In vivo hematopoietic stem cell modification by mRNA delivery

被引：124
|
作者：
Breda, Laura [1 ]
Papp, Tyler E. [2 ]
Triebwasser, Michael P. [1 ,3 ]
Yadegari, Amir [2 ]
Fedorky, Megan T. [1 ]
Tanaka, Naoto [1 ]
Abdulmalik, Osheiza [1 ]
Pavani, Giulia [4 ]
Wang, Yongping [5 ,6 ]
Grupp, Stephan A. [7 ,8 ]
Chou, Stella T. [1 ,5 ]
Ni, Houping [2 ]
Mui, Barbara L. [9 ]
Tam, Ying K. [9 ]
Weissman, Drew [2 ]
Rivella, Stefano [1 ,10 ,11 ,12 ,13 ,14 ]
Parhiz, Hamideh [2 ]
机构：
[1] Childrens Hosp Philadelphia, Dept Pediat, Hematol, Philadelphia, PA USA
[2] Univ Penn, Perelman Sch Med, Div Infect Dis, Philadelphia, PA USA
[3] Univ Michigan, Dept Pediat, Ann Arbor, MI USA
[4] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Ctr Cellular & Mol Therapeut, Philadelphia, PA USA
[5] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Transfus Med, Philadelphia, PA USA
[6] Univ Penn, Perelman Sch Med, Dept Clin Pathol & Lab Med, Philadelphia, PA USA
[7] Childrens Hosp Philadelphia, Div Oncol, Dept Pediat, Philadelphia, PA USA
[8] Univ Penn, Perelman Sch Med, Dept Pediat, Philadelphia, PA USA
[9] Acuitas Therapeut, Vancouver, BC V6T1Z3, Canada
[10] Univ Penn, Perelman Sch Med, Philadelphia, PA USA
[11] Univ Penn, Cell & Mol Biol affin Grp, Philadelphia, PA USA
[12] Childrens Hosp Philadelphia, Raymond G Perelman Ctr Cellular & Mol Therapeut, Philadelphia, PA USA
[13] Childrens Hosp Philadelphia, Penn Ctr Musculoskeletal Disorders, Philadelphia, PA USA
[14] Univ Penn, Penn Inst RNA Innovat, Philadelphia, PA USA
来源：
SCIENCE | 2023年 / 381卷 / 6656期
基金：
美国国家卫生研究院;
关键词：
BONE-MARROW-TRANSPLANTATION; LONG-TERM; LATE COMPLICATIONS; CHIMERISM; RECEPTOR;
D O I：
10.1126/science.ade6967
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
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.
引用
收藏
页码：436 / 443
页数：8
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