ScienceDaily (May 11, 2009) — Individuals with hemophilia B have a genetic mutation in their F9 gene that leads to deficiency in the blood clotting protein Factor IX. A recent gene therapy trial, using the viral vector AAV2 to transfer the F9 gene into liver cells, failed to establish long-lived Factor IX expression.

It was suggested that immune responses (specifically CTL responses) against the virus (specifically its capsid protein) destroyed gene-corrected liver cells, thereby preventing long-term Factor IX expression. However, whether the molecular events underlying this mechanistic explanation occur has not been formally demonstrated.

But now, Katherine High and colleagues, at Children's Hospital of Philadelphia, Philadelphia, have shown that the required molecular events do occur in AAV-transduced human liver cells.

Briefly, they detected on the surface of AAV-transduced human liver cells fragments of the AAV capsid protein bound to the human protein MHCI, and CTL recognition of this protein complex triggered CTL killing of the AAV-transduced cells. As blocking CTL recognition of this protein complex prevented the killing of the AAV-transduced human liver cells, the authors suggest that blocking CTL responses therapeutically might improve the success of liver-targeted AAV-mediated gene therapy.

Journal reference:

1. . Capsid antigen presentation flags human hepatocytes for destruction after transduction by adeno-associated viral vectors. Journal of Clinical Investigation,

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