In vivo hematopoietic stem cell modification by mRNA delivery-Reference-Cited by-同舟云学术

In vivo hematopoietic stem cell modification by mRNA delivery

Published:2023-07-28 Issue:6656 Volume:381 Page:436-443
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Breda Laura¹^ORCID,Papp Tyler E.²^ORCID,Triebwasser Michael P.¹³^ORCID,Yadegari Amir²^ORCID,Fedorky Megan T.¹,Tanaka Naoto¹,Abdulmalik Osheiza¹^ORCID,Pavani Giulia⁴^ORCID,Wang Yongping⁵⁶^ORCID,Grupp Stephan A.⁷⁸^ORCID,Chou Stella T.¹⁵^ORCID,Ni Houping²,Mui Barbara L.⁹^ORCID,Tam Ying K.⁹^ORCID,Weissman Drew²^ORCID,Rivella Stefano¹¹⁰¹¹¹²¹³^ORCID,Parhiz Hamideh²^ORCID

Affiliation:

1. Department of Pediatrics, Hematology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA.

2. Division of Infectious Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

3. Department of Pediatrics, The University of Michigan, Ann Arbor, MI, USA.

4. Department of Pathology and Laboratory Medicine, Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA.

5. Department of Pathology and Laboratory Medicine, Transfusion Medicine, Children’s Hospital of Philadelphia, Philadelphia, PA, USA.

6. Department of Clinical Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.

7. Division of Oncology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA.

8. Departments of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

9. Acuitas Therapeutics, Vancouver, BC V6T1Z3, Canada.

10. University of Pennsylvania, Perelman School of Medicine, Philadelphia, PA, USA.

11. Cell and Molecular Biology affinity group, University of Pennsylvania, Philadelphia, PA, USA.

12. Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA.

13. Penn Center for Musculoskeletal Disorders, Children’s Hospital of Philadelphia, Philadelphia, PA, USA.

Abstract

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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

Link

https://www.science.org/doi/pdf/10.1126/science.ade6967

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