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Related Experiment Video

Updated: Mar 9, 2026

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Rationally and in silico guided APOBEC3F-directed CBE for enhanced PDAC genetic therapy.

Qingxiao Fang1, Jin Zhang1, Keshan Wang2

  • 1Pancreas Center, National Clinical Research Center for Cancer, State Key Laboratory of Druggability Evaluation and Systematic Translational Medicine, Tianjin Key Laboratory of Digestive Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.

Communications Biology
|March 7, 2026
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Summary

Researchers developed advanced cytosine base editors (CBEs) using evolutionary scale modeling and structure-guided mutagenesis. These novel CBEs show enhanced precision and efficiency for potential cancer gene therapy, effectively silencing oncogenes in pancreatic cancer models.

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Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Genetics

Background:

  • Cytosine base editors (CBEs) offer precise C-to-T conversion with therapeutic potential.
  • The application of CBEs in oncology requires further exploration and optimization.

Purpose of the Study:

  • To engineer high-performance human APOBEC3F (A3F)-based CBEs using evolutionary scale modeling (ESM) and structure-guided mutagenesis.
  • To evaluate the efficiency, accuracy, and specificity of the developed A3F-CBEs.
  • To demonstrate the therapeutic efficacy of A3F-CBEs in preclinical models of pancreatic ductal adenocarcinoma (PDAC).

Main Methods:

  • Integration of evolutionary scale modeling (ESM) with structure-guided mutagenesis to remodel human APOBEC3F (A3F).
  • Characterization of on-target editing efficiency and specificity across various loci.
  • In vitro and in vivo testing using a dual-AAV delivery platform targeting KRAS and MYC oncogenes in PDAC models.

Main Results:

  • Engineered A3F-CBEs exhibited significantly higher on-target editing efficiency compared to existing A3A- and Anc689-BE4max systems.
  • Developed A3F-CBEs demonstrated improved accuracy over haA3A-G without compromising specificity.
  • Dual-AAV delivered A3F-BE4max effectively silenced oncogenes, inhibited PDAC cell proliferation in vitro and in patient-derived organoids (PDOs), and suppressed tumor growth in vivo, extending survival.

Conclusions:

  • ESM-guided engineering yields highly efficient and accurate A3F-based CBEs.
  • A3F-CBEs represent a versatile and precise platform for genetic therapy in cancer.
  • The developed CBEs show significant therapeutic promise for pancreatic ductal adenocarcinoma treatment.