Abstract
Summary
Gene therapy can be broadly defined as the transfer of defined genetic
material to specific target cells of a patient for the ultimate purpose of
preventing or altering a particular disease state. Genes and DNA are now being
introduced without the use of vectors and various techniques are being used to
modify the function of genes in vivo without gene transfer. If one adds to
this the cell therapy particularly with use of genetically modified cells, the
scope of gene therapy becomes much broader. Gene therapy can now combined with
antisense techniques such as RNA interference (RNAi), further increasing the
therapeutic applications. This report takes broad overview of gene therapy and
is the most up-to-date presentation from the author on this topic built-up
from a series of gene therapy report written by him during the past decade
including a textbook of gene therapy and a book on gene therapy companies.
This report describes the setbacks of gene therapy and renewed interest in the
topic
Gene therapy technologies are described in detail including viral vectors,
nonviral vectors and cell therapy with genetically modified vectors. Gene
therapy is an excellent method of drug delivery and various routes of
administration as well as targeted gene therapy are described. There is an
introduction to technologies for gene suppression as well as molecular
diagnostics to detect and monitor gene expression.
Clinical applications of gene therapy are extensive and cover most systems and
their disorders. Full chapters are devoted to genetic syndromes, cancer,
cardiovascular diseases, neurological disorders and viral infections with
emphasis on AIDS. Applications of gene therapy in veterinary medicine,
particularly for treating cats and dogs, are included.
Research and development is in progress in both the academic and the
industrial sectors. The National Institutes of Health (NIH) of the US is
playing an important part. As of 2011, over 2030 clinical trials have been
completed, are ongoing or have been approved worldwide.A breakdown of these
trials is shown according to the areas of application.
Since the death of Jesse Gelsinger in the US following a gene therapy
treatment, the FDA has further tightened the regulatory control on gene
therapy. A further setback was the reports of leukemia following use of
retroviral vectors in successful gene therapy for adenosine deaminase
deficiency. Several clinical trials were put on hold and many have resumed
now. The report also discusses the adverse effects of various vectors, safety
regulations and ethical aspects of gene therapy including germline gene
therapy.
The markets for gene therapy are difficult to estimate as there is only one
approved gene therapy product and it is marketed in China since 2004. Gene
therapy markets are estimated for the years 2011-2021. The estimates are based
on epidemiology of diseases to be treated with gene therapy, the portion of
those who will be eligible for these treatments, competing technologies and
the technical developments anticipated in the next decades. In spite of some
setbacks, the future for gene therapy is bright.The markets for DNA vaccines
are calculated separately as only genetically modified vaccines and those
using viral vectors are included in the gene therapy markets
The voluminous literature on gene therapy was reviewed and selected 700
references are appended in the bibliography.The references are constantly
updated. The text is supplemented with 72 tables and 14 figures.
Profiles of 185 companies involved in developing gene therapy are presented
along with 185 collaborations. There were only 44 companies involved in this
area in 1995. In spite of some failures and mergers, the number of companies
has increased more than 4-fold within a decade. These companies have been
followed up since they were the topic of a book on gene therapy companies by
the author of this report. John Wiley & Sons published the book in 2000 and
from 2001 to 2003, updated versions of these companies (approximately 160 at
mid-2003) were available on Wiley's web site. Since that free service was
discontinued and the rights reverted to the author, this report remains the
only authorized continuously updated version on gene therapy companies.
Benefits of this report
- Up-to-date on-stop information on gene therapy with 72 tables and 13
figures
- Evaluation of gene therapy technologies
- 700 selected references from the literature
- Estimates of gene therapy markets from 2011-2021
- Profiles of 185 companies involved and collaborations in this area
Who should read this report?
- Biotechnology companies developing gene therapy
- Academic institutions doing research in gene therapy
- Drug delivery companies
- Pharmaceutical companies interested in gene therapy
- Gene therapy companies
- Venture capital and investment companies
Table of Contents
Part-I
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
- Gene editing
- 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 vector for treatment of chronic inflammatory disease
- Polymer molecules
- 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
- 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
- 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)
- ΦC31 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
- 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
- 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
- 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
- Insertion of gene encoding for IL-4
- 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 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/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
- Degenerative retinal disorders
- Age-related macular degeneration
- Inherited retinal degenerations
- Inherited disorders affecting vision
- Gene therapy for color blindness
- Leber congenital amaurosis
- Retinitis pigmentosa
- Stargardt disease
- Usher syndrome
- X-linked juvenile retinoschisis
- 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
- 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
- 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 α1-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
- iPSCs for targeted gene correction of α1-antitrypsin deficiency
- Adrenoleukodystrophy
- Canavan disease
- Lesch-Nyhan syndrome
- LPL deficiency
- 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
- 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
- Antisense approach to DMD
- Exon-skipping technology 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
- 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
- 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
- Cancer terminator virus
- Cytokine-induced killer cells for delivery of an oncolytic virus
- Monitoring of viral-mediated oncolysis by PET
- Oncolytic HSV
- Oncolytic adenoviruses
- Oncolytic vesicular stomatitis virus
- Oncolytic paramyxovirus
- Oncolytic vaccinia 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
- 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.
- 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-b-
- Viral oncolysis of brain tumors
- 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
- Clinical trials
- Gene therapy of head and neck cancer
- Adenoviral vector based P53 gene therapy
- Gene therapy of pancreatic cancer
- Rexin-G™ for targeted gene delivery in cancer
- Targeted Expression of BikDD gene
- Concluding remarks on gene therapy of pancreatic cancer
- 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
- 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
- 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
- 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
- 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
- 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
- miRNA gene therapy for ischemic heart disease
- 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-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
- 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: 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 of 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 --2011 to
2021
- Table 11-2: Gene therapy markets according to therapeutic areas --2011 to
2021
- Table 11-3: Cancer gene therapy market according to type of cancer - 2011
to 2021
- Table 11-4: Gene therapy market for selected genetic disorders - 2011 to
2021
- Table 11-5: DNA vaccines markets according to technologies - 2011 to 2021
- Table 11-6: DNA vaccines markets according to therapeutic indications -
2011 to 2021
- Table 11-7: DNA vaccines markets according to geographical areas - 2011 to
2021
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 9-3: Proportions of various vectors used in gene therapy trials
- 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
