Article

Gene therapy clinical trials worldwide to 2012—An update

Gene Therapy Research Unit, Children's Medical Research Institute and The Children's Hospital at Westmead, Locked Bag 23, Wentworthville, NSW, 2145, Australia
The Journal of Gene Medicine (Impact Factor: 2.47). 02/2013; 15(2). DOI: 10.1002/jgm.2698
Source: PubMed

ABSTRACT

To date, over 1800 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide. Our database brings together global information on gene therapy clinical trials from official agency sources, published literature, conference presentations and posters kindly provided to us by individual investigators or trial sponsors.
This review presents our analysis of clinical trials that, to the best of our knowledge, have been or are being performed worldwide. As of our June 2012 update, we have entries on 1843 trials undertaken in 31 countries. We have analysed the geographical distribution of trials, the disease indications (or other reasons) for trials, the proportions to which different vector types are used, and which genes have been transferred. Details of the analyses presented, and our searchable database are available on The Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide website at: http://www.wiley.co.uk/genmed/clinical. We also provide an overview of the progress being made in clinical trials of gene therapy approaches around the world and discuss the prospects for the future. Copyright

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Available from: Samantha L Ginn
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    • "Alternate non-viral vectors can be suggested for the development of " artificial viruses " synthetic polycations that equal viral counterparts in terms of their transfection efficacy, while being much safer, targetcell specific, non-immunogenic and relatively inexpensive to prepare at scales that permit clinical use [2]. However, despite a significant progress in development of novel carrier systems, only a limited number has been successfully tested in primary cells or in animal models and thus became appropriate for future clinical trials [3]. In general, the efficacy of non-viral carriers remains low. "
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    ABSTRACT: Absence of safe and efficient methods of nucleic acids delivery is one of the major issues which limits the development of human gene therapy. Highly efficient viral vectors raise questions due to safety reasons. Among non-viral vectors peptide-based carriers can be considered as good candidates for the development of " artificial viruses "-multifunctional polyplexes that mimic viruses. Suggested strategy to obtain multifunctionality is to combine several peptide modules into one modular carrier. Different kinds of peptide modules are needed for successful overcoming barriers of nucleic acids transport into the cells. Design of such modules and establishment of structure-function relationships are issues of importance to researchers working in the field of nucleic acids delivery.
    Full-text · Article · Jan 2016 · Current Topics in Medicinal Chemistry
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    • "Direct intramuscular (i.m.) injection of naked plasmid DNA (pDNA) for skeletal muscle transfection was pioneered by J.A. Wolff in 1990 [1]. As of today i.m. injection of pDNA makes up around 18% of worldwide gene therapy human clinical trials [2]. These trials are related to DNA vaccines, Duchene muscular dystrophy, hind limb ischemia and cardiac ischemia [3e5]. "
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    ABSTRACT: Intramuscular administration of plasmid DNA (pDNA) with non-ionic Pluronic block copolymers increases gene expression in injected muscles and lymphoid organs. We studied the role of immune cells in muscle transfection upon inflammation. Local inflammation in murine hind limb ischemia model (MHLIM) drastically increased DNA, RNA and expressed protein levels in ischemic muscles injected with pDNA/Pluronic. The systemic inflammation (MHLIM or peritonitis) also increased expression of pDNA/Pluronic in the muscles. When pDNA/Pluronic was injected in ischemic muscles the reporter gene, Green Fluorescent Protein (GFP) co-localized with desmin+ muscle fibers and CD11b+ macrophages (MØs), suggesting transfection of MØs along with the muscle cells. P85 enhanced (∼4 orders) transfection of MØs with pDNA in vitro. Moreover, adoptively transferred MØs were shown to pass the transgene to inflamed muscle cells in MHLIM. Using a co-culture of myotubes (MTs) and transfected MØs expressing a reporter gene under constitutive (cmv-luciferase) or muscle specific (desmin-luciferase) promoter we demonstrated that P85 enhances horizontal gene transfer from MØ to MTs. Therefore, MØs can play an important role in muscle transfection with pDNA/Pluronic during inflammation, with both inflammation and Pluronic contributing to the increased gene expression. pDNA/Pluronic has potential for therapeutic gene delivery in muscle pathologies that involve inflammation.
    Full-text · Article · Oct 2015 · Biomaterials
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    • "Besides strong immunological reactions against viral proteins (Raper et al. 2003; Wilson 2009), human subjects also suffered from therapy-induced leukemia (Gore 2003; Hacein-Bey-Abina et al. 2008; Howe et al. 2008). To date, the technology has resulted in only a single recently approved therapy (Yla- Herttuala 2012) in the Western world, although more than 2000 clinical trials have been conducted since the first approval of a FIH gene therapy trial in 1989 (Ginn et al. 2013). The failure of gene therapy, and recent unanticipated serious adverse events with the antibody TGN1412 (Suntharalingam et al. 2006; Wood and Darbyshire 2006), have highlighted that despite the existence of promising pre-clinical data, it is often unknown how well results can be extrapolated and translated to humans. "
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    ABSTRACT: Recent progress in synthetic biology (SynBio) has enabled the development of novel therapeutic opportunities for the treatment of human disease. In the near future, first-in-human trials (FIH) will be indicated. FIH trials mark a key milestone in the translation of medical SynBio applications into clinical practice. Fostered by uncertainty of possible adverse events for trial participants, a variety of ethical concerns emerge with regards to SynBio FIH trials, including 'risk' minimization. These concerns are associated with any FIH trial, however, due to the novelty of the approach, they become more pronounced for medical applications of emerging technologies (emTech) like SynBio. To minimize potential harm for trial participants, scholars, guidelines, regulations and policy makers alike suggest using 'risk assessment' as evaluation tool for such trials. Conversely, in the context of emTech FIH trials, we believe it to be at least questionable to contextualize uncertainty of potential adverse events as 'risk' and apply traditional risk assessment methods. Hence, this issue needs to be discussed to enable alterations of the evaluation process before the translational phase of SynBio applications begins. In this paper, we will take the opportunity to start the debate and highlight how a misunderstanding of the concept of risk, and the possibilities and limitations of risk assessment, respectively, might impair decision-making by the relevant regulatory authorities and research ethics committees, and discuss possible solutions to tackle the issue.
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Questions & Answers about this publication

  • Bernardino Isaac Cerda-Cristerna added an answer in Adeno-associated Virus:
    What is the most common virus used in clinical trials in gene therapy?

    I wonder if it is adeno or adeno-associated virus?

    Bernardino Isaac Cerda-Cristerna

    "Recent years have seen a decline in the use of retroviral vectors (currently, only 19.7% of trials compared to 22.8% in 2007 and 28% in 2004), presumably as a result of the severe adverse events observed in the SCID trials, and research is well underway towards engineering safer retroviral vectors. Adenoviruses are the most commonly used vector (23.3% of all trials)". From Ginn et al. The paper is free here https://www.researchgate.net/publication/235377142_Gene_therapy_clinical_trials_worldwide_to_2012_-_an_update?ev=srch_pub&_sg=0kuhTM7mdLSNcFCqpave%2FFokSjoKfCqUx9VdoVkGPAWfIEy7DFjp5kbHzyu%2FpGhb_jzpfkQaU5PeZB%2BeoH9jOl1WlWGKNjNlSFAKkpgkUNilM5BJ1aywW0EBQ8ILj9MK6_mDsIAWi7Xxzsd6Y36DXmPnoUj5SJWLJbllPLzZZ7C97CwrMe4%2Bukb1G%2Ba%2FYE%2FpZL

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      [Show abstract] [Hide abstract]
      ABSTRACT: To date, over 1800 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide. Our database brings together global information on gene therapy clinical trials from official agency sources, published literature, conference presentations and posters kindly provided to us by individual investigators or trial sponsors. This review presents our analysis of clinical trials that, to the best of our knowledge, have been or are being performed worldwide. As of our June 2012 update, we have entries on 1843 trials undertaken in 31 countries. We have analysed the geographical distribution of trials, the disease indications (or other reasons) for trials, the proportions to which different vector types are used, and which genes have been transferred. Details of the analyses presented, and our searchable database are available on The Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide website at: http://www.wiley.co.uk/genmed/clinical. We also provide an overview of the progress being made in clinical trials of gene therapy approaches around the world and discuss the prospects for the future. Copyright
      Full-text · Article · Feb 2013 · The Journal of Gene Medicine