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CRISPR-Cas9n-mediated ELANE promoter editing for gene therapy of severe congenital neutropenia. | LitMetric

AI Article Synopsis

  • Severe congenital neutropenia (CN), linked to ELANE mutations, is a serious genetic disorder that can lead to serious blood issues, including leukemia, with current treatments not effective for all patients.
  • Researchers developed a gene therapy called MILESTONE using CRISPR technology to specifically target and edit the ELANE gene, restoring proper neutrophil differentiation in affected stem cells.
  • This gene-editing method showed high on-target efficiency and a safe off-target profile, suggesting it could serve as a viable treatment option for ELANE-CN patients undergoing stem cell transplantation.

Article Abstract

Severe congenital neutropenia (CN) is an inherited pre-leukemia bone marrow failure syndrome commonly caused by autosomal-dominant ELANE mutations (ELANE-CN). ELANE-CN patients are treated with daily injections of recombinant human granulocyte colony-stimulating factor (rhG-CSF). However, some patients do not respond to rhG-CSF, and approximately 15% of ELANE-CN patients develop myelodysplasia or acute myeloid leukemia. Here, we report the development of a curative therapy for ELANE-CN through inhibition of ELANE mRNA expression by introducing two single-strand DNA breaks at the opposing DNA strands of the ELANE promoter TATA box using CRISPR-Cas9D10A nickases-termed MILESTONE. This editing effectively restored defective neutrophil differentiation of ELANE-CN CD34 hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo, without affecting the functions of the edited neutrophils. CRISPResso analysis of the edited ELANE-CN CD34 HSPCs revealed on-target efficiencies of over 90%. Simultaneously, GUIDE-seq, CAST-Seq, and rhAmpSeq indicated a safe off-target profile with no off-target sites or chromosomal translocations. Taken together, ex vivo gene editing of ELANE-CN HSPCs using MILESTONE in the setting of autologous stem cell transplantation could be a universal, safe, and efficient gene therapy approach for ELANE-CN patients.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11184331PMC
http://dx.doi.org/10.1016/j.ymthe.2024.03.037DOI Listing

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