ArticlebioRxiv : the preprint server for biology2025
Adeno-associated viruses (AAVs) induce dose-dependent neonatal ventriculomegaly following intracerebroventricular administration.
Article in bioRxiv : the preprint server for biology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Cell-type-specific expression of synthetic/endogenous proteins or genetic sequences has significantly advanced our understanding of the central nervous system (CNS). Adeno-associated virus (AAV)-delivery to cerebrospinal fluid (CSF) mediates transfection of target cells to enable sustained delivery of secretory proteins into the CSF, offering promising avenues for both CNS therapy and mechanistic studies. However, despite the advantages afforded by AAV tropism-based cellular selectivity and transgene delivery, both preclinical studies and clinical trials report short- and long-term adverse effects, particularly immune activation. Especially relevant for CSF biology, CNS immune insults raise the risk of CSF dysregulation, including hydrocephalus. These risks may be exacerbated in pediatric populations, where ongoing CNS development, including immature meninges, choroid plexus (ChP), and skull structures, may further impair any ability to compensate for CSF dysregulation. To systematically address these risks and provide guidelines for minimizing CNS immune insults by AAVs, we test the dose-dependent effects of intracerebroventricular (ICV) injections of 3 AAV serotypes (AAV2/5, AAV2/4, and AAV.PHP.eB) to neonatal (P0.5) CD1 mouse pups. Histological analysis verified AAV2/5 tropism limited to ChP epithelial cells (CPECs), whereas AAV.PHP.eB transfected both CPECs and ependymal regions. By contrast, AAV2/4 shows limited transfection in the brain. Further, we find that ICV injections of all 3 AAV serotypes at the high dose (4×10
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