Neural organoids as preclinical tools for viral infection and gene therapy: Insights from enterovirus D68 and adeno associated virus studies - PhDData

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Neural organoids as preclinical tools for viral infection and gene therapy: Insights from enterovirus D68 and adeno associated virus studies

The thesis was published by Depla, J.A., in January 2023, University of Amsterdam.

Abstract:

Viruses causes neurological diseases, but are also used for drug delivery into the central nervous system (CNS), e.g. in gene therapy. The current preclinical models that are used to investigate viral CNS disease pathogenesis and to develop virus-based gene therapies, are limited in translation to the human patient. As an alternative, neural organoids are increasingly being implemented. In this thesis the usefulness of neural organoids as preclinical tools for studying viral infection and virus based gene therapy in the CNS is explored. First, neural organoids are used to study adeno associated virus (AAV), a delivery vector for gene therapy. We compare the transduction efficiency of two AAV variants for neuronal cells using neural organoids and demonstrate therapeutic efficacy of an AAV delivered transgene. Second, neural organoids are applied to the study of enterovirus D68 (EV-D68), a pathogenic virus responsible for a recent rise in polio-like CNS disease. We show that binding to heparan sulfate proteoglycan does not seem to increase EV-D68 neurotropism. In addition, we show no differences in neurotropism between EV-D68 variants, and investigate EV-D68 infection induced innate immune responses. Our data and literature review demonstrate the broad applications and benefits of using neural organoids in virology studies. The usefulness of neural organoids can be further improved by standardization of protocols and by incorporating additional CNS components to the model. The broader implementation of neural organoids in viral infection studies could improve our understanding of viral CNS pathogenesis and bring effective treatments to patients of neurological diseases.



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