In vivo hematopoietic stem cell modification by mRNA delivery

• 成果类型: Article
• 署名作者: Breda, Laura; Papp, Tyler E.; Triebwasser, Michael P.; Yadegari, Amir; Fedorky, Megan T.; Tanaka, Naoto; Abdulmalik, Osheiza; Pavani, Giulia; Wang, Yongping; Grupp, Stephan A.; Chou, Stella T.; Ni, Houping; Mui, Barbara L.; Tam, Ying K.; Weissman, Drew; Rivella, Stefano; Parhiz, Hamideh
• 署名单位: University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; University of Michigan System; University of Michigan; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of Pennsylvania
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-11495
• DOI: 10.1126/science.ade6967
• 发表日期: 2023-07-28
• 页码: 436-443
• 关键词: bone-marrow-transplantation; long-term; late complications; chimerism; receptor

摘要

Hematopoietic stem cells ( HSCs) are the source of all blood cells over an individual's lifetime. Diseased HSCs can be replaced with gene-engineered or healthy HSCs through HSC transplantation (HSCT). However, current protocols carry major side effects and have limited access. We developed CD117/ LNP-messenger RNA (mRNA), a lipid nanoparticle (LNP) that encapsulates mRNA and is targeted to the stem cell factor receptor (CD117) on HSCs. Delivery of the anti-human CD117/LNP-based editing system yielded near- complete correction of hematopoietic sickle cells. Furthermore, in vivo delivery of pro-apoptotic PUMA (p53 up-regulated modulator of apoptosis) mRNA with CD117/LNP affected HSC function and permitted nongenotoxic conditioning for HSCT. The ability to target HSCs in vivo offers a nongenotoxic conditioning regimen for HSCT, and this platform could be the basis of in vivo genome editing to cure genetic disorders, which would abrogate the need for HSCT.