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Gene Therapy - Technologies, Markets & Companies

  • ID: 4748173
  • Report
  • March 2020
  • Region: Global
  • 798 Pages
  • Jain PharmaBiotech
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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. Gene editing technologies such as CRISPR-Cas9 and CAR-T cell therapies are also included

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 2016, over 2050 clinical trials were completed, were ongoing or had been approved worldwide.A breakdown of these trials is shown according to the geographical areas and applications.

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. Four gene medicines have been approved by the FDA. The report also discusses the adverse effects of various vectors, safety regulations and ethical aspects of gene therapy including gene editing and germline gene therapy.

The markets for gene therapy have been difficult to estimate as there only a few approved gene therapy products Gene therapy markets are estimated for the years 2019-2029. 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 750 references are appended in the bibliography.The references are constantly updated. The text is supplemented with 79 tables and 25 figures.

Profiles of 202 companies involved in developing gene therapy are presented along with 266 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 in 2 decades. 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 79 tables and 25 figures
  • Evaluation of gene therapy technologies
  • 750 selected references from the literature
  • Estimates of gene therapy markets from 2018-2028
  • Profiles of 202 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
Note: Product cover images may vary from those shown
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Part I: Technologies & Markets

0. Executive Summary

1. Introduction
Historical evolution of gene therapy
Relation of gene therapy to other biotechnologies
Molecular biological basics for gene therapy
RNA splicing
Silent gene mutations
Gene regulation
Gene expression

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
Applications of electroporation
Clinical applications of electroporation
Advantages of electroporation
Limitations of electroporation
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
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
Quantification of viral vectors
Future 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 of nonviral vs viral vectors
Nanobiotechnology for gene therapy
Antisense nanoparticles
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)
Human artificial chromosomes (HACs)
ΦC31 integrase system
Companies using nonviral vectors
Concluding remarks about vectors
Gene repair and replacement
Gene repair by single-stranded oligonucleotides
History and current status of chimeraplasty
Genome editing
Gene editing by zinc finger nucleases
Gene editing by using short synthetic oligonucleotides
Genome engineering by using TALENs
Genome editing by homologous recombination
GeneRide technology for genome editing
Gene editing by homing endonucleases
ARCUS genome editing technology
Genome editing by using CRISPR system
A method for generating genome-wide gRNA libraries for CRISPR
CRISPR-genome organization system
CRISPR vs other gene editing tools
CRISPR for studying human embryogenesis
CRISPER system for creating animal models of human diseases
CRISPR/Cas9 technology for drug discovery
CRISPR/Cas9-mediated epigenetic editing system
Expanding the range of Cas9s
Inducible CRISPR/Cas9 for multiple gene targeting
Lipid nanoparticles for delivery of CRISPR-Cas9 for genome-editing
Nanocapsules for delivery of CRISPR-Cas9 for genome editing
Photoactivatable CRISPR-Cas9
Protein delivery and genome editing
Potential clinical applications of CRISPR systems
Autosomal dominant retinitis pigmentosa
Clinical trial of CRISPR in human cancer
Correction of a gene mutation in the human embryo
PERV blockage by CRISPR to facilitate xenotransplantation
RNA editing with CRISPR
Use of CRISPR for β-hemoglobinopathies
Use of CRISPR to restore hereditary hearing loss
Complications and limitations of CRISPR/Cas9 technology
Companies developing CRISPR technology
Clinical studies of gene editing
Targeted genome editing by artificial nucleases
Ex vivo gene editing
Future gene editing tools
DNA medicines based on gene editing
Comparison of gene editing with techniques for suppression of gene mutations
Base editing of the genome
Base editing by protein engineering
Adenine base editors for genomic DNA
Messenger RNA gene therapy
Spliceosome mediated RNA trans-splicing
Cell-mediated gene therapy
Skeletal muscle cells
Vascular smooth muscle cells
Regulating protein delivery by genetically encoded lymphocytes
Implantation of microencapulated genetically modified cells
Stem cell gene therapy
Combination of gene therapy with therapeutic cloning
Expansion of transduced HSCs in vivo
Gene delivery to stem cells by artificial chromosome expression
Improving delivery of genes to stem cells
In utero gene therapy using stem cells
Lentiviral vectors for gene transfer to marrow stem cells
Linker based sperm-mediated gene transfer technology
Mesenchymal stem cells for gene therapy
Microporation for transfection of MSCs
Preventing immune rejection of transplanted stem cells
Therapeutic applications for hematopoietic stem cell gene transfer
Transdermal gene therapy for drug addiction
The future of hematopoietic stem cell gene therapy
Chimeric antigen receptor T cells in relation to gene therapy
Basics of CAR-T cell
Basis of anticancer effect of CAR-T cells
Smart T-cells
CAR-T cell manufacture
Companies developing CAR-T cell therapy
CAR NK cells derived from human iPSCs
Genome editing of CAR-T cells
Safety and efficacy of CAR-T cell therapy
Cytokine release syndrome
Precautions for CAR-T cell 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
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
Peptide nucleic acid
Intracellular delivery of PNAs
Locked nucleic acid
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
Viral vectors for RNAi and miRNA 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
Formulation, transport and storage of materials for gene therapy

3. Clinical Applications of Gene Therapy
Aging-related disorders
Telomerase gene therapy in aging
Combination gene therapy for treatment of multiple age-related diseases
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 of gene therapy for rheumatoid arthritis
Gene therapy for osteoarthritis
Gene therapy strategies for osteoarthritis
Clinical trials of 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
Tissue engineering in dental implant defects
Endocrine and metabolic disorders
Gene therapy of obesity
AAV vector-mediated delivery of GDNF for obesity
Oligopeptide for targeted nonviral gene delivery to adipocytes
Viral vector-mediated leptin gene therapy
Diabetes mellitus
Methods of gene therapy of diabetes mellitus
Viral vector-mediated gene transfer in diabetes
Endogenous reprogramming of α cells into  cells
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
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
Gene therapy of hemophilia
Hemophilia A
Hemophilia B
Concluding remarks about gene therapy of hemophilias
Gene therapy for β-thalassemia
Gene therapy for sickle cell disease
HSC-targeted gene therapy for SCD
Gene therapy and RNAi for SCD based on stem cells
Gene editing in sickle cell disease
Gene editing using ZFN as treatment for both SCD and β-thalassemia
Gene editing using CRISPR-Cas9 for both SCD and β-thalassemia
Gene therapy of Fanconi's anemia
Acquired hematopoietic disorders
Chronic acquired anemias
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
Gene therapy for fetal growth restriction
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
Bone marrow stem cells for renal disease
Gene transfer into kidney by viral vectors
Gene transfer into the glomerulus by HVJ-liposome
Gene transfer to tubules with cationic polymer polyethylenimine
Liposome-mediated gene transfer into the tubules
Mesangial cell therapy
Non-viral gene transfer to the kidneys
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
Wilson’s disease
Gene therapy of acquired diseases affecting the liver
Cirrhosis of liver
Ophthalmic disorders
Introduction to gene therapy of ophthalmic disorders
Methods of gene therapy for ophthalmic disorders
Delivery of gene therapy by intravitreal injection
DNA nanoparticles for nonviral gene transfer to the eye
Optogenetic gene therapy for blindness due to retinal degeneration
Age-related macular degeneration
Inherited disorders of optic nerve affecting vision
Leber hereditary optic neuropathy
Gene therapy for LHON
Inherited retinal degenerations
Leber congenital amaurosis
Monogenic macular degeneration due to mutations in the BEST1 gene
Retinitis pigmentosa
Stargardt disease
Other inherited disorders affecting vision
Color blindness
Usher syndrome
X-linked retinoschisis
Diabetic retinopathy
Future of gene therapy of inherited retinal degenerations
Combining cell and gene therapies for retinal disorders
Prevention of complications associated with eye surgery
Prevention of proliferative retinopathy by gene therapy
Posterior capsule opacification after cataract surgery
Autoimmune uveitis
Retinal ischemic injury
Corneal disorders
Corneal scarring
Companies developing gene therapy for eye disorders
Organ transplantation
DNA vaccines for transplantation
Gene therapy for prolonging allograft survival
Genetically modified Tregs expressing CAR for preventing GVHD
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 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 epidermolysis bullosa
Gene therapy for xeroderma pigmentosa
Gene therapy for lamellar ichthyosis
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
Gene therapy of miscellaneous disorders
Primary Sjögren's syndrome
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
Primary immunodeficiency disorders
Severe combined immune deficiency
Gene therapy for SCID
Lentiviral gene therapy combined with low-dose busulfan for SCID-X1
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 α1-antitrypsin deficiency
iPSCs for targeted gene correction of α1-antitrypsin deficiency
Gene editing for AAT deficiency
Canavan disease
Lesch-Nyhan syndrome
Lipoprotein lipase deficiency
Alipogene tiparvovec
Ornithine transcarbamylase deficiency
Gene therapy for OTCD
AAV-mediated gene editing for OTCD using CRISPR-Cas9
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
Glycogen storage disorders
Glycogen storage disease type I
Gene therapy of GSD1a
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/Sandhoff disease
Future of gene therapy of lysosomal storage disorders
Trinucleotide repeat disorders
Muscular dystrophies
Duchenne muscular dystrophy (DMD)
Animal models for gene therapy of DMD
Antisense approaches to DMD
CRISPR/Cas9 gene editing for DMD
Exon-skipping for DMD
Galgt2 gene therapy
Liposome-mediated gene transfer
Microdystrophin gene therapy
Myoblast-based gene transfer in DMD
Plasmid-mediated gene therapy
Purinoreceptor P2RX7 ablation
Post-transcriptional modulation of gene expression in DMD
Repair/Editing of dystrophin gene
Routes of administration of gene therapy in DMD
Types of dystrophin constructs
Viral vectors for DMD
Conclusions and future of gene therapy of DMD
Limb-girdle muscular dystrophy
Myotonic dystrophy
Spinal muscular atrophy
Gene therapy strategies for SMA
Zolgensma® gene therapy for SMA
Antisense approaches for SMA
Nusinersen vs Zolgensma® gene therapy for SMA
X-linked myotubular myopathy (XLMTM)
Hereditary neuropathies
Charcot-Marie-Tooth disease
Hereditary axonal neuropathies of the peripheral nerves
Gene therapy of mitochondrial disorders
Techniques for mitochondrial replacement therapy
Status of mitochondrial replacement and transfer therapies
Barth syndrome
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 of cancer
Nanoparticles to facilitate combination of hyperthermia and gene therapy
Immunogene therapy of cancer
Cell-based cancer gene therapy
Adoptive cell therapy
CAR-T cell therapy for cancer
CAR-T cells for tumor targeting
CAR-T cells targeting both CD19 and CD22
Remote control of CAR-T cells for cancer immunotherapy
CAR-T cell therapy for leukemia
CAR-T cell therapy for multiple myeloma
CAR-T cell therapy for lymphoma
CAR-T cell therapy for solid tumors
Cytokine gene therapy
Genetic modification of human hematopoietic stem cells
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
Vaccines based on genetically engineered nonviral vectors
Future 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 therapy techniques for immunotherapy of cancer
CRISPR for immunogene therapy
Engineered viruses as anticancer immunotherapy vectors
Fas (Apo-1)
Major Histocompatibility Complex (MHC) Class I
IGF (Insulin-Like Growth Factor)
Cancer immunotherapies targeting multiple mechanisms
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 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
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
Olig2 targeting to hinder growth of treatment-resistant glioblastomas
RNAi gene therapy of brain cancer
Targeting normal brain cells with an AAV vector encoding interferon-β
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
Immunogene therapy
Nonviral immunogene therapy for malignant melanoma
Oncogene targeted therapy
Targeted 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 of gene therapy for prostate cancer
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 tumors
Pancreatic neuroendocrine tumors
Pancreatic ductal adenocarcinoma
Editing 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
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 nervous system
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
Cerebral endothelial cells
Implantation of genetically modified encapsulated cells into the brain
Gene transfer for neuromodulation
Monitoring of CNS gene therapy
Gene therapy of neurodegenerative disorders
Gene therapy for Parkinson disease
Techniques of gene therapy for PD
Augmenting CNS glucocerebrosidase activity
Delivery of neurotrophic factors by gene therapy
Delivery of parkin gene
Gene editing in PD
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
Viral vector-based ubiquitination to prevent spread of α-synuclein
Prospects of gene therapy for PD
Concluding remarks about gene therapy of PD
Companies developing gene therapy for PD
Gene therapy for Alzheimer disease
NGF gene therapy for AD
FGF2 gene transfer in AD
Gene therapy for restoring brain cholesterol metabolism
Neprilysin gene therapy
Viral gene transfer of APPsα for rescuing synaptic failure in AD
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
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
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
Catecholaminergic polymorphic ventricular tachycardia
Genetic disorders predisposing to atherosclerosis
Familial hypercholesterolemia
Apolipoprotein E deficiency
Genetic factors for myocardial infarction
Acquired cardiovascular diseases
Coronary artery disease with angina pectoris
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
β-ARKct gene therapy
Elevating cardiac dATP by gene therapy to improve cardiac function
Elevating cardiac adenyl cylase type 6 to improve cardiac function
Intracoronary adenovirus-mediated gene therapy for CHF
nNOS gene transfer in CHF
Cardiac arrhythmias
Gene transfer approaches for biological pacemakers
Genetically engineered biological pacemakers
Gene therapy for ventricular arrhythmia
Gene therapy and heart transplantation
Hyperlipidemia and hypercholesterolemia
Antisense approach to hypertriglyceridemia
Cholesterol reduction by genetic engineering of PCSK9 gene
Inactivating variants in ANGPTL4 for lowering circulating triglycerides
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 of gene therapy of cardiovascular disorders

8. Gene therapy of viral infections
Acquired Immunodeficiency Syndrome (AIDS)
Current management of AIDS
Gene therapy strategies in HIV/AIDS
Cell/gene therapies for HIV/AIDS
Anti-HIV ribozyme delivered in hematopoietic progenitor cells
Autocrine interferon (INF)- production by somatic cell gene therapy
Gene editing for HIV-1
Transplantation of genetically modified T cells
Transplantation of genetically modified hematopoietic cells
Inhibition of HIV-1 replication by lentiviral vectors
Insertion of protective genes into target cells
HIV/AIDS vaccines
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
Antisense approaches to AIDS
RNA decoys
Antisense oligodeoxynucleotides
RNA decoys
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
Vector analytics for clinical trials using rAAV vectors
Gene therapy in China
Future of 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, Ethical Patent 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
Gene therapy INDs placed on hold by the FDA
FDA policy for advancing development of gene therapy
Future for approval of gene therapy in the US
Do-it-yourself gene therapy
Regulation of gene therapy in Europe
European Union
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
Ethical aspects of mitochondrial replacement therapy
Ethical aspects of gene editing
Ethical aspects of clinical trials of germline editing
Gene editing in the UK
Gene editing in the US
Guidelines for gene editing by Alliance for Regenerative Medicine
UNESCO’s view on gene editing in humans
Concluding remarks on the ethical aspects of genome editing
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
Gene therapy patents
CRISP/Cas9 patents

11. Markets for Gene Therapy
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
Cell therapy
Strategies for developing gene therapy markets
Collaboration with pharmaceutical companies
Collaboration with companies developing cell-based therapies
Collaboration with academic gene therapy centers
Developing safer and cost-effective gene medicines
Intellectual property and commercialization of gene therapy
Overcoming obstructions to the development of gene therapy
Unmet needs in gene therapy  
Promises and challenges for the development of gene therapy
Development of gene therapy market in China
Challenges of developing gene therapy in the USA
Challenges of developing gene therapy in the European Union

12. References

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 nonviral gene therapy methods.
Table 2-8: CRISPR vs other gene editing tools
Table 2-9: Companies developing CRISPR technology
Table 2-10: Companies developing CAR-T cell therapy
Table 2-11: Potential routes for administration of DNA
Table 2-12: Companies with gene delivery devices/technologies
Table 2-13: Strategies for targeted gene therapy
Table 2-14: Animal experimental studies of in vivo gene delivery with polymer systems
Table 2-15: Approaches to controlling gene expression in gene therapy
Table 2-16: Companies with regulated/targeted gene therapy and special techniques
Table 2-17: Potential applications of human germline genome modification
Table 2-18: Applications of molecular diagnostics in gene therapy
Table 2-19: 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: Clinical trials of gene therapy for hemophilia A and B
Table 3-7: Companies involved in gene therapy of hematological disorders
Table 3-8: Techniques of gene transfer to the kidneys
Table 3-9: Gene therapy in animal experimental models of renal disease.
Table 3-10: Applications of gene therapy in ophthalmological disorders
Table 3-11: Companies developing gene therapy for eye disorders
Table 3-12: Strategies for gene delivery to the lungs
Table 3-13: 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 − 2019 to 2029
Table 11-2: Gene therapy markets according to therapeutic areas − 2019 to 2029
Table 11-3: Cancer gene therapy market according to type of cancer - 2019 to 2029
Table 11-4: Gene therapy market for selected genetic disorders - 2019 to 2029
Table 11-5: DNA vaccines markets according to technologies - 2019 to 2028
Table 11-6: DNA vaccines markets according to therapeutic indications - 2019 to 2029
Table 11-7: DNA vaccines markets according to geographical areas - 2019 to 2029

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: Categories of rAAV-based gene therapy strategies
Figure 2-4: Bacteria plus nanoparticles for drug delivery into cells
Figure 2-5: Gene editing by zinc finger nucleases
Figure 2-6: Genome engineering by transcription-activator–like-effector-nucleases
Figure 2-7: Mechanism of action of GeneRide technology
Figure 2-8: A scheme of CRISPR/Cas9 gene editing
Figure 2-9: Use of CRISPR-Cas9 for hereditary hearing loss
Figure 2-10: Gene editing vs suppression of gene expression
Figure 2-11: Chimeric antigen receptor (CAR)-T cells attacking tumor cells
Figure 2-12: Schematic of suppression of gene expression by RNAi
Figure 3-1: Retina and routes of administration of gene therapy for retinal disorders
Figure 4-1: Targeted gene correction of α1-antitrypsin deficiency by iPSCs
Figure 4-2: Application of CRISPR-Cas9 in a mouse model of DMD
Figure 4-3: Techniques for mitochondrial nuclear transfer
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 11-1: Unmet needs in gene therapy

Part 2: Companies

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

Table 13-1: Major players in gene therapy
Table 13-2: Companies with supporting services for gene therapy
Table 13-3: Collaborations of gene therapy companies

Note: Product cover images may vary from those shown
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