1? gene therapy for peripheral arterial disease
HGF gene therapy for peripheral arterial disease
Prevention of restenosis after angioplasty
Antisense approaches
Gene therapy to prevent restenosis after angioplasty
hTIMP-1 gene therapy to prevent intimal hyperplasia
miRNA-based gene therapy for restenosis
NOS gene therapy for restenosis
Techniques of gene therapy for restenosis
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)-? 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
Vaccine for hepatitis C
Gene therapy for hepatitis C
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
Funding of gene therapy research in Europe
Gene therapy funding in Horizon 2020 of European Commission
Financing by the industry
Clinical trials in gene therapy
Clinical trials worldwide
Clinical trials in cancer gene therapy
Trials of gene therapy for neurological disorders
Clinical trials for genetic disorders
Clinical trials in cardiovascular gene therapy
Clinical trials for infectious diseases
Gene therapy for other disorders
Clinical trials in the US
Vectors used in gene therapy clinical trials
Future prospects for the gene therapy
How to improve gene therapy
International Gene Therapy Consortium
Future opportunities and challenges for 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
Implantation of genetically manipulated cells
Modification of oocytes for use in IVF
Clinical trials in gene therapy
Cell and gene therapy INDs placed on hold by the FDA
Regulation of gene therapy in Europe
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 Italy
Regulation of gene therapy in the Netherlands
Gene therapy regulation in Switzerland
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
Regulatory and ethical issues for in utero gene therapy
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
Development of gene therapy market in China

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: Animal experimental studies of in vivo gene delivery with polymer 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: Companies developing gene therapy for eye disorders
Table 3-11: Strategies for gene delivery to the lungs
Table 3-12: 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 oncolytic virotherapy against glioblastoma multiforme
Table 5-9: Clinical trials of gene therapy in ovarian cancer
Table 5-10: Gene therapy for malignant melanoma
Table 5-11: Clinical trials of gene therapy for prostate cancer
Table 5-12: 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 that are potential indications for gene therapy
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: Geographical distribution of gene therapy clinical trials
Table 9-2: Opportunities and challenges for gene therapy and resources needed
Table 9-3: Potential 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 ? 2013 to 2023
Table 11-2: Gene therapy markets according to therapeutic areas ? 2013 to 2023
Table 11-3: Cancer gene therapy market according to type of cancer - 2013 to 2023
Table 11-4: Gene therapy market for selected genetic disorders - 2013 to 2023
Table 11-5: DNA vaccines markets according to technologies - 2013 to 2023
Table 11-6: DNA vaccines markets according to therapeutic indications - 2013 to 2023
Table 11-7: DNA vaccines markets according to geographical areas - 2013 to 2023

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: Bacteria plus nanoparticles for drug delivery into cells
Figure 2-4: Schematic of suppression of gene expression by RNAi

Figure 4-1: Targeted gene correction of a1-antitrypsin deficiency by iPSCs
Figure 5-1: Gene therapy approaches for pancreatic cancer
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 9-3: Proportions of various vectors used in gene therapy trials
Figure 10-1: Evaluation system of gene therapy clinical studies in Japan
Figure 11-1: Unmet needs in gene therapy

Part II

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

Professor K. K. Jain is a neurologist/neurosurgeon by training and has been working in the biotechnology/biopharmaceuticals industry for several years. He received graduate training in both Europe and USA, has held academic positions in several countries and is a Fellow of the Faculty of Pharmaceutical Medicine of the Royal Colleges of UK. Currently he is a consultant at Jain PharmaBiotech. Prof. Jain is the author of 415 publications including 16 books (2 as editor) and 48 special reports, which have covered important areas in biotechnology, gene therapy and biopharmaceuticals.

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