In vivo delivery of CRISPR-Cas9 using lipid nanoparticles enables antithrombin gene editing for sustainable hemophilia A and B therapy
| Autor: | Jeong Pil Han, MinJeong Kim, Beom Seok Choi, Jeong Hyeon Lee, Geon Seong Lee, Michaela Jeong, Yeji Lee, Eun-Ah Kim, Hye-Kyung Oh, Nanyeong Go, Hyerim Lee, Kyu Jun Lee, Un Gi Kim, Jae Young Lee, Seokjoong Kim, Jun Chang, Hyukjin Lee, Dong Woo Song, Su Cheong Yeom |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: | |
| Zdroj: | Science Advances |
| ISSN: | 2375-2548 |
| Popis: | 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. Description We showed that lipid nanoparticle–packed CRISPR- mediated antithrombin gene editing offers a sustainable and safe hemophilia therapy. |
| Databáze: | OpenAIRE |
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