Thesis Josse Depla on neural organoids as preclinical tools for viral infection and gene therapy

On the 20th of April 2023, Josse Depla (PhD student at OrganoVIR Labs) successfully defended his thesis “Neural organoids as preclinical tools for viral infection and gene therapy: Insights from enterovirus D68 and adeno associated virus studies” and was granted a PhD diploma. Read his dissertation here.

Neurological diseases result in high mortality and disability worldwide [1,2]. Despite the high burden of diseases of the central nervous system (CNS), effective therapies and a good understanding of pathogenesis are lacking [3]. One of the many causes of neurological disease is viral infection. Viral infection leads to disease through direct infection of neuronal cells and/or due to damage caused by virus induced immune responses [4,5]. Neurotropic viruses are able to invade the CNS, overcoming barriers that protect the brain such as the blood brain barrier [6,7]. The ability of viruses to invade and spread in the CNS is, besides a cause of neurological disease, also a useful trait for drug delivery into the CNS. Therefore, in gene therapy, non-pathogenic viruses are used as a delivery vector for therapeutic transgenes that treat CNS diseases.

The therapeutic transgene is intended to correct the genetic origin of the disease, by removing or replacing a mutated gene in the target cell [8]. As investigating viral CNS disease pathogenesis and developing and testing virus-based gene therapies in the human brain is unethical and impractical, preclinical models such as cell lines and animals are used.

Despite the contribution of studies in cell lines and animal models to our advancement in understanding and treatment of CNS disease, they are limited in translation to the human patient. For instance, cell lines fail to model complex interactions between multiple cell types of the CNS in 3 dimensions (3D) [9]. Animal models do model 3D complexity, but cannot represent human-specific features of virus-CNS interactions and come with ethical concerns [10–12]. As an alternative, neural organoids are increasingly being implemented in studies on neurodevelopment, neurological disorders, and CNS infections. Neural organoids are self-organizing in vitro cell cultures that consist of multiple cell types and exhibit cytoarchitectural and functional features of the human CNS [13]. 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 by two case studies. First, neural organoids are used to study adeno associated virus (AAV), a delivery vector for gene therapy. Second, neural organoids are applied to the study of enterovirus D68 (EV-D68), a pathogenic virus responsible for polio-like CNS diseas


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