Megalin-mediated deterministic pseudotransduction in proximal tubules fundamentally challenges current understanding of AAV kidney transduction

Megalin-mediated deterministic pseudotransduction largely explains previously reported proximal tubule transduction after intravenous AAV-GFP or AAV-mCherry, challenging current AAV kidney transduction understanding.

• Why it matters: Contradictory, non-reproducible reports of systemic AAV delivery to proximal tubules create uncertainty about whether true stochastic gene delivery is occurring.
• What they did: The study used rigorous mechanistic investigation showing megalin-dependent uptake of circulating reporter proteins released from transduced organs, including liver, and filtered through glomeruli.
• The result: The findings imply that small reporters like GFP or mCherry can yield misleading proximal tubule signals, underscoring the challenge of achieving genuine proximal tubule transduction with systemic AAV.