Current clinical applications of AAV-mediated gene therapy

  • Mol Ther. 2025 Jun 4;33(6):2479-2516. doi: 10.1016/j.ymthe.2025.04.045.
Barry J Byrne  1 ,  Kevin M Flanigan  2 ,  Susan E Matesanz  3 ,  Richard S Finkel  4 ,  Megan A Waldrop  2 ,  Eleonora S D'Ambrosio  5 ,  Nicholas E Johnson  6 ,  Barbara K Smith  7 ,  Carsten Bönnemann  8 ,  Sean Carrig  9 ,  Joseph W Rossano  10 ,  Barry Greenberg  11 ,  Laura Lalaguna  12 ,  Enrique Lara-Pezzi  13 ,  Sub Subramony  14 ,  Manuela Corti  15 ,  Claudia Mercado-Rodriguez  16 ,  Carmen Leon-Astudillo  17 ,  Rebecca Ahrens-Nicklas  18 ,  Diana Bharucha-Goebel  19 ,  Guangping Gao  20 ,  Dominic J Gessler  20 ,  Wuh-Liang Hwu  21 ,  Yin-Hsiu Chien  22 ,  Ni-Chung Lee  22 ,  Sanford L Boye  15 ,  Shannon E Boye  23 ,  Lindsey A George  24
Affiliations
  • 1. Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, FL, USA; Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA. Electronic address: [email protected].
  • 2. Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, USA; Department of Pediatrics and Neurology, The Ohio State University, Columbus, OH, USA.
  • 3. Clinical In Vivo Gene Therapy, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, Philadelphia, PA, USA.
  • 4. Center for Experimental Neurotherapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
  • 5. Department of Neurology, University of Massachusetts Chan School of Medicine, Worcester, MA, USA.
  • 6. Department of Neurology and Center for Inherited Muscle Research, Virginia Commonwealth University, Richmond, VA, USA.
  • 7. Department of Physical Therapy, College of Public Health and Health Professions, University of Florida Gainesville, FL, USA.
  • 8. Neuromuscular and Neurogenetic Disorders of Childhood, NINDS/NIH, Bethesda, MD, USA.
  • 9. Clinical In Vivo Gene Therapy, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 10. Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA; Division of Cardiology, Children's Hospital of Philadelphia, Philadelphia PA, USA.
  • 11. Cardiology Department, University of California, California, San Diego, La Jolla, CA, USA.
  • 12. Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain.
  • 13. Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain; Centro de Investigación Biomédica en Red Cardiovascular (CIBERCV), Madrid, Spain.
  • 14. Department of Neurology, University of Florida College of Medicinem, Gainesville, FL, USA.
  • 15. Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, FL, USA; Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA.
  • 16. Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, FL, USA.
  • 17. Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA.
  • 18. Clinical In Vivo Gene Therapy, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA.
  • 19. Neuromuscular and Neurogenetic Disorders of Childhood, NINDS/NIH, Bethesda, MD, USA; Division of Neurology, Children's National Hospital, Washington, DC, USA.
  • 20. Department of Genetic and Cellular Medicine, Horae Gene Therapy Center, University of Massachusetts Chan School of Medicine, Worcester, MA, USA.
  • 21. Department of Medical Genetics and Pediatrics, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei, Taiwan; Center for Precision Medicine, China Medical University Hospital, Taichung, Taiwan.
  • 22. Department of Medical Genetics and Pediatrics, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei, Taiwan.
  • 23. Powell Gene Therapy Center, University of Florida College of Medicine, Gainesville, FL, USA; Division of Cellular and Molecular Therapy, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL, USA.
  • 24. Clinical In Vivo Gene Therapy, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Electronic address: [email protected].
PMID: 40329530 DOI: 10.1016/j.ymthe.2025.04.045
Abstract

Currently, there are an estimated 8,000 genetic disorders that cumulatively affect approximately 10% of the population. Even among the 5% of patients with genetic disease that have treatment options, these therapeutics rarely address the underlying cause of disease but rather focus on managing or modifying symptoms and typically require recurrent, lifelong therapy. A therapeutic approach to genetic disease that in vivo delivers a functional copy of the aberrant gene is an intuitive solution that has thus far taken 3 decades to reduce to clinical practice, predominantly using adeno-associated viral (AAV) vectors. Among available viral and non-viral gene delivery approaches, AAV vectors remain the most efficient means for in vivo delivery of DNA to the nucleus. AAV vectors now constitute a bone fide novel therapeutic drug class composed of seven US Food and Drug Administration-approved products with over 10-fold more in clinical development for an expanding number of disease indications and an identified list of problems to overcome for widespread clinical application. Here, we review current progress in clinical AAV gene therapy, including for neuromuscular disorders, hemophilia, primary cardiovascular disorders, or disorders with cardiovascular manifestations, lysosomal storage disorders, mucopolysaccharide disorders, primary central nervous systemic disorders, and ocular disorders.

Keywords
adeno-associated viral vectors; in vivo gene therapy.