AAV VP1 unique region (VP1u) determines GPR108 dependence for AAV transduction of human airway epithelium and its rescue by Doxorubicin

10 Jul 20264 min read0 viewsVerified Feed

GIST (Key Takeaways)

rAAV2.5T was identified through directed evolution of an AAV capsid library in polarized human airway epithelium (HAE) cultured at an air-liquid interface (ALI). The capsid gene of rAAV2.5T is a chimera of the N-terminal unique region of AAV2 VP1 (VP1u) and the VP2 and VP3 regions of AAV5 with a single A581T substitution at the variable region (VR) VIII of the capsids.
GPR108, a G protein-coupled receptor, is known as an essential host factor for the transduction of rAAV2 but not of rAAV5. Both AAV2 and AAV5 VP1u colocalized well with GPR108 and, to a lesser extent, with the trans-Golgi network (TGN).
GPR108 knockout (KO) abolished rAAV2.5T transduction in both HeLa cells and HAE-ALI cultures. Remarkably, short-term treatment with doxorubicin (DOX) at 2 M completely restored transduction, indicating that DOX can compensate for the loss of GPR108 function.
DOX enhanced rAAV2.5T transduction by 50-100-fold in wild-type HAE-ALI cultures and by over 300-fold in the GPR108-deficient cultures.

Clinical Editorial

bioRxiv (Biomedical Preprints) published a clinical update in Research Highlights on 10 Jul 2026.

The item focuses on AAV VP1 unique region (VP1u) determines GPR108 dependence for AAV transduction of human airway epithelium and its rescue by Doxorubicin.

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