Scientists developed and optimized lipid nanoparticles (LNPs) for the purpose of delivering Cas9 mRNA along with single guide RNA that targeted antithrombin (AT) in the livers of mouse models and discovered that it was both safe and efficient as a potential form of therapy for hemophilia, as published in Science Advances.

Hemophilia is a genetic disease that results in spontaneous bleeding due to a lack of certain clotting factors. The most common approach to managing hemophilia is prophylactic clotting factor replacement therapy, depending on the type of hemophilia.

However, “a fundamental treatment has not yet been developed,” the authors wrote. Gene therapy provides hope for a curative approach to become available. Genome editing has been proven effective as a therapeutic strategy in a number of hereditary illnesses.


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“We hypothesized that CRISPR-Cas9–mediated AT editing may represent a long-term and versatile therapeutic option for treating hemophilia A and B,” the researchers said. They sought to investigate whether the in vivo delivery of CRISPR-Cas9 using LNPs was effective in enabling AT gene editing to treat hemophilia A and B.

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Han et al first developed and optimized LNPs to deliver the Cas9 mRNA (together with a potent single guide RNA) to target mouse AT in the mouse liver. They then generated gene editing-mediated thrombin and evaluated their therapeutic efficacy in hemophilia A and B mouse models.

The results demonstrated that this method of inhibiting AT resulted in an improvement in thrombin generation. The research team wrote that “bleeding-associated phenotypes were recovered in both hemophilia A and B mice” and that “no active off-targets, liver-induced toxicity, and substantial anti-Cas9 immune responses were detected.”

The findings of this study thus confirm the promise of AT gene editing for the development of a sustainable therapeutic approach for both hemophilia A and B.

Reference

Han JP, Kim M, Choi BS, et al. In vivo delivery of CRISPR-Cas9 using lipid nanoparticles enables antithrombin gene editing for sustainable hemophilia A and B therapy. Sci Adv. Published online January 21, 2022. doi:10.1126/sciadv.abj6901