Clinical Considerations for Capsid Choice in the Development of Liver-Targeted AAV-Based Gene Transfer

Overview

Journal Mol Ther Methods Clin Dev

Publisher Cell Press

Date 2019 Oct 30

PMID 31660419

Citations 38

Authors

Steven Pipe

Frank W G Leebeek

Valerie Ferreira

Eileen K Sawyer

John Pasi

Affiliations

Soon will be listed here.

Abstract

As gene transfer with adeno-associated virus (AAV) vectors is starting to enter clinical practice, this review examines the impact of vector capsid choice in liver-directed gene transfer for hemophilia. Given that there are multiple clinical trials completed and ongoing in this field, it is important to review the clinical evidence, particularly as a range of AAV-vector serotypes including AAV2, AAV5, AAV8, and AAV10 have been tested. Although there have been a number of successful trials, the development of two investigational AAV vectors for hemophilia B has been discontinued because they did not meet efficacy and/or safety expectations. Whether this difference between success and failure of gene transfer approaches reflects capsid choice, vector design, manufacturing system, or other variables is a question of great interest. Here, we examine the body of evidence across trials to determine the possible influences of serotype choice on key clinical outcomes such as safety, vector clearance, treatment eligibility, occurrence of transaminase elevations, activation of capsid-directed cytotoxic T cell responses, and clinical efficacy. In summary, gene transfer requires a balance between achieving sufficient transgene expression and minimizing destructive immune responses, which may be affected by AAV-vector serotype choice.

Citing Articles

The combination of rAAV pseudo-lipid nanoparticle and triamcinolone acetonide enables multi-administration to liver.

Gan C, Leng M, Liu Y, Zheng Z, He S, Qiao W Mol Ther Methods Clin Dev. 2025; 33(1):101399.

PMID: 39897641 PMC: 11787516. DOI: 10.1016/j.omtm.2024.101399.

Application of aqueous two-phase extraction for separation and purification of various adeno-associated viruses.

Fu X, Leong H, Qiao L, Zhou J, Hu W, Yao S Biotechnol Lett. 2025; 47(1):16.

PMID: 39777562 DOI: 10.1007/s10529-024-03555-3.

Clinical and Translational Landscape of Viral Gene Therapies.

Yudaeva A, Kostyusheva A, Kachanov A, Brezgin S, Ponomareva N, Parodi A Cells. 2024; 13(22).

PMID: 39594663 PMC: 11592828. DOI: 10.3390/cells13221916.

UKHCDO gene therapy taskforce: Guidance for implementation of haemophilia gene therapy into routine clinical practice for adults.

Chowdary P, Duran B, Batty P, Lowe G, Jones A, Pollard D Haemophilia. 2024; 31(1):26-38.

PMID: 39565651 PMC: 11780224. DOI: 10.1111/hae.15125.

Engineering viral vectors for acoustically targeted gene delivery.

Li H, Harb M, Heath J, Trippett J, Shapiro M, Szablowski J Nat Commun. 2024; 15(1):4924.

PMID: 38858354 PMC: 11164914. DOI: 10.1038/s41467-024-48974-y.

References

Davidoff A, Gray J, Ng C, Zhang Y, Zhou J, Spence Y . Comparison of the ability of adeno-associated viral vectors pseudotyped with serotype 2, 5, and 8 capsid proteins to mediate efficient transduction of the liver in murine and nonhuman primate models. Mol Ther. 2005; 11(6):875-88. DOI: 10.1016/j.ymthe.2004.12.022. View

Maurer A, Pacouret S, Cepeda Diaz A, Blake J, Andres-Mateos E, Vandenberghe L . The Assembly-Activating Protein Promotes Stability and Interactions between AAV's Viral Proteins to Nucleate Capsid Assembly. Cell Rep. 2018; 23(6):1817-1830. PMC: 5983388. DOI: 10.1016/j.celrep.2018.04.026. View

Majowicz A, Nijmeijer B, Lampen M, Spronck L, de Haan M, Petry H . Therapeutic hFIX Activity Achieved after Single AAV5-hFIX Treatment in Hemophilia B Patients and NHPs with Pre-existing Anti-AAV5 NABs. Mol Ther Methods Clin Dev. 2019; 14:27-36. PMC: 6586596. DOI: 10.1016/j.omtm.2019.05.009. View

Mitchell A, Nicolson S, Warischalk J, Samulski R . AAV's anatomy: roadmap for optimizing vectors for translational success. Curr Gene Ther. 2010; 10(5):319-340. PMC: 3920455. DOI: 10.2174/156652310793180706. View

Rajasekaran S, Thatte J, Periasamy J, Javali A, Jayaram M, Sen D . Infectivity of adeno-associated virus serotypes in mouse testis. BMC Biotechnol. 2018; 18(1):70. PMC: 6211462. DOI: 10.1186/s12896-018-0479-1. View

Mingozzi F, Anguela X, Pavani G, Chen Y, Davidson R, Hui D . Overcoming preexisting humoral immunity to AAV using capsid decoys. Sci Transl Med. 2013; 5(194):194ra92. PMC: 4095828. DOI: 10.1126/scitranslmed.3005795. View

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

Calcedo R, Vandenberghe L, Gao G, Lin J, Wilson J . Worldwide epidemiology of neutralizing antibodies to adeno-associated viruses. J Infect Dis. 2009; 199(3):381-90. PMC: 10826927. DOI: 10.1086/595830. View

Kuranda K, Jean-Alphonse P, Leborgne C, Hardet R, Collaud F, Marmier S . Exposure to wild-type AAV drives distinct capsid immunity profiles in humans. J Clin Invest. 2018; 128(12):5267-5279. PMC: 6264647. DOI: 10.1172/JCI122372. View

10.

High K . Gene therapy for hemophilia: the clot thickens. Hum Gene Ther. 2014; 25(11):915-22. PMC: 4236063. DOI: 10.1089/hum.2014.2541. View

11.

Nathwani A, Gray J, Ng C, Zhou J, Spence Y, Waddington S . Self-complementary adeno-associated virus vectors containing a novel liver-specific human factor IX expression cassette enable highly efficient transduction of murine and nonhuman primate liver. Blood. 2005; 107(7):2653-61. PMC: 1895379. DOI: 10.1182/blood-2005-10-4035. View

12.

Srivastava A . In vivo tissue-tropism of adeno-associated viral vectors. Curr Opin Virol. 2016; 21:75-80. PMC: 5138125. DOI: 10.1016/j.coviro.2016.08.003. View

13.

Boutin S, Monteilhet V, Veron P, Leborgne C, Benveniste O, Montus M . Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors. Hum Gene Ther. 2010; 21(6):704-12. DOI: 10.1089/hum.2009.182. View

14.

Bell C, Gurda B, Van Vliet K, Agbandje-Mckenna M, Wilson J . Identification of the galactose binding domain of the adeno-associated virus serotype 9 capsid. J Virol. 2012; 86(13):7326-33. PMC: 3416318. DOI: 10.1128/JVI.00448-12. View

15.

Wang L, Wang H, Bell P, McCarter R, He J, Calcedo R . Systematic evaluation of AAV vectors for liver directed gene transfer in murine models. Mol Ther. 2009; 18(1):118-25. PMC: 2839210. DOI: 10.1038/mt.2009.246. View

16.

Kaplitt M, Feigin A, Tang C, Fitzsimons H, Mattis P, Lawlor P . Safety and tolerability of gene therapy with an adeno-associated virus (AAV) borne GAD gene for Parkinson's disease: an open label, phase I trial. Lancet. 2007; 369(9579):2097-105. DOI: 10.1016/S0140-6736(07)60982-9. View

17.

Majowicz A, Salas D, Zabaleta N, Rodriguez-Garcia E, Gonzalez-Aseguinolaza G, Petry H . Successful Repeated Hepatic Gene Delivery in Mice and Non-human Primates Achieved by Sequential Administration of AAV5 and AAV1. Mol Ther. 2017; 25(8):1831-1842. PMC: 5542767. DOI: 10.1016/j.ymthe.2017.05.003. View

18.

Gao G, Alvira M, Wang L, Calcedo R, Johnston J, Wilson J . Novel adeno-associated viruses from rhesus monkeys as vectors for human gene therapy. Proc Natl Acad Sci U S A. 2002; 99(18):11854-9. PMC: 129358. DOI: 10.1073/pnas.182412299. View

19.

Meliani A, Boisgerault F, Hardet R, Marmier S, Collaud F, Ronzitti G . Antigen-selective modulation of AAV immunogenicity with tolerogenic rapamycin nanoparticles enables successful vector re-administration. Nat Commun. 2018; 9(1):4098. PMC: 6173722. DOI: 10.1038/s41467-018-06621-3. View

20.

Bennett J, Ashtari M, Wellman J, Marshall K, Cyckowski L, Chung D . AAV2 gene therapy readministration in three adults with congenital blindness. Sci Transl Med. 2012; 4(120):120ra15. PMC: 4169122. DOI: 10.1126/scitranslmed.3002865. View