Risks of Gene Therapy

4 Key excerpts on "Risks of Gene Therapy"

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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)

  The first failures and some (though extremely rare) accidents led unfairly to the perception that the promises of gene therapy were more than what it could deliver. Efficacy, safety, and ethical aspects became focuses of furious debate (Wilson, 2008). Gene therapy involves a whole lot of complicated sets of activities involving tissue targeting, cellular trafficking, delivery of genes to organs, safety of the vector, activity of therapeutic protein, etc. For example, in gene therapy for cystic fibrosis a very early indication is hampered by the complications involved in penetrating the natural barriers that impede viral entry into the obstructed air-ways. 20 Advanced Textbook on Gene Transfer, Gene Therapy and Genetic Pharmacology 3.2 Obstacles to the Development of Gene Therapy 3.2.1 Short Life of Treatment The therapeutic genetic material introduced into target cells must remain func-tional. Naked DNA or certain viruses (e.g. AAVs) may remain episomal and allow sustained expression in stable tissues (e.g. neurons or skeletal muscles). However, promoters and/or gene sequences different from host codon usage may be subjected to epigenetically induced extinction. In addition, long-term benefit, due to the rapidly dividing nature of many cells, often requires either integration of the therapeutic DNA into the host-cell genome or multiple rounds of gene therapy. 3.2.2 Toxicity and Inflammatory Responses In the OTCD trial, the patient J. Gelsinger died from fulminant hepatitis four days after beginning treatment with an adenovirus vector. Since then, work using adenovirus vectors has focused on genetically crippled versions of the virus, safer production standards and clinical protocols. It is now being restricted to indica-tions compatible with short-term expression of the transgene (such as vaccination) and more favorable risk:benefit ratio (i.e. cancer or cardiovascular diseases).

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  Advances In Pharmaceutical Cell Therapy: Principles Of Cell-based Biopharmaceuticals

  Principles of Cell-Based Biopharmaceuticals

  • Christine Günther, Andrea Hauser, Ralf Huss(Authors)
  • 2015(Publication Date)
  • WSPC

    (Publisher)

  As the expression of viral genes in the host cells is usually the reason for cellular toxicity and immunological complications associated with viral infections, transduction with recombinant viral vectors lacking these genes is typically well tolerated. However, problems that might be encountered using viral vectors in gene therapy approaches and that need to be considered are:

  •Acute toxicity. •Immune responses: Humoral immune reactions against the transgene or the viral vector, or both, and cellular immune responses against the transduced cells.

  •Risk of insertional mutagenesis by integrating viral vectors.25

  As adverse events due to insertional transformation by integrating vectors have posed a problem in several clinical trials so far, this important topic will be discussed in this chapter in more detail.

  14.4.1Insertional transformation

  The risk of insertional mutagenesis to date is one of the major safety concerns for ex vivo gene therapy approaches using (stem) cells. Viral vectors like retroviral and lentiviral integrate their genetic information quasi-randomly into the host genome, with gamma-retroviruses tending to integrate near gene regulatory sites like transcriptional start sites, while lentiviruses have the presumably safer preference of integrating into actively transcribed genes.

  57 ,58

  Integration close to transcriptional control elements of genes can lead to their deregulation by the action of strong enhancer elements present in the viral LTRs, conveying a growth advantage to the affected clones, which in turn can lead to clonal expansion and malignancies.

  5 ,8

  Examples of such severe adverse events, in which the integration of a retroviral vector with strong enhancer elements in the LTRs close to a proto-oncogene lead to transactivation of that gene and in the end leukoproliferative disease are the clinical trials for SCID-X1,11 CGD12 and WAS.13

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  Gene Therapy

  Developments and Future Perspectives

  • Chunsheng Kang(Author)
  • 2011(Publication Date)
  • IntechOpen

    (Publisher)

  Almost half a century later, the initial enthusiasm and euphoria have been greatly tempered by the sober recognition that while gene therapy is simple in concept, it is highly complex and challenging in execution. The early promises of human gene therapy raised unrealistically high expectations that gene medicine was round the corner. Compounded by well publicised serious iatrogenic complications from a small number of clinical trials, a pall quickly descended on the field from the late 1990s that led many investigators to flee from a field of research that came to be perceived as both unfeasible and unfundable. Gene therapy has now emerged from a much needed phase of reflection and correction. There is clear evidence that appropriately selected monogenic and acquired diseases can benefit from gene-based therapy. Notwithstanding that there remains a risk to certain viral vectors, the decision to reinitiate gene therapy trials for SCID-X1 (NCT01129544) is acknowledgement of what gene therapy may offer to diseases that are currently difficult to treat effectively or at reasonable cost. Failures of gene therapy should not discredit the field but ought to be opportunities to deepen scientific understanding of the complex processes demanded for therapeutic success. Safety is a key consideration, particularly with respect to genotoxicity. The confluence of autologous cell therapy with conventional gene therapy appears to be a promising approach. Cells that are first modified ex vivo lend themselves readily to comprehensive biosafety assessments that are not feasible with conventional in vivo gene therapy. The ability to thoroughly characterize cells for the desired phenotype, and for genotoxicity and other risks before in vivo implantation or administration should go some way to making such novel treatments safe. (The authors were unable to cite all relevant publications owing to page limitations.) Gene Therapy - Developments and Future Perspectives 176 6.

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  Drug Safety Evaluation

  • Shayne Cox Gad, Dexter W. Sullivan(Authors)
  • 2022(Publication Date)
  • Wiley

    (Publisher)

  35 Drug Safety Evaluation, Fourth Edition. Shayne Cox Gad and Dexter W. Sullivan, Jr. © 2023 John Wiley & Sons, Inc. Published 2023 by John Wiley & Sons, Inc. 789 This chapter seeks to overview three closely related therapeutic products that are either living biologic compo- nents or genetic material directly derived from such compo- nents (delivered in or by another living component—a virus). All three share many of the same potential mechanisms of adverse outcome. These are sometimes called advanced and cellular therapies: 1. Infection if improperly prepared or contaminated with pathogens 2. Inflammatory responses if contaminated with endotoxins 3. “Off-target hits”—the therapeutic entity going some- where it is not intended to be and remaining viable The AOPs underlying these concerns can be categorized as route related, immunologically related, or proliferation related (Amuzie and Faqi, 2017). Gene therapy medicinal products (GTMPs) have additional potential adverse effects as a result of modifying genetic function—potentially including cancer. There are numerous regulatory guidances on the pro- duction of clinical material for these products. This is as it should be, as tight manufacturing controls and ensuring sta- bility of cell and genetic stock involved are the key to safety, and what are to be used in any nonclinical safety evaluations are intended clinical materials. But there are limited guid- ances available for the nonclinical safety evaluation—EMEA (2008) gene therapy product (GTPs) and Japan (Pharmaceu- tical and Medical Device Agency—PMDA) (2000–2008) and FDA (2013) for cellular and GTPs. In the United States, scientific advice is provided by the cellular, tissue, and gene therapeutics advisory committee (CTG-TAC).

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