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In vivo delivery of CRISPR-Cas9 using lipid nanoparticles enables antithrombin gene editing for sustainable hemophilia A and B therapy

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 patie...

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Detalles Bibliográficos
Autores principales: Han, Jeong Pil, Kim, MinJeong, Choi, Beom Seok, Lee, Jeong Hyeon, Lee, Geon Seong, Jeong, Michaela, Lee, Yeji, Kim, Eun-Ah, Oh, Hye-Kyung, Go, Nanyeong, Lee, Hyerim, Lee, Kyu Jun, Kim, Un Gi, Lee, Jae Young, Kim, Seokjoong, Chang, Jun, Lee, Hyukjin, Song, Dong Woo, Yeom, Su Cheong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8782450/
https://www.ncbi.nlm.nih.gov/pubmed/35061543
http://dx.doi.org/10.1126/sciadv.abj6901
Descripción
Sumario: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.