265. Polysialic Acid as a Novel Regulator of AAV Tropism in the Developing Brain

Abstract

Recombinant AAV vectors are currently being exploited in a number of clinical trials that aim to correct neurological diseases. In many cases, it is important that therapeutic intervention occurs in the infantile stage of life. Thus, it is important to understand how AAV vectors interact with the constantly changing environment in the brain during neurodevelopment. Recombinant AAV is thought to spread through the central nervous system (CNS) by exploiting cerebrospinal fluid (CSF) flux and hijacking axonal transport pathways. The role of host receptors that mediate these processes in the developing brain are not well understood. In the current study, we utilized AAV serotype 4 as a model to evaluate whether ubiquitously expressed 2,3-linked sialic acid and the developmentally regulated marker, 2,8-linked polysialic acid (PSA) regulate viral transport and tropism in the neonatal brain. Modulation of the levels of SA and PSA in cell culture studies using specific neuraminidases revealed possibly opposing roles of the two glycans on AAV4 transduction. Interestingly, upon intracranial injection into lateral ventricles of the neonatal mouse brain, a low affinity AAV4 mutant displayed a striking shift in cellular tropism from 2,3-linked SA+ ependymal lining to 2,8-linked PSA+ migrating progenitors in the rostral migratory stream and olfactory bulb. In addition, this gain-of-function phenotype correlated with robust CNS spread of the mutant through paravascular transport pathways. Consistent with these observations, altering glycan dynamics within the brain by co-administering SA and PSA specific neuraminidases resulted in striking changes to the cellular tropisms and transduction efficiencies of both parental and mutant vectors. We postulate that glycan signatures associated with host development can be exploited to redirect novel AAV vectors to specific cell types in the brain.