Gene therapy—the process of modifying, replacing, or regulating genes to treat disease—has emerged as one of the most transformative innovations in modern medicine. While ex vivo strategies, such as engineered immune or hematopoietic cells, have achieved clinical success, the next frontier lies in in vivo gene therapy—directly delivering therapeutic genetic material into target tissues within the body.

A recent review published in Genes & Diseases by researchers from the Naval Medical University and the 922nd Hospital of the Joint Service Support Force of the PLA provides a comprehensive overview of the technological and therapeutic advances driving in vivo gene therapy toward clinical realization.

The review systematically examines the evolution of gene-editing nucleases — from zinc finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) to next-generation CRISPR-Cas systems, base editors (BEs), and prime editors (PEs)—and evaluates their precision, efficiency, and safety in correcting genetic errors. The authors further emphasize the critical role of delivery vectors, including adeno-associated viruses (AAVs), adenoviruses, lentiviruses, lipid nanoparticles (LNPs), and virus-like particles (VLPs), which enable targeted transport of editing tools to affected cells and organs.

Notably, the review highlights the growing number of in vivo gene therapy products and clinical trials targeting monogenic disorders, neurodegenerative conditions, and cancers. Key examples include the FDA-approved Luxturna for retinal dystrophy, Zolgensma for spinal muscular atrophy, and NTLA-2001, the first CRISPR-based in vivo therapy for transthyretin amyloidosis. These milestones underscore the therapeutic promise of combining genome editors with advanced delivery platforms.

The authors also discuss safety considerations, such as off-target effects, immune responses, and chromosomal instability, proposing ongoing refinements in molecular design and vector engineering to enhance clinical safety and efficacy. Furthermore, they highlight the emerging potential of LNPs and VLPs as non-viral alternatives with scalable, programmable designs suited for RNA and protein delivery.

Despite remarkable progress, significant challenges remain—including precise organ targeting, long-term safety assessment, and immune tolerance. The review calls for multidisciplinary collaboration to optimize nuclease performance, expand delivery specificity, and establish robust clinical pipelines for diverse diseases.
Ultimately, the authors envision in vivo gene therapy as a powerful, next-generation therapeutic strategy capable of curing hereditary disorders, regenerating degenerative tissues, and combating tumors. As the technology advances, it holds immense potential to redefine the landscape of precision and regenerative medicine.

Reference

Title of Original Paper: In vivo gene therapy: A strategy for mutations, degenerations, and tumors

Journal: Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101808

Funding Information:

1. The Shanghai Science and Technology Development Funds (China) (No. 23YF1458800)
2. China Postdoctoral Science Foundation (No. GZC20233559, No. 2023M744286)
3. Research Fund for the Basic Medical Research for the Youth of the Changhai Hospital (No. 2023QD24)
4. Research Fund for the Basic Medical Research for the Youth of Naval Medical University (No. 2024QN024)
5. Special Program for Clinical Medicine Research (No. 2024LYC015)
6. Research Fund for the Basic Medical Research for the Youth of the Changhai Hospital (Shanghai, China) (No. 20230024)
7. National Natural Science Foundation of China (No. 82100162, No. 82270202)

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

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