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Cited by 28

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High-fidelity PAMless base editing of hematopoietic stem cells to treat chronic granulomatous disease

Bzhilyanskaya, Vera, Ma, Linyuan, Liu, Siyuan, Fox, Lauren R., Whittaker, Madelynn N., Meis, Ronald J., Choi, Uimook, Lawson, Amanda, Ma, Michelle, Theobald, Narda, Burkett, Sandra, Sweeney, Colin L., Lazzarotto, Cicera R., Tsai, Shengdar Q., Lack, Justin B., Wu, Xiaolin, Dahl, Gary A., Malech, Harry L., Kleinstiver, Benjamin P., De Ravin, Suk See·2024·Science Translational Medicine
DOI 10.1126/scitranslmed.adj6779PMC PMC11753194
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Abstract

X-linked chronic granulomatous disease (X-CGD) is an inborn error of immunity (IEI) resulting from genetic mutations in the cytochrome b-245 beta chain ( CYBB ) gene. The applicability of base editors (BEs) to correct mutations that cause X-CGD is constrained by the requirement of Cas enzymes to recognize specific protospacer adjacent motifs (PAMs). Our recently engineered PAMless Cas enzyme, SpRY, can overcome the PAM limitation. However, the efficiency, specificity, and applicability of SpRY-based BEs to correct mutations in human hematopoietic stem and progenitor cells (HSPCs) have not been thoroughly examined. Here, we demonstrated that the adenine BE ABE8e-SpRY can access a range of target sites in HSPCs to correct mutations causative of X-CGD. For the prototypical X-CGD mutation CYBB c.676C>T, ABE8e-SpRY achieved up to 70% correction, reaching efficiencies greater than three-and-one-half times higher than previous CRISPR nuclease and donor template approaches. We profiled potential off-target DNA edits, transcriptome-wide RNA edits, and chromosomal perturbations in base-edited HSPCs, which together revealed minimal off-target or bystander edits. Edited alleles persisted after transplantation of the base-edited HSPCs into immunodeficient mice. Together, these investigational new drug–enabling studies demonstrated efficient and precise correction of an X-CGD mutation with PAMless BEs, supporting a first-in-human clinical trial (NCT06325709) and providing a potential blueprint for treatment of other IEI mutations.

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Cited by

Metadata

Authors
Bzhilyanskaya, V., Ma, L., Liu, S., Fox, L. R., Whittaker, M. N., Meis, R. J., Choi, U., Lawson, A., Ma, M., Theobald, N., Burkett, S., Sweeney, C. L., Lazzarotto, C. R., Tsai, S. Q., Lack, J. B., Wu, X., Dahl, G. A., Malech, H. L., Kleinstiver, B. P., & De Ravin, S. S.
Affiliations
  • Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
  • Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA 02114, USA.
  • Molecular Cytogenetic Core Facility, Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
  • CELLSCRIPT, Madison, WI 53713, USA.
  • Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN 38105, USA.
  • Bioinformatics (NCBR)/Integrated Data Sciences Section (IDSS), Research Technology Branch/DIR/NIAID, Frederick, MD 21702, USA.
ORCID
Venue
Science Translational Medicine
Publisher
American Association for the Advancement of Science (AAAS)
Published
2024-10-16
Volume
16
Issue
769
ISSN
  • 1946-6234
  • 1946-6242
DOI
10.1126/scitranslmed.adj6779
PMC
PMC11753194
Cited by
28
References
14
Language
en

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