Directed evolution of adeno-associated virus 5 capsid enables specific liver tropism

Wang, Yuqiu; Yang, Czau‐Siung; Hu, Hanyang; Chen, Chen; Yan, Ming; Ling, Feixiang; Wang, Kathy Cheng; Wang, Xintao; Deng, Zhe; Zhou, Xin-Yue; Zhang, Feixu; Lin, Sen; Du, Zengmin; Zhao, Kai; Xiao, Xiao

doi:10.1016/j.omtn.2022.03.017

Cited by 13 publications

(13 citation statements)

References 73 publications

(107 reference statements)

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“…Additionally, the seroreactivity of this engineered capsid variant to NAbs in serum from hemophilia B patient serum was similar to AAV5, the parental capsid serotype. 40 …”

Section: Intrinsic Properties Of Aavs Implicated In Immunogenicitymentioning

confidence: 99%

Immunogenicity assessment of AAV-based gene therapies: An IQ consortium industry white paper

Yang

Braun

Lembke³

et al. 2022

Molecular Therapy - Methods & Clinical Development

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“…Additionally, the seroreactivity of this engineered capsid variant to NAbs in serum from hemophilia B patient serum was similar to AAV5, the parental capsid serotype. 40 …”

Section: Intrinsic Properties Of Aavs Implicated In Immunogenicitymentioning

confidence: 99%

Immunogenicity assessment of AAV-based gene therapies: An IQ consortium industry white paper

Yang

Braun

Lembke³

et al. 2022

Molecular Therapy - Methods & Clinical Development

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“…We instantiated and evaluated our library design approach by designing a 7-mer peptide insertion library for AAV serotype 5 (AAV5) to optimally balance diversity and overall packaging fitness. Among the natural AAV serotypes, AAV5 has been suggested as a promising candidate for clinical gene delivery because of the low prevalence of pre-existing neutralizing antibodies and successful clinical development for hemophilia B [21][22][23][24]. We focus, specifically, on peptide insertion libraries because they are both simple and highly practical, having already been translated to the clinic (e.g., NCT03748784, NCT04645212, NCT04483440, NCT04517149, NCT04519749, NCT03326336, NCT05197270) [25].…”

Section: Introductionmentioning

confidence: 99%

Optimal trade-off control in machine learning-based library design, with application to adeno-associated virus (AAV) for gene therapy

Zhu

Brookes

Busia

et al. 2021

Preprint

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AAVs hold tremendous promise as delivery vectors for clinical gene therapy. Yet the ability to design libraries comprising novel and diverse AAV capsids, while retaining the ability of the library to package DNA payloads, has remained challenging. Deep sequencing technologies allow millions of sequences to be assayed in parallel, enabling large-scale probing of fitness landscapes. Such data can be used to train supervised machine learning (ML) models that predict viral properties from sequence, without mechanistic knowledge. Herein, we leverage such models to rationally trade-off library diversity with packaging capability. In particular, we show a proof-of-principle application of a general approach for ML-guided library design that allows the experimenter to rationally navigate the trade-off between sequence diversity and fitness of the library. Consequently, this approach, instantiated with an AAV capsid library designed for packaging, enables the selection of starting libraries that are more likely to yield success in downstream selections for therapeutics and beyond. We demonstrated this increased success by showing that the designed libraries are able to more easily infect primary human brain tissue. We expect that such ML-guided design of AAV libraries will have broad utility for the development of novel variants for therapeutic applications in the near future.One Sentence SummaryComputational, data-driven re-design of a state-of-the-art therapeutically relevant AAV initial library improves downstream selection for therapeutic uses.

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“…A high dose of the vector is required for the efficient transduction using AAV5 because of its low transduction efficacy to liver cells. 38,39 We previously demonstrated that a high-dose vector (1 Â 10 13 vg/kg) could evade NAbs for liver transduction with AAV8 vector. 40 We also confirmed transduction with a lower vector dose (0.5 Â 10 12 vg/kg) was inhibited by 1:1 Nab ratio even with an AAV5 vector (data not shown).…”

Section: Discussionmentioning

confidence: 99%

“…One possibility is the dose of AAV5 employed in the previous study. A high dose of the vector is required for the efficient transduction using AAV5 because of its low transduction efficacy to liver cells 38,39 . We previously demonstrated that a high‐dose vector (1 × 10 13 vg/kg) could evade NAbs for liver transduction with AAV8 vector 40 .…”

Section: Discussionmentioning

confidence: 99%

Successful liver transduction by re‐administration of different adeno‐associated virus vector serotypes in mice

Baatartsogt

Kashiwakura

Hiramoto

et al. 2023

The Journal of Gene Medicine

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Background Intravenous administration of adeno‐associated virus (AAV) vectors is a promising gene therapy approach for monogenic diseases. However, re‐administration of the same AAV serotype is impossible because of the induction of anti‐AAV neutralizing antibodies (NAbs). Here, we examined the feasibility of re‐administrating AAV vector serotypes different from the initial AAV vector serotype. Methods Liver‐targeting AAV3B, AAV5, and AAV8 vectors were intravenously injected in C57BL/6 mice, and the emergence of NAbs and the transduction efficacy following re‐administration were evaluated. Results For all serotypes, re‐administration of the same serotype was not possible. Although the highest neutralizing activity of NAb was induced by AAV5, anti‐AAV5 NAbs did not react with other serotypes, resulting in successful re‐administration with the other serotypes. AAV5 re‐administration was also successful in all mice treated with AAV3B and AAV8. Effective secondary administration of AAV3B and AAV8 was observed in most mice initially administrated AAV8 and AAV3B, respectively. However, few mice developed NAbs cross‐reacting with the other serotypes, especially those with close sequence homology. Conclusions In summary, AAV vector administration induced NAbs relatively specific to the administrated serotype. Secondary administration of AAVs targeting liver transduction could be successfully achieved by switching AAV serotypes in mice.

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Directed evolution of adeno-associated virus 5 capsid enables specific liver tropism

Cited by 13 publications

References 73 publications

Immunogenicity assessment of AAV-based gene therapies: An IQ consortium industry white paper

Immunogenicity assessment of AAV-based gene therapies: An IQ consortium industry white paper

Optimal trade-off control in machine learning-based library design, with application to adeno-associated virus (AAV) for gene therapy

Successful liver transduction by re‐administration of different adeno‐associated virus vector serotypes in mice

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