Different Serotypes of Adeno-Associated Virus Vector- and Lentivirus-Mediated Tropism in Choroid Plexus by Intracerebroventricular Delivery

Abstract

Regulation of gene expression by viral vectors is an effective method for researchers to explore the function of gene products in a target tissue. The choroid plexus (CP) is an important target for gene therapy of neuropsychiatric diseases such as Alzheimer's disease and major depressive disorder. However, viral tropism in CP has not been well studied as a result of limited viral vector applications. To identify CP-specific viral vectors, we intracerebroventricularly administered six different serotypes of adeno-associated virus (AAV) vectors (AAV2/1, AAV2/5, AAV2/8, AAV2/9, AAV2-BR1, and AAV2-PHP.eB) and lentivirus in adult mice. Tropism in CP was compared among these viruses. We found that AAV2/5 and AAV2/8 displayed remarkable infections in CP, while AAV2/1 infected both ependymal cells and cells in the CP. Except for the low infection intensity of AAV2/9 and lentivirus in the CP, no infection intensity was found for CP tissues injected with AAV2-BR1 or AAV2-PHP.eB. Green fluorescence protein expression in the CP after AAV2/5 infection was confirmed by Western blotting. AAV2/5-mediated tropism in epithelial cells of the CP was verified by immunostaining with transthyretin. In this study, we identified for the first time that serotype-specific AAVs 5 and 8 may be robust research tools for intracerebroventricular gene delivery.

MEIS-WNT5A axis regulates development of fourth ventricle choroid plexus

“…Thus, elucidating the regionalized signaling pathways underlying ChP development may expose molecular mechanisms that lend one ventricle more or less susceptible to cancer. Because the ChP represents a tissue amenable to genetic manipulation (Chen et al, 2020), and it adopts distinct, ventricle-specific morphologies owing to inherent differences in activation of WNT5A-driven PCP signaling, the ChP provides a tractable model for future research investigating the mechanistic basis of WNT5A signaling in tissue morphogenesis.…”

Choroid Plexus: The Orchestrator of Long-Range Signalling Within the CNS

“…Considering the overarching influence of the CP as the signalling hub of the brain, the recent emergence of experimental approaches for closer examination and manipulation of various facets of CP secretory activity promises to shed light on various outstanding challenges facing the field. Virus-based vectors, have been described as an exciting new tool for targeted and highly efficient gene delivery, enabling gene manipulation in the CP [187] and providing a powerful technique for modulation of CNS biological functions via specific alterations of CP proteome [188]. In addition, there is growing scientific interest in leveraging the potential of exosomes and lipoproteins for brain-targeted drug delivery [189,190].…”

Experimental approaches for manipulating choroid plexus epithelial cells

“…3 ), and gene expression can be sustained for months [ 88 ]. AAV2/5-mediated ChP gene expression in adult mice has been reported to occur within weeks of injection [ 89 ] and persists up to 12 months [ 74 ]. Other serotypes have been tested in several conditions with variable outcomes (see Table 2 and [ 89 ]); none have been as successful as AAV2/5.…”

“…AAV2/5-mediated ChP gene expression in adult mice has been reported to occur within weeks of injection [ 89 ] and persists up to 12 months [ 74 ]. Other serotypes have been tested in several conditions with variable outcomes (see Table 2 and [ 89 ]); none have been as successful as AAV2/5. Importantly, genes introduced with AAV2/5 encode functional and demonstrably therapeutic proteins.…”

“…d Adult Yes No 6 weeks [ 93 ] AAV2/8 I.C.V. c 8–16 weeks Yes No 21 days [ 89 ] AAV2/9 I.C.V. c E15 Yes No 130 days [ 88 ] 8–16 weeks Yes (low) No 21 days [ 89 ] a Expression beyond ChP and ependyma were reported.…”