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<p>The selection of genetically engineered immune or hematopoietic cells in vivo after gene editing remains a clinical problem and requires a method to spare on-target toxicity to normal cells. Here, we develop a base editing approach exploiting a naturally occurring <i>CD33</i> single nucleotide polymorphism leading to removal of full-length CD33 surface expression on edited cells. <i>CD33</i> editing in human and nonhuman primate hematopoietic stem and progenitor cells protects myeloid progeny from CD33-targeted therapeutics without affecting normal hematopoiesis in vivo, thus demonstrating potential for improved immunotherapies with reduced off-leukemia toxicity. For broader application to gene therapies, we demonstrate highly efficient (&gt;70%) multiplexed adenine base editing of the <i>CD33</i> and gamma globin genes, resulting in long-term persistence of dual gene-edited cells with HbF reactivation in nonhuman primates. Using the CD33 antibody-drug conjugate Gemtuzumab Ozogamicin, we show resistance of engrafted, multiplex edited human cells in vivo, and a 2-fold enrichment for edited cells in vitro. Together, our results highlight the potential of adenine base editors for improved immune and gene therapies.</p>

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Multiplex base editing to protect from CD33 directed drugs for immune and gene therapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年5月27日

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  • Florence Borot,
  • Olivier Humbert,
  • Jeffrey T. Ehmsen,
  • Emily Fields,
  • Sajeev Kohli,
  • Stefan Radtke,
  • Kyle Swing,
  • Dnyanada Pande,
  • Mark R. Enstrom,
  • George S. Laszlo,
  • Thiyagaraj Mayuranathan,
  • Abdullah Mahmood Ali,
  • Mitchell J. Weiss,
  • Jonathan S. Yen,
  • Gregory A. Newby,
  • Roland B. Walter,
  • David R. Liu,
  • Siddhartha Mukherjee,
  • Hans-Peter Kiem

摘要

The selection of genetically engineered immune or hematopoietic cells in vivo after gene editing remains a clinical problem and requires a method to spare on-target toxicity to normal cells. Here, we develop a base editing 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 hematopoietic stem and progenitor cells protects myeloid progeny from CD33-targeted therapeutics without affecting normal hematopoiesis in vivo, thus demonstrating potential for improved immunotherapies with reduced off-leukemia toxicity. For broader application to gene therapies, we demonstrate highly efficient (>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 nonhuman primates. Using the CD33 antibody-drug conjugate Gemtuzumab Ozogamicin, we show resistance of engrafted, multiplex edited human cells in vivo, and a 2-fold enrichment for edited cells in vitro. Together, our results highlight the potential of adenine base editors for improved immune and gene therapies.