Link to bioRxiv paper:
http://biorxiv.org/cgi/content/short/2023.02.23.529353v1?rss=1

Authors: Borot, F., Humbert, O., Newby, G. A., Fields, E., Kohli, S., Radtke, S., Laszlo, G. S., Mayuranathan, T., Ali, A. M., Weiss, M. J., Yen, J. S., Walter, R. B., Liu, D. R., Mukherjee, S., Kiem, H.-P.

Abstract:
On-target toxicity to normal cells is a major safety concern with targeted immune and gene therapies. Here, we developed a base editing (BE) approach exploiting a naturally occurring CD33 single nucleotide polymorphism leading to removal of full-length CD33 surface expression on edited cells. CD33 editing in human and nonhuman primate (NHP) hematopoietic stem and progenitor cells (HSPCs) protects from CD33-targeted therapeutics without affecting normal hematopoiesis in vivo, thus demonstrating potential for novel immunotherapies with reduced off-leukemia toxicity. For broader applications to gene therapies, we demonstrated highly efficient ( greater than 70%) multiplexed adenine base editing of the CD33 and gamma globin genes, resulting in long-term persistence of dual gene-edited cells with HbF reactivation in NHPs. In vitro, dual gene-edited cells could be enriched via treatment with the CD33 antibody-drug conjugate, gemtuzumab ozogamicin (GO). Together, our results highlight the potential of adenine base editors for improved immune and gene therapies.

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