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Immune Cells Hold Back Gene Therapy

Date:
May 11, 2009
Source:
Journal of Clinical Investigation
Summary:
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.
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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.


Story Source:

The above post is reprinted from materials provided by Journal of Clinical Investigation. Note: Materials may be edited for content and length.


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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Journal of Clinical Investigation. "Immune Cells Hold Back Gene Therapy." ScienceDaily. ScienceDaily, 11 May 2009. <www.sciencedaily.com/releases/2009/05/090511180647.htm>.
Journal of Clinical Investigation. (2009, May 11). Immune Cells Hold Back Gene Therapy. ScienceDaily. Retrieved July 1, 2015 from www.sciencedaily.com/releases/2009/05/090511180647.htm
Journal of Clinical Investigation. "Immune Cells Hold Back Gene Therapy." ScienceDaily. www.sciencedaily.com/releases/2009/05/090511180647.htm (accessed July 1, 2015).

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