Current clinical applications of AAV-mediated gene therapy

Barry J Byrne¹, Kevin M Flanigan², Susan E Matesanz³, Richard S Finkel⁴, Megan A Waldrop², Eleonora S D'Ambrosio⁵, Nicholas E Johnson⁶, Barbara K Smith⁷, Carsten Bönnemann⁸, Sean Carrig⁹, Joseph W Rossano¹⁰, Barry Greenberg¹¹, Laura Lalaguna¹², Enrique Lara-Pezzi¹³, Sub Subramony¹⁴, Manuela Corti¹⁵, Claudia Mercado-Rodriguez¹⁶, Carmen Leon-Astudillo¹⁷, Rebecca Ahrens-Nicklas¹⁸, Diana Bharucha-Goebel¹⁹, Guangping Gao²⁰, Dominic J Gessler²⁰, Wuh-Liang Hwu²¹, Yin-Hsiu Chien²², Ni-Chung Lee²², Sanford L Boye¹⁵, Shannon E Boye²³, Lindsey A George²⁴

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: barry.byrne@ufl.edu.
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: georgel@chop.edu.

PMID: 40329530
PMCID: PMC12172329 (available on 2026-06-04)
DOI: 10.1016/j.ymthe.2025.04.045

Review

Current clinical applications of AAV-mediated gene therapy

Barry J Byrne et al. Mol Ther. 2025.

. 2025 Jun 4;33(6):2479-2516.

doi: 10.1016/j.ymthe.2025.04.045. Epub 2025 May 5.

Authors

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: barry.byrne@ufl.edu.
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: georgel@chop.edu.

PMID: 40329530
PMCID: PMC12172329 (available on 2026-06-04)
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.

Published by Elsevier Inc.

PubMed Disclaimer

Conflict of interest statement

Declaration of interests B.J.B. has received research support from Sarepta Therapeutics and Pfizer and is a member of the Global Pompe Advisory Board supported by Sanofi. B.J.B. has received consulting fees from Amicus Therapeutics, Rocket Pharma, and Tenaya. B.J.B. is a co-founder of Ventura Life Sciences, LLC. The University of Florida is entitled to licensing revenue related to AAV technology. B.J.B. is an uncompensated member of the MDA Board of Directors. B.J.B. has grant funding from R01-HD052682 and U01-NS116752-01A1. R.S.F. declares personal compensation for advisory board participation from Astellas, Biogen, Dyne, Genentech, Ionis, Italfarmaco, Novartis, ReveraGen, Roche, Sarepta, and Scholar Rock; data safety monitoring board participation for a Sarepta-sponsored study on Duchenne muscular dystophry and Nationwide Children's Hospital study on SMA; research funding from Biogen, Dyne, Genentech, Genethon, Italfarmaco, Roche, Sarepta, and Scholar Rock; editorial fees from Elsevier for co-editing a neurology textbook; and license fees from the Children's Hospital of Philadelphia. R.S.F. is affiliated with an institution (St. Jude Children’s Research Hospital) that receives funds for an SMA disease registry (ISMAR). R.S.F. has received funding to support clinical trial participation to his institution from Biogen, Dyne, Genentech, Genethon, Italfarmaco, Roche, Sarepta, and Scholar Rock. M.A.W. receives clinical trial support from Novartis and Sarepta Therapeutics and serves as a consultant for Sarepta Therapeutics. AHRQ-PCORI funded the PEDSnet Scholars Training Program 5K12HS026393-03, which is a national faculty development program that trains individuals in the competencies of learning health systems science. N.E.J. has received grant funding from NINDS (R01NS104010, U01NS124974), NCATS (R21TR003184), CDC (U01DD001242), and the FDA (7R01FD006071). N.E.J. receives royalties from the CCMDHI and the CMTHI. N.E.J. receives research funds from Novartis, Takeda, PepGen, Sanofi Genzyme, Dyne, Vertex Pharmaceuticals, Fulcrum Therapeutics, AskBio, ML Bio, and Sarepta. N.E.J. has provided consultation for Arthex, Angle Therapeutics, Juvena, Rgenta, PepGen, AMO Pharma, Takeda, Design, Dyne, AskBio, Avidity, and Vertex Pharmaceuticals. N.E.J. has stock options in Juvena, Angle Therapeutics, and Myogene Therapies. J.W.R. is a consultant for AskBio, Bayer, Bristol Myers Squibb, and Merck. B.G. is the principal site investigator for clinical trials of gene therapy that are funded by Rocket Pharma. B.G. chairs two DSMB committees overseeing clinical trials of gene therapy sponsored by Tenaya. B.G. has served as a consultant for Astellas, AstraZeneca, Bristol Myers Squibb, and Tenaya. Rocket Pharma provides support to UCSD for clinical trials of gene therapy. B.G. serves as a chair of the DSMB for two clinical trials in gene therapy funded by Tenaya. B.G. has also received honoraria for consulting activities with Astellas, AstraZeneca, Bristol Myers Squibb, and Tenaya. L.L. is an inventor of the patent application EP25382006.2 entitled “Method for improving cardiac function in arrhythmogenic right ventricular cardiomyopathy type 5.” E.L.-P. is an inventor of the patent application EP25382006.2 entitled “Method for improving cardiac function in arrhythmogenic right ventricular cardiomyopathy type 5.” E.L.-P. has received support from the European Innovation Council (Award Number: 101115416 - Enabling advances in diagnosis, patient stratification and treatment for dilated cardiomyopathy patients and families [DCM-NEXT]). M.C. has received research support from the Friedreich's Ataxia Research Alliance. M.C. and B.J.B. are co-founders of Ventura Life Sciences, LLC. The University of Florida is entitled to licensing revenue related to Pompe disease inventions. M.C. has grant funding from R01-HD052682 and U01-NS116752-01A1. R.A.-N. is an advisor to LatusBio and serves on a DSMB for AskBio. Y.-H.C. declares receiving compensation for consultations and serving as an advisory board member for PTC Therapeutics, Roche, and Novartis. S.L.B. is a co-founder and consultant for Atsena Theraepeutics and has patents related to technologies described in this manuscript. S.E.B. is a co-founder and consultant for Atsena Theraepeutics and has patents related to technologies described in this manuscript. S.E.B. has funding from the National Eye Institute (R01 EY024280), the Foundation Fighting Blindness, Friedreich's Ataxia Research Alliance, Stiftung für Medizininnovationen, and Atsena Therapeutics. L.A.G. is on the Scientific Advisory Board of Form Bio, is a consultant for CSL Behring, Myogene, Pfizer, Regeneron, and Spark Therapeutic and holds patents related to data discussed in this work.

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Current clinical applications of AAV-mediated gene therapy

Affiliations

Current clinical applications of AAV-mediated gene therapy

Authors

Affiliations

Abstract

Conflict of interest statement

References

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