# Are viral vector-mediated therapies compatible with aberrant glycosylation?

## TL;DR

This study shows that altered glycosylation in certain diseases can reduce the effectiveness of AAV-based therapies by decreasing key glycan and receptor levels.

## Contribution

The study introduces a glycoproteomics and proteomics approach to assess how aberrant glycosylation impacts AAV transduction in disease models.

## Key findings

- AAV-binding glycan species were downregulated in all CDG subtypes, with significant effects in PGM1-CDG for AAV5, AAV8, and AAV9.
- Coreceptor PDGFRβ abundance was significantly decreased in ALG13-CDG.
- Downregulation of glycans and coreceptors suggests the need for glycosylation-aware AAV vector selection in therapies.

## Abstract

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.

Muffels and colleagues demonstrate here that altered glycosylation, which is observed in congenital-, liver-, and neurodegenerative disorders, can reduce AAV-binding glycan expression, potentially impairing transduction efficacy. These findings underscore the need for glycosylation-aware vector selection in AAV-therapies for disorders with glycosylation defects, such as CDGs and Alzheimer’s disease.