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Human cell surface-AAV interactomes identify LRP6 as blood-brain-barrier transcytosis receptor and immune cytokine IL3 as AAV9 binder

ABSTRACT: Adeno-associated viruses (AAVs) are foundational gene delivery tools for basic science and clinical therapeutics. However, lack of mechanistic insight, especially for engineered vectors created by directed evolution, can hamper their application. Here, we adapted an unbiased human cell microarray platform to determine the extracellular and cell surface interactomes of natural and engineered AAVs. We identified a naturally-evolved and serotype-specific interaction of AAV9 with human interleukin 3 (IL3), with possible roles in host immune modulation, as well as lab-evolved low-density-lipoprotein-receptor-related-protein 6 (LRP6) interactions specific to engineered capsids that cross the blood-brain barrier in non-human primates upon intravenous administration. The unbiased cell microarray screening approach also allowed us to identify off-target tissue binding interactions of engineered brain-enriched AAVs that may inform vectors’ peripheral organ tropism and side effects. These results allow confident application of engineered AAVs in diverse organisms and unlock future target-informed engineering of improved viral and non-viral vectors for non-invasive therapeutic delivery to the brain.

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Cell Culture

SUBMITTER: Ting-Yu Wang

LAB HEAD: Tsui-Fen Chou

PROVIDER: PXD045380 | Pride | 2024-07-31

REPOSITORIES: Pride

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			Action	DRS
	Tyler_20230811_QE_Aur30min_il3.raw	Raw
	tyler_20230811_QE_Aur30min_BS3_2-3_csms.xlsx	Xlsx
	tyler_20230811_QE_Aur30min_BS3_2-3_xlinks.xlsx	Xlsx
	tyler_20230811_QE_Aur30min_BS3_2_3.msf	Msf

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