Recombinant Adeno-Associated Virus Gene Therapy in Light of Luxturna (and Zolgensma and Glybera): Where Are We, and How Did We Get Here?

Overview

Journal Annu Rev Virol

Publisher Annual Reviews

Specialty Microbiology

Date 2019 Jul 9

PMID 31283441

Citations 164

Authors

Allison M Keeler

Terence R Flotte

Affiliations

Soon will be listed here.

Abstract

The recent market approvals of recombinant adeno-associated virus (rAAV) gene therapies in Europe and the United States are landmark achievements in the history of modern science. These approvals are also anticipated to herald the emergence of a new class of therapies for monogenic disorders, which had hitherto been considered untreatable. These events can be viewed as stemming from the convergence of several important historical trends: the study of basic virology, the development of genomic technologies, the imperative for translational impact of National Institutes of Health-funded research, and the development of economic models for commercialization of rare disease therapies. In this review, these historical trends are described and the key developments that have enabled clinical rAAV gene therapies are discussed, along with an overview of the current state of the field and future directions.

Citing Articles

Adeno-Associated Virus Vectors: Principles, Practices, and Prospects in Gene Therapy.

Zwi-Dantsis L, Mohamed S, Massaro G, Moeendarbary E Viruses. 2025; 17(2).

PMID: 40006994 PMC: 11861813. DOI: 10.3390/v17020239.

Genetic advancements in breast cancer treatment: a review.

Shokoohi M, Sedaghatshoar S, Arian H, Mokarami M, Habibi F, Bamarinejad F Discov Oncol. 2025; 16(1):127.

PMID: 39918655 PMC: 11805739. DOI: 10.1007/s12672-025-01884-x.

Structural basis for nuclear import of adeno-associated virus serotype 6 capsid protein.

Hoad M, Nematollahzadeh S, Petersen G, Roby J, Alvisi G, Forwood J J Virol. 2024; 99(1):e0134524.

PMID: 39692478 PMC: 11784021. DOI: 10.1128/jvi.01345-24.

Physicochemical and biological impacts of light stress on adeno-associated virus serotype 6.

Takino R, Yamaguchi Y, Maruno T, Ramadhani E, Furukawa M, Torisu T Mol Ther Methods Clin Dev. 2024; 32(4):101362.

PMID: 39624799 PMC: 11609365. DOI: 10.1016/j.omtm.2024.101362.

Adeno-Associated Viral Vectors in the Treatment of Epilepsy.

Mullagulova A, Timechko E, Solovyeva V, Yakimov A, Ibrahim A, Dmitrenko D Int J Mol Sci. 2024; 25(22).

PMID: 39596149 PMC: 11593886. DOI: 10.3390/ijms252212081.

References

Wagner J, Moran M, Messner A, Daifuku R, Conrad C, Reynolds T . A phase I/II study of tgAAV-CF for the treatment of chronic sinusitis in patients with cystic fibrosis. Hum Gene Ther. 1998; 9(6):889-909. DOI: 10.1089/hum.1998.9.6-889. View

Fisher K, Kelley W, Burda J, Wilson J . A novel adenovirus-adeno-associated virus hybrid vector that displays efficient rescue and delivery of the AAV genome. Hum Gene Ther. 1996; 7(17):2079-87. DOI: 10.1089/hum.1996.7.17-2079. View

Muramatsu S, Fujimoto K, Kato S, Mizukami H, Asari S, Ikeguchi K . A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson's disease. Mol Ther. 2010; 18(9):1731-5. PMC: 2956925. DOI: 10.1038/mt.2010.135. View

Ahmed S, Li H, Cao C, Sikoglu E, Denninger A, Su Q . A single intravenous rAAV injection as late as P20 achieves efficacious and sustained CNS Gene therapy in Canavan mice. Mol Ther. 2013; 21(12):2136-47. PMC: 3863789. DOI: 10.1038/mt.2013.138. View

Flotte T, Carter B, Conrad C, Guggino W, Reynolds T, Rosenstein B . A phase I study of an adeno-associated virus-CFTR gene vector in adult CF patients with mild lung disease. Hum Gene Ther. 1996; 7(9):1145-59. DOI: 10.1089/hum.1996.7.9-1145. View

Nault J, Datta S, Imbeaud S, Franconi A, Mallet M, Couchy G . Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas. Nat Genet. 2015; 47(10):1187-93. DOI: 10.1038/ng.3389. View

Xiao X, Li J, Samulski R . Production of high-titer recombinant adeno-associated virus vectors in the absence of helper adenovirus. J Virol. 1998; 72(3):2224-32. PMC: 109519. DOI: 10.1128/JVI.72.3.2224-2232.1998. View

Mingozzi F, Maus M, Hui D, Sabatino D, Murphy S, Rasko J . CD8(+) T-cell responses to adeno-associated virus capsid in humans. Nat Med. 2007; 13(4):419-22. DOI: 10.1038/nm1549. View

Wagner J, Nepomuceno I, Messner A, Moran M, Batson E, DiMiceli S . A phase II, double-blind, randomized, placebo-controlled clinical trial of tgAAVCF using maxillary sinus delivery in patients with cystic fibrosis with antrostomies. Hum Gene Ther. 2002; 13(11):1349-59. DOI: 10.1089/104303402760128577. View

10.

McCown T, Xiao X, Li J, Breese G, Samulski R . Differential and persistent expression patterns of CNS gene transfer by an adeno-associated virus (AAV) vector. Brain Res. 1996; 713(1-2):99-107. DOI: 10.1016/0006-8993(95)01488-8. View

11.

Flotte T, Afione S, Zeitlin P . Adeno-associated virus vector gene expression occurs in nondividing cells in the absence of vector DNA integration. Am J Respir Cell Mol Biol. 1994; 11(5):517-21. DOI: 10.1165/ajrcmb.11.5.7946381. View

12.

Yan Z, Sun X, Feng Z, Li G, Fisher J, Stewart Z . Optimization of Recombinant Adeno-Associated Virus-Mediated Expression for Large Transgenes, Using a Synthetic Promoter and Tandem Array Enhancers. Hum Gene Ther. 2015; 26(6):334-46. PMC: 4492606. DOI: 10.1089/hum.2015.001. View

13.

Johnston J, Tazelaar J, Rivera V, Clackson T, Gao G, Wilson J . Regulated expression of erythropoietin from an AAV vector safely improves the anemia of beta-thalassemia in a mouse model. Mol Ther. 2003; 7(4):493-7. DOI: 10.1016/s1525-0016(03)00043-1. View

14.

Hocquemiller M, Giersch L, Audrain M, Parker S, Cartier N . Adeno-Associated Virus-Based Gene Therapy for CNS Diseases. Hum Gene Ther. 2016; 27(7):478-96. PMC: 4960479. DOI: 10.1089/hum.2016.087. View

15.

Foust K, Nurre E, Montgomery C, Hernandez A, Chan C, Kaspar B . Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes. Nat Biotechnol. 2008; 27(1):59-65. PMC: 2895694. DOI: 10.1038/nbt.1515. View

16.

Conway J, Zolotukhin S, Muzyczka N, Hayward G, Byrne B . Recombinant adeno-associated virus type 2 replication and packaging is entirely supported by a herpes simplex virus type 1 amplicon expressing Rep and Cap. J Virol. 1997; 71(11):8780-9. PMC: 192344. DOI: 10.1128/JVI.71.11.8780-8789.1997. View

17.

Koerber J, Jang J, Schaffer D . DNA shuffling of adeno-associated virus yields functionally diverse viral progeny. Mol Ther. 2008; 16(10):1703-9. PMC: 2683895. DOI: 10.1038/mt.2008.167. View

18.

Borel F, Gernoux G, Sun H, Stock R, Blackwood M, Brown Jr R . Safe and effective superoxide dismutase 1 silencing using artificial microRNA in macaques. Sci Transl Med. 2018; 10(465). DOI: 10.1126/scitranslmed.aau6414. View

19.

Hosel M, Broxtermann M, Janicki H, Esser K, Arzberger S, Hartmann P . Toll-like receptor 2-mediated innate immune response in human nonparenchymal liver cells toward adeno-associated viral vectors. Hepatology. 2011; 55(1):287-97. DOI: 10.1002/hep.24625. View

20.

Flotte T, Brantly M, Terry Spencer L, Byrne B, Spencer C, Baker D . Phase I trial of intramuscular injection of a recombinant adeno-associated virus alpha 1-antitrypsin (rAAV2-CB-hAAT) gene vector to AAT-deficient adults. Hum Gene Ther. 2004; 15(1):93-128. DOI: 10.1089/10430340460732490. View