In utero lipid nanoparticle delivery achieves robust editing in hematopoietic stem cells

Atesh K Worthington; Beltran Borges; Tony Lum; Elisa Schrader Echeverri; Fareha Moulana Zada; Marco A Cordero; Hyejin Kim; Ryan Zenhausern; Ozgenur Celik; Cindy Shaw; Paula Gutierrez-Martinez; Marzhana Omarova; Chris Blanchard; Sean Burns; M Kyle Cromer; James E Dahlman; Tippi C MacKenzie

doi:10.1101/2025.05.12.652147

In utero lipid nanoparticle delivery achieves robust editing in hematopoietic stem cells

bioRxiv [Preprint]. 2025 May 12:2025.05.12.652147. doi: 10.1101/2025.05.12.652147.

Authors

Atesh K Worthington^{1

2}, Beltran Borges^{1

2}, Tony Lum^{1

2}, Elisa Schrader Echeverri³, Fareha Moulana Zada^{1

2}, Marco A Cordero^{1

2}, Hyejin Kim³, Ryan Zenhausern³, Ozgenur Celik³, Cindy Shaw⁴, Paula Gutierrez-Martinez⁴, Marzhana Omarova⁴, Chris Blanchard⁴, Sean Burns⁴, M Kyle Cromer^{1

2}, James E Dahlman³, Tippi C MacKenzie^{1

2

5}

Affiliations

¹ Department of Surgery, University of California, San Francisco, CA, USA.
² The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California, San Francisco, CA, USA.
³ Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University School of Medicine, Atlanta, GA, 30332, USA.
⁴ Intellia Therapeutics, Cambridge, MA.
⁵ The Center for Maternal-Fetal Precision Medicine, University of California, San Francisco, CA, USA.

Abstract

In vivo genome editing for hematologic malignancies is limited by inefficient delivery of genome editors to hematopoietic stem cells (HSC) in the bone marrow. To overcome this limitation, we capitalized on the inherent liver tropism of lipid nanoparticles (LNPs) and the liver niche of fetal HSCs. We demonstrate that in utero delivery of LNPs without active targeting ligands to the fetal liver results in potentially therapeutic levels of HSC editing.

Publication types

Preprint

Abstract

Publication types

Grants and funding