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Discovering human cell-compatible gene therapy virus variants via optimized screening in mouse models.

ABSTRACT: In gene therapy, intravenous injection of viral vectors reigns as the primary administration route. These vectors include adeno-associated viruses, adenoviruses, herpes viruses, rhabdoviruses and others. However, these naturally occurring viruses lack inherent tissue or organ tropism for tailored disease treatment. To address this, we devised an optimized process involving directed viral capsid evolution, organ-specific humanized mouse models and in vitro-in vivo virus screening. Our approach allows for the rapid generation specifically modified adeno-associated virus variants, surpassing the time required for natural evolution, which spans millions of years. Notably, these variants exhibit robust targeting of the liver, favouring chimeric human liver cells over murine hepatocytes. Furthermore, certain variants achieve augmented targeting with reduced off-target organ infection, thereby mitigating dosage requirements and enhancing safety in gene therapy.

SUBMITTER: Dai M

PROVIDER: S-EPMC10905335 | biostudies-literature | 2024 Mar

REPOSITORIES: biostudies-literature

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Discovering human cell-compatible gene therapy virus variants via optimized screening in mouse models.

Dai Moyu M Yang Ning N Xu Kai K Zhang Jingwen J Li Xueke X Zhang Ying Y Li Wei W

Cell proliferation 20231020 3

In gene therapy, intravenous injection of viral vectors reigns as the primary administration route. These vectors include adeno-associated viruses, adenoviruses, herpes viruses, rhabdoviruses and others. However, these naturally occurring viruses lack inherent tissue or organ tropism for tailored disease treatment. To address this, we devised an optimized process involving directed viral capsid evolution, organ-specific humanized mouse models and in vitro-in vivo virus screening. Our approach al ...[more]

PMID: 37864397

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Project description:BackgroundThe inducible Kras/p53 lung adenocarcinoma mouse model, which faithfully recapitulates human disease, is routinely initiated by the intratracheal instillation of a virus-based Cre recombinase delivery system. Handling virus-based delivery systems requires elevated biosafety levels, e.g., biosafety level 2 (BSL-2). However, in experimental animal research facilities, following exposure to viral vectors in a BSL-2 environment, rodents may not be reclassified to BSL-1 according to standard practice, preventing access to small animal micro-computed tomography (micro-CT) scanners that are typically housed in general access areas such as BSL-1 rooms. Therefore, our goal was to adapt the protocol so that the Cre-induced KP mouse model could be handled under BSL-1 conditions during the entire procedure.ResultsThe Kras-Lox-STOP-Lox-G12D/p53 flox/flox (KP)-based lung adenocarcinoma mouse model was activated by intratracheal instillation of either an adenoviral-based or a gutless, adeno-associated viral-based Cre delivery system. Tumor growth was monitored over time by micro-CT. We have successfully substituted the virus-based Cre delivery system with a commercially available, gutless, adeno-associated, Cre-expressing vector that allows the KP mouse model to be handled and imaged in a BSL-1 facility. By optimizing the anesthesia protocol and switching to a microscope-guided vector instillation procedure, productivity was increased and procedure-related complications were significantly reduced. In addition, repeated micro-CT analysis of individual animals allowed us to monitor tumor growth longitudinally, dramatically reducing the number of animals required per experiment. Finally, we documented the evolution of tumor volume for different doses, which revealed that individual tumor nodules induced by low-titer AAV-Cre transductions can be monitored over time by micro-CT.ConclusionModifications to the anesthesia and instillation protocols increased the productivity of the original KP protocol. In addition, the switch to a gutless, adeno-associated, Cre-expressing vector allowed longitudinal monitoring of tumor growth under BSL-1 conditions, significantly reducing the number of animals required for an experiment, in line with the 3R principles.

Dataset Information

Discovering human cell-compatible gene therapy virus variants via optimized screening in mouse models.

Publications

Discovering human cell-compatible gene therapy virus variants via optimized screening in mouse models.

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