Adeno-associated virus vector modification based on directed evolution technology for gene therapy targeting head and neck squamous cell carcinoma
IntroductionAdeno-associated virus (AAV) vectors are promising tools for cancer gene therapy, yet their clinical application in head and neck squamous cell carcinoma (HNSCC) is hindered by suboptimal transduction efficiency and off-target risks. Bioengineered AAV capsids require optimization to enha...
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| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-06-01
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| Series: | Frontiers in Oncology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2025.1566584/full |
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| Summary: | IntroductionAdeno-associated virus (AAV) vectors are promising tools for cancer gene therapy, yet their clinical application in head and neck squamous cell carcinoma (HNSCC) is hindered by suboptimal transduction efficiency and off-target risks. Bioengineered AAV capsids require optimization to enhance tumor-specific targeting while minimizing systemic toxicity.MethodsWe employed a directed evolution strategy combining DNA shuffling and site-directed mutagenesis to generate AAV variants. Five rounds of in vitro selection were performed using HNSCC cell lines (SCC-090, SCC-152, FaDu), followed by validation through in vitro transduction assays and in vivo studies in HNSCC xenograft mouse models. AAVzy9-3, a lead capsid variant, was further tested for α2δ1-targeted gene silencing efficacy.ResultsThis capsid demonstrated superior transduction efficiency in SCC-090, SCC-152 and FaDu cells when compared to the most efficient parental capsid. The validation of AAVzy9–3 targeting of HNSCC cells was validated through both in vitro and in vivo methods, employing a transplanted tumor mouse model. The results showed that AAVzy9–3 was more effective at infecting HNSCC cells than the wild type, while demonstrating reduced infectious potential toward other cells and organs. Additionally, the study used AAVzy9-3 to knockdown α2δ1 expression in a mouse model of HNSCC transplanted tumors, resulting in reduced tumor size.DiscussionThe development of AAVzy9-3, a novel AAV variant with HNSCC-specific tumor tropism, addresses critical limitations of conventional AAVs. The in vivo antitumor activity validates its therapeutic potential for HNSCC. |
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| ISSN: | 2234-943X |