Types of Gene Therapy

9 Key excerpts on "Types of Gene Therapy"

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  eBook - ePub

  Molecular Medicine

  An Introduction

  • Jens Kurreck, Cy Aaron Stein(Authors)
  • 2015(Publication Date)
  • Wiley-Blackwell

    (Publisher)

  However, advances in vector technology are likely to overcome these obstacles in the near future. The term gene therapy refers to the transfer of genetic material into the cells of an individual's body with the intention of treating a disease. Classically, the affected patient carries a defective gene, the cause of the disease. The methods of molecular biology can be used to transfer the functional form of the gene to hopefully correct the defect (Figure 11.1). Examples of gene therapy include correction of metabolic functions, the replacement of missing blood coagulation factors, or the transfer of tumor suppressor genes for the treatment of cancer. In addition, gene therapy can be used to create cells with novel properties. For example, the body's own defense mechanisms against tumor cells can be triggered by the use of genes encoding cytokines. Genes for enzymes can be transferred, which convert the inactive precursor of a drug (prodrug) into the active form. DNA vaccination involves transferring viral genes, which trigger an immune response against the virus. Indeed, any transfer of nucleic acids designed to manipulate genes or to regulate gene expression may also be considered gene therapy. Examples also include antisense and RNA interference therapies, which will be addressed in Chapter 13. Fig. 11.1 Principles of gene therapy. Due to a defective gene, a protein may not be produced in the cells of the affected patient. With the aid of vectors, the intact version of the gene can be introduced into these cells. Whether or not the therapeutic gene is integrated into the genome of the host or remains episomal is determined by the choice of vector. The functional gene can then be expressed so that the active protein is synthesized and the defect corrected

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  Nanomaterials in Advanced Medicine

  • Hossein Hosseinkhani(Author)
  • 2019(Publication Date)
  • Wiley-VCH

    (Publisher)

  4 Nanomaterials in Gene Therapy Technology 4.1 Introduction The development over the past decade of methods for delivering genes to mammalian cells has stimulated great interest in the possibility of treating human disease by gene‐based therapies. However, despite substantial progress, a number of key technical issues need to be resolved before gene therapy can be safely and effectively applied in the clinic. The major aim of gene therapy is to effectively deliver the genetic materials into cells, genetically modifying and repairing cell functions, which may induce therapeutic healing of disease conditions. While most current gene therapy clinical trials are based on cell‐ and viral‐mediated approaches, nonviral gene medicines are emerging as potentially safe and effective in the treatment of a wide variety of genetic and acquired diseases. Viral vectors have been mainly used because of their inherently high transfection efficiency of gene. However, there are some problems to be resolved for the clinical applications, such as the pathogenicity and immunogenicity of viral vectors themselves. Therefore, many research trials with nonviral vectors have been performed to enhance their efficiency to a level comparable to the viral vector. Nonviral technologies consist of plasmid‐based expression systems containing a gene encoding a therapeutic protein and synthetic gene delivery systems. Gene therapy with nanoparticle technologies aims to control the in vivo location and function of administered genes. Gene transfection is a powerful and promising technique that involves the in vitro or in vivo introduction of exogenous genes into cells for experimental and therapeutic purposes. Whichever is the final goal for experimental biology and gene therapy, the first key issue to be dealt with is to enable the gene to internalize into the cell as efficiently as possible and to facilitate the expression for a long or short time

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  Advances in Animal Genomics

  • Sukanta Mondal, Ram Lakhan Singh(Authors)
  • 2020(Publication Date)
  • Academic Press

    (Publisher)

  Due to gene delivery, the generation of active drugs at the site where they are needed is possible. Parkinson's disease is caused by a deficiency of dopamine in the brain. The dopaminergic neurons, die leading to loss of movement control and tremors. The common treatment for Parkinson’s disease is a tablet delivering a dopamine precursor combined with a drug to enhance blood–brain barrier permeability of dopamine. This works well in early-stage diseases but declines in effectiveness as time progresses. A gene therapy approach, directly delivering the enzymes to produce dopamine transferred into the brain, might provide more stable local dopamine concentration. The first clinical trial used a lentiviral vector and was reported as safe and had some level of effectiveness, but more efficient delivery or higher gene expression will be necessary for furthering this method.

  11.5. Types of vectors

  The organisms and methods by which transfer of the genetic material during Gene Therapy occurs are called vectors. Viral vectors introduce the genetic material into the host cell by joining it to the cell chromosomes, which use them as a blueprint for the manufacturing of proteins. Different types of viruses have been utilized for gene therapy, such as Retroviruses, Adenoviruses (McConnell and Imperiale, 2004 ), and AAVs (Wu et al., 2006 ; Schultz and Chamberlain, 2008 ), herpes virus (Oehmig et.al., 2004 ), etc.

  Nonviral methods of Gene Therapy are complex and involve direct transfer of the genes into the host. These include the gene gun, electroporation, sonoporation, injection of naked DNA, etc. They have several advantages over viral vectors, but also some disadvantages. Some advantages include the ability to have large scale production and the lack of risk factor associated with viruses, but the disadvantage of nonviral methods is that there is reduced levels of DNA integration and expression of the new genes, lowering overall effectiveness.

  11.6. Techniques of gene therapy

  Gene augmentation, replacement of a mutated copy of the gene by a healthy copy (via recombination), correction of mutation by gene editing (CRISPR, TALEN, ZFN, etc.) methods, silencing of a dominant mutation (via shRNA or gene editing), altering the expression of genes by affecting transcription (transcription factors, epigenetic modulators) or splicing (exon skipping) are all considered to be GTP.

  Techniques of Gene Therapy include Gene augmentation, inhibition, and specific cell targeting. Gene Augmentation Therapy, when cells contain nonfunctional DNA, which prevents the formation of final protein, functional DNA is inserted. Gene Inhibition Therapy helps treat disorders such as cystic fibrosis; if there is a faulty gene in the cell, a gene is inserted, which either suppresses or overrides the faulty gene. This is used to treat cancer and inherited diseases and Specific Cell Therapy, where gene alteration is done for specific faulty cells in cancer treatment. It can be done by the insertion of a suicide gene to kill the cell or a marker gene to allow the cell to be targeted by the immune system.

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  Advanced Textbook On Gene Transfer, Gene Therapy And Genetic Pharmacology: Principles, Delivery And Pharmacological And Biomedical Applications Of Nucleotide-based Therapies

  Principles, Delivery and Pharmacological and Biomedical Applications of Nucleotide-Based Therapies

  • Daniel Scherman(Author)
  • 2013(Publication Date)
  • ICP

    (Publisher)

  8 Advanced Textbook on Gene Transfer, Gene Therapy and Genetic Pharmacology effect, or which encodes a missing protein or any protein or peptide allowing a therapeutic or vaccination effect. The distinction between genetic pharmacology and gene therapy (Fig. 2.1) will be preferentially used in the present textbook. However, other authors employ the generic expression “gene therapy” to designate all approaches implying the use of any natural or modified DNA or RNA nucleotide molecule. Gene therapy might be used, in a non-exhaustive list: • to compensate for a missing protein in a genetic disease, • to inhibit the production of a given protein (by generating an antisense mRNA), for instance to render cells resistant to viral infection, • to express a trophic factor or an anti-inflammatory cytokine, • to introduce a suicide gene for the treatment of cancer, Examples of potential applications of gene therapy are just too many to be listed here. Several genetic diseases have attracted large interest for application of a gene-replacement strategy (Table 2.1). Small-drug molecules generally target proteins Gene Therapy delivers a gene flanked by a eukaryotic promoter and a transcription termination signal Genetic Pharmacology : Small oligonucleotides target either DNA or RNA Genomic DNA mRNA Protein Function FIGURE 2.1 While chemical drugs classically target proteins (except in the case of anticancer cytotoxic compounds), small-chemical oligonucleotides used in genetic pharmacology generally target DNA and/or RNA, with the exception of aptamers (Chapter 4). Gene therapy consists of administering a gene-expressing cassette (promoter — gene — polyadenylation signal) to the cells.

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  Tissue Engineering

  • John P. Fisher, Antonios G. Mikos, Joseph D. Bronzino(Authors)
  • 2007(Publication Date)
  • CRC Press

    (Publisher)

  14 Gene Therapy J.M. Munson W.T. Godbey Tulane University 14.1 Introduction .............................................. 14 -1 14.2 Nucleotides for Delivery ................................. 14 -2 DNA (deoxyribonucleic acid) • RNA 14.3 Gene Delivery ............................................ 14 -2 Biological Delivery Methods • Chemical Delivery Methods • Physical Delivery Methods 14.4 Intracellular Pathways ................................... 14 -6 14.5 Cell and Tissue Targeting ................................ 14 -7 14.6 Applications .............................................. 14 -8 In Vitro • Ex Vivo • In Vivo 14.7 Clinical Applications .................................... 14 -9 14.8 Summary ................................................. 14 -10 References ....................................................... 14 -10 14.1 Introduction Gene therapy is the delivery of genetic material into cells for the purpose of altering cellular function. This seemingly straightforward definition encompasses a variety of situations that can at times seem unrelated. The delivered genetic material can be composed of deoxyribonucleic acid (DNA) or RNA, or even involve proteins in some cases. The alteration in cellular function can be an increase or decrease in the amount of a native protein that is produced, or the production of a protein that is foreign. The delivery of the genetic material can occur directly, as is the case with microinjection, or involve carriers that interact with cell membranes or membrane-bound proteins as a part of cellular entry. Polynucleotides can be single or double stranded, and can code for a message, or not (as is the case for antisense gene delivery). Even the location of cells at the time of gene delivery is not restricted. Cells can be part of a living organism, can exist as a culture on a plate, or can be removed from an organism, transfected, and replaced into the same or a different organism at a later time.

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  Genetically Modified Organisms and Genetic Engineering in Research and Therapy

  • P. Piguet, P. Poindron, P., Piguet, P., Poindron, P. Poindron, P. Piguet, P., Poindron, P., Piguet(Authors)
  • 2012(Publication Date)
  • S. Karger

    (Publisher)

  This review provides insights into the state-of-the-art accomplishments made with gene-based therapies. The review will focus on cancer gene therapy applications describing the general approaches and providing a summary of the recent advances and will discuss some examples of gene delivery and targeting strategies.

  Despite improved diagnostic methods and therapeutic regimens, cancer has a poor prognosis in the majority of cases. There is an increasing demand for novel diagnostic and therapeutic approaches. From new insights into the molecular basis of tumorigenesis and from the advent of recombinant DNA technology, the opportunity to treat cancer by using genetic information has emerged.

  Gene therapy has the potential to provide cancer treatments based on novel mechanisms of action with potentially low toxicities. However, application of this type of cancer treatment requires an understanding of tumor biology, methods for delivering genes to specific cell types, and strategies to regulate the level and duration of gene expression. Several strategies have been developed and ongoing clinical protocols can be divided into four groups: (1) suppression of oncogenes or transfer of tumor-suppressor genes; (2) enhancement of immunological response; (3) transfer of suicide genes, and (4) protection of bone marrow using drug resistance genes.

  The therapeutic effect of the gene should be targeted and last as long as required in an appropriately regulated fashion. In recent years, there have been intensive efforts to generate targetable, injectable vectors based on a variety of viral and nonviral gene delivery systems. Then, it is expected that this therapy may provide more effective control of locoregional recurrence in diseases as well as systemic control of micrometastases.

  Tumor Targeting

  The potential of gene therapy to target the expression of therapeutic genes to the desired target cells makes it particularly attractive for cancer treatment. Some progresses have been made in vector targeting with viral (nonreplicative and replication-competent) and nonviral vectors.

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  Liposomes in Gene Delivery

  • Danilo D. Lasic(Author)
  • 2019(Publication Date)
  • CRC Press

    (Publisher)

  GENE THERAPY Medicine has passed in its history through several breakthroughs, from Galen and Pasteur to the introduction of anesthesia, surgery, vaccines, antibiotics, novel imaging techniques, lasers, and remote operating devices. Direct treatment on the molecular level of diseases themselves and not their symptoms may be the next important development in human therapy. Gene therapy is emerging as a new modality as well as a technology in medical practice. It offers the potential to cure disease on its most basic level and has therefore captured the imagination of scientific and popular media. The therapy requires the insertion of a functional gene or other molecule with an information sequence into a cell to achieve a therapeutic effect, and the gene therefore serves as a drug (Anderson, 1992; Miller, 1992; Mulligan, 1993; Goldspiel et al., 1993). All the organisms of a particular species have an identical number and type of genes. Obviously, because we are not absolutely identical, small variations among genes exist within the species. While most of these polymorphisms have no effect on the protein function and some of them bring only innocuous variations in physical appearance, such as the color of eyes or hair, some of them produce serious inherited disorders. These disorders can be apparent immediately after birth or can develop only later in the life span; they can also make some individuals more susceptible to environmental factors. It is anticipated that gene therapy can handle or eliminate such problems. ■ ■ STRATEGIES IN GENE DELIVERY Several thousand diseases can be traced to defective or missing functional genes, and it is hoped that by delivering the appropriate gene into the appropriate cells, the mutated or missing proteins can be synthesized and the signs of the disease alleviated. In the majority of cases the mutation is in the coding region of the gene.

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  Novel Gene Therapy Approaches

  • Ming Wei, David Good, Ming Wei, David Good(Authors)
  • 2013(Publication Date)
  • IntechOpen

    (Publisher)

  Section 3 Gene Therapy for Cancer Chapter 10 Challenges in Advancing the Field of Cancer Gene Therapy: An Overview of the Multi-Functional Nanocarriers Azam Bolhassani and Tayebeh Saleh Additional information is available at the end of the chapter http://dx.doi.org/10.5772/54862 1. Introduction Recent developments in molecular biology and cell biology have led to the discovery of novel genes and proteins having therapeutic potentials for various diseases including cancers. Based on these findings, novel categories of therapeutic biomacromolecules in‐ cluding genes, small interfering RNA (siRNAs), antisense oligonucleic acids, bioactive proteins and peptides have been developed. These macromolecules can be more advanta‐ geous than small-molecular-weight therapeutic agents in terms of their specificity and high potency to the target molecules [Nakase et al., 2010]. Gene therapy is the newest therapeutic strategy for treating human diseases. The basic idea of gene therapy is a gene or gene product that can be selectively delivered to a specific cell/tissue with mini‐ mal toxicity. This product can inhibit the expression of a specific defective gene or ex‐ press a normal gene. Efficient and safe delivery is one of the key issues for the clinical application of nucleic acids as therapeutic agents [Du et al., 2010]. The goal of the Phar‐ maceutical Industry is to have a gene therapy medical product that can be delivered sys‐ temically. In vivo gene therapies have focused on viral vectors for gene delivery and have had marginal clinical successes. Major disadvantage of these delivery systems is the integration of some viral vectors into human chromosomes of normal tissue.

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  Animal Cell Technology

  From Biopharmaceuticals to Gene Therapy

  • Leda Castilho, Angela Moraes, Elisabeth Augusto, Mike Butler(Authors)
  • 2008(Publication Date)
  • Taylor & Francis

    (Publisher)

  With the advent of new knowledge in cell and molecular biology, it has become evident that the causes of many human diseases are related to changes in genes. Genes represent the starting point for all events that subsequently lead to changes in expression of proteins in cells. Protein function determines, in turn, the cell phenotype and cell function. When genes are changed in such a way that the proteins encoded by them are unable to perform their normal function, a genetic disorder may occur. The cumulative effect of events triggered by atypical or defective genes in an organ leads to the disease phenotype. Gene therapy is a technique used to correct genetic defects that may cause the development of diseases, and consists of blocking an undesirably activated gene, or correcting or replacing the defective gene with a normal gene (Figure 21.1). The diseases primarily targeted by human gene therapy are monogenic, that is, those caused by defects in a single gene (Anderson, 1998). Since the 1990s, the development of DNA vaccines has led to the concept of gene therapy being extended to prophylaxis and treatment of infectious diseases (Brun-nell and Morgan, 1998).

  The first step in gene therapy is to identify the gene causing the problem. Then the appropriate genetic material is introduced into the target cells, with the aim of correcting the problem. Two main strategies are used: (i) in vivo therapy, in which the genetic material is introduced directly into the individual by a systemic route, or when possible, at a specific site; (ii) ex vivo therapy, in which the target cells are treated with

  Figure 21.1 In a normal cell, genes are transcribed into messenger RNA (mRNA), and thereafter, translated into proteins with specific functions (A). When the gene responsible for encoding a protein has a defect, this may cause the translation of a defective protein, unable to perform its function and leading to a disease (B). Gene therapy aims to rectify the defect, by blocking, correcting, or replacing the gene.

  the gene product outside the individual. The cells are expanded and then transferred back to the patient (Figure 21.2 ).

  The key to successful in vivo gene therapy is the transfer of the genetic material to the target cells or tissues and the effective expression of the gene in question. However, this is a complex process, requiring several barriers to be overcome. Ex vivo gene therapy involves the transfer of genes to cells maintained in culture and their subsequent transplantation to the target tissue. The cells to be transfected must be available in large amounts, have a long life after transfer to the host, express the gene of interest for a long time period, and not trigger any kind of immune response. The advantages of ex vivo therapy include the possibility of characterizing the modified cell population before transfer. This makes it easier to introduce the genetic material into the cells and it can be insured that the clonal population of cells expresses a high amount of the product encoded by the transgene before transfer back into the patient.

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