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December 8, 2025BloodOpen Access

Toward ‘n of one’ gene therapies: Scalable ex vivo adenine base editing via lipid nanoparticles in a sickle cell disease model

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Authors

SCSarah CottetaOBOmar BandaBMBernard McDonald

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Overview

This research demonstrates efficient editing of hematopoietic stem cells in sickle cell disease, highlighting lipid nanoparticles' role in enhancing fetal hemoglobin production.

Key Points

  • This research aims to develop a scalable, ex vivo platform for gene editing in sickle cell disease using lipid nanoparticles.
  • Utilized lipid nanoparticles to deliver adenine base editor mRNA and small guide RNA to hematopoietic stem cells.
  • Conducted experiments on CD34+ HSCs obtained from healthy donors with two sgRNA candidates targeting gamma-globin promoter.
  • Assessed editing efficiency and off-target effects using in silico tools and iGUIDE-sequencing.
  • Achieved over 70% A-to-G edits in targeted nucleotides within 48 hours.
  • Demonstrated significant upregulation of fetal hemoglobin and increased frequency of colony-forming units compared to untreated cells.
  • No significant off-target editing was associated with known oncogenes or observed toxicity.

Cite This Study

Cotteta et al. (2025) studied this question.

synapsesocial.com/papers/69362f604fa91c937236dd09https://doi.org/10.1182/blood-2025-7835
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Multiplex base editing enhances fetal hemoglobin production in sickle cell disease erythroid cells2025
  2. 2In Vivo correction of the sickle cell disease mutation in hematopoietic stem cells using RNA gene writers2025 · 2 citations
  3. 3Development and IND-enabling studies of a novel Cas9 genome-edited autologous CD34<sup>+</sup>cell therapy to induce fetal hemoglobin for sickle cell disease2024
  4. 4Base editing of β <sup>0</sup> -thalassemia mutations as a therapeutic strategy for severe β-hemoglobinopathies2025 · 1 citations
  5. 5In utero delivery of targeted ionizable lipid nanoparticles facilitates in vivo gene editing of hematopoietic stem cells2024 · 44 citations