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State-of-the-art gene-based therapies: the road ahead

Key Points

  • Gene therapy approaches include gene addition, gene knockdown and gene alteration/correction.

  • Gene transfer vectors involve the use of non-viral DNA plasmids or are derived from the modification of natural viruses.

  • Vectors can be designed to express therapeutic protein coding and/or non-coding RNAs. Therapeutic non-coding RNAs include RNAi and microRNAs.

  • Improvements in gene transfer vector technologies are responsible for early clinical successes in treated inherited blindness, immunodeficiency syndromes and a neurodegenerative disease.

  • Some technical barriers still exist that limit the wide-scale implementation of gene therapy.

  • Improved vectors and a better understanding of vector–host interactions are two of the most important goals of gene therapy research.

  • The advancement in disease prediction using personalized genomics will ultimately influence the use of gene transfer in preventative medical applications.

Abstract

Improvements in the gene transfer vectors used in therapeutic trials have led to substantial clinical successes in patients with serious genetic conditions, such as immunodeficiency syndromes, blindness and some cancer types. Several barriers need to be overcome before this type of therapy becomes a widely accepted treatment for a broad group of medical diseases. However, recent progress in the field is finally realizing some of the promises made more than 20 years ago, providing optimism for additional successes in the near future.

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Figure 1: The four barriers to successful gene therapy.
Figure 2: Adeno-associated virus capsid shuffling and directed evolution.
Figure 3: Robust minicircle production.
Figure 4: Combining stem cells and gene therapy: an example application.

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Acknowledgements

I would like to thank my previous mentors, past and current trainees, and colleagues for all they have taught me. I apologize for not being able to include many other important approaches and studies owing to a lack of space. This work was funded by grants from the US National Institutes of Health (National Heart, Lung and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, and National Institute of Allergy and Infectious Diseases) and the Juvenile Diabetes Research Foundation.

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Correspondence to Mark A. Kay.

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American Society of Gene and Cell Therapy

ClinicalTrials.gov

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RNA molecules designed to bind and inhibit a biologically active RNA from binding to its target.

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An inherited connective tissue disease resulting in mild to severe (fatal) skin blisters owing to a mutation in collagen or keratin genes.

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A toxicity reaction that resolves without intervention.

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An inherited and incurable blindness disorder.

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The use of imaging technologies, such as real-time magnetic resonance imaging, to pinpoint the delivery of a vector through a catheter.

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Expression cassettes that are devoid of the plasmid DNA backbone.

Sleeping Beauty

An ancient inactive transposon isolated from salmon. The transposase was reactivated by introducing various mutations.

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Kay, M. State-of-the-art gene-based therapies: the road ahead. Nat Rev Genet 12, 316–328 (2011). https://doi.org/10.1038/nrg2971

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