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Addressing the dark matter of gene therapy: technical and ethical barriers to clinical application

Abstract

Gene therapies for genetic diseases have been sought for decades, and the relatively recent development of the CRISPR/Cas9 gene-editing system has encouraged a new wave of interest in the field. There have nonetheless been significant setbacks to gene therapy, including unintended biological consequences, ethical scandals, and death. The major focus of research has been on technological problems such as delivery, potential immune responses, and both on and off-target effects in an effort to avoid negative clinical outcomes. While the field has concentrated on how we can better achieve gene therapies and gene editing techniques, there has been less focus on when and why we should use such technology. Here we combine discussion of both the technical and ethical barriers to the widespread clinical application of gene therapy and gene editing, providing a resource for gene therapy experts and novices alike. We discuss ethical problems and solutions, using cystic fibrosis and beta-thalassemia as case studies where gene therapy might be suitable, and provide examples of situations where human germline gene editing may be ethically permissible. Using such examples, we propose criteria to guide researchers and clinicians in deciding whether or not to pursue gene therapy as a treatment. Finally, we summarize how current progress in the field adheres to principles of biomedical ethics and highlight how this approach might fall short of ethical rigour using examples in the bioethics literature. Ultimately by addressing both the technical and ethical aspects of gene therapy and editing, new frameworks can be developed for the fair application of these potentially life-saving treatments.

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Acknowledgements

We gratefully acknowledge feedback during the preparation of this review from Sabateeshan Mathavarajah and Dr. Françoise Baylis.

Funding

K.K. is a trainee of the Cancer Research Training Program of the Beatrice Hunter Cancer Research Institute, with funds provided by the Dalhousie Medical Research Foundation (DMRF) C. MacDougall Cancer Research Studentship, as well as being supported by a Genomics in Medicine Graduate Studentship from the Dalhousie Faculty of Medicine –DMRF and a Nova Scotia Scholar Award. L.J.G. is funded by a Vanier Canadian Graduate Scholarship from the Natural Science and Engineering Research Council of Canada (NSERC) as well as a Killam Pre-Doctoral Scholarship from the Killam Trusts. J-Y.M. is a Canada Research Chair in DNA repair and Cancer Therapeutics. This work is also supported by a Canadian Institutes of Health Research (CIHR) Project Grant (PJT-156017) to J-Y.M. and G.D.

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KK and GD conceived of the review. KK, LG and GD generated Figs. 1 and 3, and J-YM and TP generated Figs. 2 and 4. All authors contributed to the writing and edited of the manuscript.

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Correspondence to Jean-Yves Masson or Graham Dellaire.

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The authors have no conflicts to declare.

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Kratzer, K., Getz, L.J., Peterlini, T. et al. Addressing the dark matter of gene therapy: technical and ethical barriers to clinical application. Hum Genet 141, 1175–1193 (2022). https://doi.org/10.1007/s00439-021-02272-5

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  • DOI: https://doi.org/10.1007/s00439-021-02272-5