Engineered adeno-associated virus 3 vector with reduced reactivity to serum antibodies

Abstract The natural serotypes of adeno-associated virus (AAV) or their variants, such as AAV8 and AAV5, are commonly used as vectors in the clinical programs for liver-targeted gene therapy. While AAV8 vectors are not highly efficient at targeting primary human hepatocytes, AAV3 vectors have recent...

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Autores principales:	Mika Ito, Naomi Takino, Takamasa Nomura, Akihiko Kan, Shin-ichi Muramatsu
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/21dbdb3102a64787821dc94a450f9501
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spelling	oai:doaj.org-article:21dbdb3102a64787821dc94a450f95012021-12-02T13:40:51ZEngineered adeno-associated virus 3 vector with reduced reactivity to serum antibodies10.1038/s41598-021-88614-92045-2322https://doaj.org/article/21dbdb3102a64787821dc94a450f95012021-04-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-88614-9https://doaj.org/toc/2045-2322Abstract The natural serotypes of adeno-associated virus (AAV) or their variants, such as AAV8 and AAV5, are commonly used as vectors in the clinical programs for liver-targeted gene therapy. While AAV8 vectors are not highly efficient at targeting primary human hepatocytes, AAV3 vectors have recently demonstrated remarkable efficiency at targeting both human and non-human primate hepatocytes. However, the presence of high levels of neutralizing antibodies (NAbs) impedes transduction into hepatocytes, representing a major obstacle to the clinical application of AAV3 vectors. Herein, we engineered the viral capsid to reduce its reactivity with pre-existing NAbs, thereby enhancing the transduction efficiency. By introducing three substitutions (S472A, S587A, and N706A) on the surface loop of AAV3B capsid protein, we generated a triple mutant AAV3 (AAV.GT5) vector with less reactivity to anti-AAV capsid NAbs. While the transduction efficiency of AAV.GT5 into human hepatocellular cell lines was similar to those of parental AAV3B, it was 50-fold higher for hepatocytes derived from humanized mice compared to AAV8 vectors. Moreover, the AAV.GT5 vector yield was similar to those of the AAV2 and AAV3B vectors. Thus, high resistance to pre-existing NAbs makes AAV.GT5 a promising candidate for future liver-targeted gene therapy clinical trials.Mika ItoNaomi TakinoTakamasa NomuraAkihiko KanShin-ichi MuramatsuNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Mika Ito Naomi Takino Takamasa Nomura Akihiko Kan Shin-ichi Muramatsu Engineered adeno-associated virus 3 vector with reduced reactivity to serum antibodies
description	Abstract The natural serotypes of adeno-associated virus (AAV) or their variants, such as AAV8 and AAV5, are commonly used as vectors in the clinical programs for liver-targeted gene therapy. While AAV8 vectors are not highly efficient at targeting primary human hepatocytes, AAV3 vectors have recently demonstrated remarkable efficiency at targeting both human and non-human primate hepatocytes. However, the presence of high levels of neutralizing antibodies (NAbs) impedes transduction into hepatocytes, representing a major obstacle to the clinical application of AAV3 vectors. Herein, we engineered the viral capsid to reduce its reactivity with pre-existing NAbs, thereby enhancing the transduction efficiency. By introducing three substitutions (S472A, S587A, and N706A) on the surface loop of AAV3B capsid protein, we generated a triple mutant AAV3 (AAV.GT5) vector with less reactivity to anti-AAV capsid NAbs. While the transduction efficiency of AAV.GT5 into human hepatocellular cell lines was similar to those of parental AAV3B, it was 50-fold higher for hepatocytes derived from humanized mice compared to AAV8 vectors. Moreover, the AAV.GT5 vector yield was similar to those of the AAV2 and AAV3B vectors. Thus, high resistance to pre-existing NAbs makes AAV.GT5 a promising candidate for future liver-targeted gene therapy clinical trials.
format	article
author	Mika Ito Naomi Takino Takamasa Nomura Akihiko Kan Shin-ichi Muramatsu
author_facet	Mika Ito Naomi Takino Takamasa Nomura Akihiko Kan Shin-ichi Muramatsu
author_sort	Mika Ito
title	Engineered adeno-associated virus 3 vector with reduced reactivity to serum antibodies
title_short	Engineered adeno-associated virus 3 vector with reduced reactivity to serum antibodies
title_full	Engineered adeno-associated virus 3 vector with reduced reactivity to serum antibodies
title_fullStr	Engineered adeno-associated virus 3 vector with reduced reactivity to serum antibodies
title_full_unstemmed	Engineered adeno-associated virus 3 vector with reduced reactivity to serum antibodies
title_sort	engineered adeno-associated virus 3 vector with reduced reactivity to serum antibodies
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/21dbdb3102a64787821dc94a450f9501
work_keys_str_mv	AT mikaito engineeredadenoassociatedvirus3vectorwithreducedreactivitytoserumantibodies AT naomitakino engineeredadenoassociatedvirus3vectorwithreducedreactivitytoserumantibodies AT takamasanomura engineeredadenoassociatedvirus3vectorwithreducedreactivitytoserumantibodies AT akihikokan engineeredadenoassociatedvirus3vectorwithreducedreactivitytoserumantibodies AT shinichimuramatsu engineeredadenoassociatedvirus3vectorwithreducedreactivitytoserumantibodies
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Engineered adeno-associated virus 3 vector with reduced reactivity to serum antibodies

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