In vivo genome editing using 244-cis LNPs and low-dose AAV achieves therapeutic threshold in hemophilia A mice

Jeong Pil Han, Yeji Lee, Jeong Hyeon Lee, Hye Yoon Chung, Geon Seong Lee, Yu Ri Nam, Myeongjin Choi, Kyoung Sik Moon, Haeshin Lee, Hyukjin Lee, Su Cheong Yeom

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3 Scopus citations


Gene therapy and rebalancing therapy have emerged as promising approaches for treating hemophilia A, but there are limitations, such as temporary efficacy due to individual differences. Genome editing for hemophilia has shown long-term therapeutic potential in preclinical trials. However, a cautious approach is necessary because genome editing is irreversible. Therefore, we attempted to induce low-level human factor 8 (hF8) gene knockin (KI) using 244-cis lipid nanoparticles and low-dose adeno-associated virus to minimize side effects and achieve a therapeutic threshold in hemophilia A mice. We selected the serpin family C member 1, SerpinC1, locus as a target to enable a combined rebalancing strategy with hF8 KI to augment efficacy. This strategy improved blood coagulation activity and reduced hemophilic complications without adverse effects. Furthermore, hemophilic mice with genome editing exhibit enhanced survival for 40 weeks. Here, we demonstrate an effective, safe, and sustainable treatment for hemophilia A. This study provides valuable information to establish safe and long-term genome-editing-mediated treatment strategies for treating hemophilia and other protein-deficient genetic diseases.

Original languageEnglish
Article number102050
JournalMolecular Therapy - Nucleic Acids
StatePublished - 12 Dec 2023

Bibliographical note

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  • CRISPR-Cas9
  • MT: RNA/DNA Editing
  • adeno-associated virus
  • genome editing
  • hemophilia a
  • lipid nanoparticle
  • low-dose virus


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