Researchers discovered that defenestrated endothelium can cause a delay in liver-directed gene transfer in patients with hemophilia A, according to a new study published in Blood Advances.

Hemophilia A, if left untreated, can cause spontaneous bleeding into the joints, eventually leading to severe arthropathy. Medical researchers are increasingly looking at gene therapy as a potential therapeutic solution to hemophilia A because the current mainstay of treatment, the recurrent exogenous replacement of factor VIII (FVIII), is inconvenient for patients and does not fully prevent breakthrough bleeding.

Adeno-associated virus (AAV) vector-based liver-directed gene therapy has been shown to be a promising approach to hemophilia A gene therapy. However, there are 2 main challenges to this form of treatment: the huge size of the FVIII coding sequence and suboptimal synthesis of the FVIII protein post-therapy.

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The authors of the study aimed to evaluate the stability and efficacy of a liver-driven gene transfer approach using a recombinant AAV8 vector. They conducted their studies on FVIII total knockout (F8TKO) mice, which are useful models of hemophilia A. The research team chose to use green fluorescent protein as a model gene for the transduction and normal littermate mice as the controls.

They discovered that liver-directed gene transfer was delayed significantly in the F8TKO mice compared to the control group. “Remarkably, the delay in liver-directed gene transfer in F8TKO mice was associated with absence of liver sinusoidal endothelial cell (LSEC) fenestration, which can lead to altered expression of major endothelial proteins causing increased capillarization and decreased permeability of LSECs,” they wrote.

The authors of this study hope that their findings will prompt further research on the molecular mechanisms underlying the loss of endothelial fenestration and its relationship with FVIII deficiency in hemophilia A.


Kaminski TW, Ju EM, Gudapati S, et al. Defenestrated endothelium delays liver-directed gene transfer in hemophilia A miceBlood Adv. Published online April 15, 2022. doi:10.1182/bloodadvances.2021006388