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Gene Therapy and Nucleic Acid Applications: A New Era in Disease Control

Edited by T-C Wu

A thematic series in Journal of Biomedical Science. 

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Over half a century ago, Friedmann and Roblin pioneered the groundbreaking concept of using functional gene copies to treat genetic disorders (1).  Today, viral vector- and nucleic acid-based therapeutics—encompassing both DNA and RNA—have become cornerstones of modern medicine, with their recent success exemplified by our response to the COVID-19 pandemic (2-5).  Unlike conventional drugs, these therapeutics uniquely modulate gene expression, offering highly specific, potentially durable, and possibly curative effects.  However, their clinical applications face several challenges, including the risk of replication-competent viral vectors in immunocompromised patients, the susceptibility of nucleic acid-based therapies to nuclease degradation, and the suboptimal pharmacokinetic properties that hinder efficient delivery to targeted cells.  To unlock their full therapeutic potential, innovative solutions are being explored, such as the use of non-replicating vectors for viral vector-based therapies, electroporation techniques for DNA-based treatments, and lipid nanoparticles for the delivery of RNA-based therapies (6, 7).

In this current issue, we present five review articles that delve into our understanding of viral vector- and nucleic acid-based therapeutics, ongoing efforts to enhance their efficacy, and their clinical applications in cancer, neuromuscular disorders, and ultrarare diseases.  First, Hwu offers a scientific and logistical perspective on leveraging genetic therapies for the treatment of ultrarare diseases such as Duchenne muscular dystrophy and hemophilia (8).  Second, Lu et al. explore the current landscape of mRNA-based drugs, covering delivery technologies and ongoing clinical developments (9).  Third, Chi et al. discuss the use of shared and personalized antigens in the development of nucleic acid-based cancer vaccines, along with the latest nucleic acid vaccine platforms for various cancers (10).  Fourth, Liao and Liu highlight current and ongoing clinical trials for both DNA and mRNA-based cancer vaccines in combination with immune checkpoint inhibitors (11).  Lastly, Wu et al. review recent advancements in adeno-associated virus (AAV)-based gene therapy and provide updates on current FDA-approved gene therapies for genetic neuromuscular diseases (12).

Viral vector- and nucleic acid-based therapeutics represent a paradigm shift in medicine.  This issue was conceptualized to provide a comprehensive overview of current innovations and ongoing clinical applications.  We envision that one day, these therapeutics will transform patient outcomes across a multitude of human diseases.

References:

  1. Friedmann T, Roblin R. Gene therapy for human genetic disease? Science 1972;175:949-55
  2. Anderson EJ, Rouphael NG, Widge AT, Jackson LA, Roberts PC, Makhene M, et al. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N Engl J Med 2020;383:2427-38
  3. Sahin U, Muik A, Derhovanessian E, Vogler I, Kranz LM, Vormehr M, et al. COVID-19 vaccine BNT162b1 elicits human antibody and T(H)1 T cell responses. Nature 2020;586:594-9
  4. Chi WY, Li YD, Huang HC, Chan TEH, Chow SY, Su JH, et al. COVID-19 vaccine update: vaccine effectiveness, SARS-CoV-2 variants, boosters, adverse effects, and immune correlates of protection. J Biomed Sci 2022;29:82
  5. Abbasi J. India's new COVID-19 DNA vaccine for adolescents and adults is a first. JAMA 2021;326:1365
  6. Kulkarni JA, Witzigmann D, Thomson SB, Chen S, Leavitt BR, Cullis PR, et al. The current landscape of nucleic acid therapeutics. Nat Nanotechnol 2021;16:630-43
  7. Travieso T, Li J, Mahesh S, Mello J, Blasi M. The use of viral vectors in vaccine development. NPJ Vaccines 2022;7:75
  8. Hwu WL. Gene therapy for ultrarare diseases: a geneticist's perspective. J Biomed Sci 2024;31:79
  9. Lu RM, Hsu HE, Perez S, Kumari M, Chen GH, Hong MH, et al. Current landscape of mRNA technologies and delivery systems for new modality therapeutics. J Biomed Sci 2024;31:89
  10. Chi WY, Hu Y, Huang HC, Kuo HH, Lin SH, Kuo CJ, et al. Molecular targets and strategies in the development of nucleic acid cancer vaccines: from shared to personalized antigens. J Biomed Sci 2024;31:94
  11. Liao HC, Liu SJ. Advances in nucleic acid-based cancer vaccines. J Biomed Sci 2025;32:10
  12. Wu YF, Chen JA, Jong YJ. Treating neuromuscular diseases: unveiling gene therapy breakthroughs and pioneering future applications. J Biomed Sci 2025;32:30

Published articles in this Collection

  2. Nucleic acid vaccines have emerged as crucial advancements in vaccine technology, particularly highlighted by the global response to the COVID-19 pandemic. The widespread administration of mRNA vaccines agains...

    Authors: Hung-Chun Liao and Shih-Jen Liu
    Citation: Journal of Biomedical Science 2025 32:10
    Content type: Review Published on:

  3. Recent breakthroughs in cancer immunotherapies have emphasized the importance of harnessing the immune system for treating cancer. Vaccines, which have traditionally been used to promote protective immunity ag...

    Authors: Wei-Yu Chi, Yingying Hu, Hsin-Che Huang, Hui-Hsuan Kuo, Shu-Hong Lin, Chun-Tien Jimmy Kuo, Julia Tao, Darrell Fan, Yi-Min Huang, Annie A. Wu, Chien-Fu Hung and T.-C. Wu
    Citation: Journal of Biomedical Science 2024 31:94
    Content type: Review Published on:

  4. Realizing the immense clinical potential of mRNA-based drugs will require continued development of methods to safely deliver the bioactive agents with high efficiency and without triggering side effects. In th...

    Authors: Ruei-Min Lu, Hsiang-En Hsu, Ser John Lynon P. Perez, Monika Kumari, Guan-Hong Chen, Ming-Hsiang Hong, Yin-Shiou Lin, Ching-Hang Liu, Shih-Han Ko, Christian Angelo P. Concio, Yi-Jen Su, Yi-Han Chang, Wen-Shan Li and Han-Chung Wu
    Citation: Journal of Biomedical Science 2024 31:89
    Content type: Review Published on: