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Somatic_mutation_in_edited_cholangiocyte_organoids_NanoSeq

Characterisation of mutation rates and patterns in edited human cholangiocyte organoids (NanoSeq)

Type: Cancer Genomics
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 1 Publication

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Dataset ID	Description	Technology	Samples
EGAD00001015456	Primary human cells cultured in organoid format have great promise as potential regenerative cellular therapies. However, their immunogenicity and mutagenic profile remain unresolved, impeding effective long-term translation to the clinic. In this study we report, for the first time, the generation of human leukocyte antigen (HLA)-I and HLA-II knock-out human expandable primary cholangiocyte organoids (PCOs) using CRISPR-Cas9 as a potential ‘universal’ low-immunogenic therapy for bile duct disorders. HLA-edited PCOs (ePCOs) displayed the same phenotypic and functional characteristics as parental unedited PCOs. Despite minimal off-target edits, duplex sequencing approaches demonstrated that ePCOs and PCOs acquire mutations in culture at similar rates, but without evident selection for cancer-driver mutations. ePCOs induced reduced T cell-mediated immunity and donor-dependent NK cell cytotoxicity in vitro and evaded cytotoxic responses with increased graft survival in humanized mice in vivo. Our findings have important implications for assessment of safety and immunogenicity of primary cell-derived organoid cellular therapies.	Illumina NovaSeq 6000	5

Publications	Citations
Immunogenicity of autologous and allogeneic human primary cholangiocyte organoid cellular therapies. Petrus-Reurer S, Lei W, Tysoe O, Mairesse M, Baez-Ortega A, Jones J, Tan T, Rehakova S, Mahbubani KT, Brodie C, Han N, Martincorena I, Betts C, Vallier L, Saeb-Parsy K. Cell Rep Med 6: 2025 102205	0