A simplified G-CSF-free procedure allows for in vivo HSC gene therapy of sickle cell disease in a mouse model.

Autor:	Li C; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA., Anderson AK; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA., Ruminski P; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO., Rettig M; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO., Karpova D; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO., Kiem HP; Stem and Gene Therapy Program, Fred Hutchinson Cancer Research Center, Seattle, WA., DiPersio JF; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO., Lieber A; Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2024 Aug 13; Vol. 8 (15), pp. 4089-4101.
DOI:	10.1182/bloodadvances.2024012757
Abstrakt:	Abstract: We have reported the direct repair of the sickle cell mutation in vivo in a disease model using vectorized prime editors after hematopoietic stem cell (HSC) mobilization with granulocyte colony-stimulating factor (G-CSF)/AMD3100. The use of G-CSF for HSC mobilization is a hurdle for the clinical translation of this approach. Here, we tested a G-CSF-free mobilization regimen using WU-106, an inhibitor of integrin α4β1, plus AMD3100 for in vivo HSC prime editing in sickle cell disease (SCD) mice. Mobilization with WU-106 + AMD3100 in SCD mice was rapid and efficient. In contrast to the G-CSF/AMD3100 approach, mobilization of activated granulocytes and elevation of the key proinflammatory cytokine interleukin-6 in the serum were minimal. The combination of WU-106 + AMD3100 mobilization and IV injection of the prime editing vector together with in vivo selection resulted in ∼23% correction of the SCD mutation in the bone marrow and peripheral blood cells of SCD mice. The treated mice demonstrated phenotypic correction, as reflected by normalized blood parameters and spleen size. Editing frequencies were significantly increased (29%) in secondary recipients, indicating the preferential mobilization/transduction of long-term repopulating HSCs. Using this approach, we found <1% undesired insertions/deletions and no detectable off-target editing at the top-scored potential sites. Our study shows that in vivo transduction to treat SCD can now be done within 2 hours involving only simple IV injections with a good safety profile. The same-day mobilization regimen makes in vivo HSC gene therapy more attractive for resource-poor settings, where SCD does the most damage. (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu