Are viral vector-mediated therapies compatible with aberrant glycosylation?

The ability of adeno-associated viruses (AAVs) to transduce host cells relies on interactions with glycan moieties on the cellular surface. Consequently, disrupted protein glycosylation, which is seen in a range of neurodevelopmental and neurodegenerative diseases, could impair transduction efficiency. Understanding how altered glycosylation impacts AAV binding is essential to optimize AAV-mediated therapeutic strategies. We used glycoproteomics data from cortical brain organoids and iCardiomyocytes of individuals with congenital disorders of glycosylation (CDG) (ALG13-, PMM2-, and PGM1-CDG) to examine the abundance of AAV-binding glycan species. Additionally, we assessed the abundance of coreceptors in proteomics data. We found that the abundance of AAV-binding glycan species was downregulated for all CDG subtypes, but this was significant only for AAV5-, AAV8-, and AAV9-binding glycan motifs in PGM1-CDG. The proteomics data showed significantly decreased abundance of the coreceptor PDGFRβ in ALG13-CDG. The downregulation of glycan species and AAV coreceptors in models of aberrant protein glycosylation underscores the need to optimize AAV selection for conditions with altered protein glycosylation, including CDG and neurodegenerative diseases such as Parkinson's and Alzheimer's disease.