In vivo delivery of CRISPR-Cas9 using lipid nanoparticles enables antithrombin gene editing for sustainable hemophilia A and B therapy
- 주제(기타) Multidisciplinary Sciences
- 설명문(일반) [Han, Jeong Pil; Lee, Jeong Hyeon; Lee, Geon Seong; Yeom, Su Cheong] Seoul Natl Univ, Grad Sch Int Agr Technol, Pyeongchang 25354, Gangwon, South Korea; [Han, Jeong Pil; Lee, Jeong Hyeon; Lee, Geon Seong; Yeom, Su Cheong] Seoul Natl Univ, Inst Green BioSci & Technol, Pyeongchang 25354, Gangwon, South Korea; [Kim, MinJeong; Jeong, Michaela; Lee, Yeji; Kim, Eun-Ah; Chang, Jun; Lee, Hyukjin] Ewha Womans Univ, Coll Pharm, Grad Sch Pharmaceut Sci, Seoul 03760, South Korea; [Choi, Beom Seok; Oh, Hye-Kyung; Go, Nanyeong; Lee, Hyerim; Lee, Kyu Jun; Kim, Un Gi; Lee, Jae Young; Kim, Seokjoong; Song, Dong Woo] Toolgen Inc, Seoul 08501, South Korea; [Yeom, Su Cheong] Seoul Natl Univ, Dept Agr Biotechnol, WCU Biomodulat Major, Seoul 08826, South Korea
- 등재 SCIE, SCOPUS
- OA유형 Green Published
- 발행기관 AMER ASSOC ADVANCEMENT SCIENCE
- 발행년도 2022
- 총서유형 Journal
- URI http://www.dcollection.net/handler/ewha/000000190436
- 본문언어 영어
- Published As https://doi.org/10.1126/sciadv.abj6901
- PubMed https://pubmed.ncbi.nlm.nih.gov/35061543
초록/요약
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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