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

页码：436 / 443

页数：8

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