한빛사 논문
Jeong Pil Han1,†, MinJeong Kim2,†, Beom Seok Choi3,†, Jeong Hyeon Lee1, Geon Seong Lee1, Michaela Jeong2, Yeji Lee2, Eun-Ah Kim2, Hye-Kyung Oh3, Nanyeong Go3, Hyerim Lee3, Kyu Jun Lee3, Un Gi Kim3, Jae Young Lee3, Seokjoong Kim3, Jun Chang2, Hyukjin Lee2,*, Dong Woo Song3,*, Su Cheong Yeom1,4,*
1Graduate School of International Agricultural Technology and Institute of Green BioScience and Technology, Seoul National University, Pyeongchang, Gangwon 25354, Korea. 2College of Pharmacy, Graduate School of Pharmaceutical Sciences, Ewha Woman's University, Seodaemun-gu, Seoul 03760, Korea. 3Toolgen Inc., Geumcheon-gu, Seoul 08501, Korea. 4WCU Biomodulation Major, Department of Agricultural Biotechnology, Seoul National University, Gwanank-gu, Seoul 08826, Korea.
*Corresponding author.
†These authors contributed equally to this work.
Abstract
Hemophilia is a hereditary disease that remains incurable. Although innovative treatments such as gene therapy or bispecific antibody therapy have been introduced, substantial unmet needs still exist with respect to achieving long-lasting therapeutic effects and treatment options for inhibitor patients. Antithrombin (AT), an endogenous negative regulator of thrombin generation, is a potent genome editing target for sustainable treatment of patients with hemophilia A and B. In this study, we developed and optimized lipid nanoparticles (LNPs) to deliver Cas9 mRNA along with single guide RNA that targeted AT in the mouse liver. The LNP-mediated CRISPR-Cas9 delivery resulted in the inhibition of AT that led to improvement in thrombin generation. Bleeding-associated phenotypes were recovered in both hemophilia A and B mice. No active off-targets, liver-induced toxicity, and substantial anti-Cas9 immune responses were detected, indicating that the LNP-mediated CRISPR-Cas9 delivery was a safe and efficient approach for hemophilia therapy.
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