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Genetic Mutation in Immune Cells for Infectious Disease and Cancer Therapy
Emory University
Cell therapy
Oncology
Hit To Lead or Lead Optimization
• Once Deleting, changing, or inserting nucleotides within the DNMT3A gene in human CD8 T cells, the DNMT3TA gene product does not function for methylation.
• Modification of the DNMT3A gene provides an improvement in antigen-specific T cells functions and/or an enhancement of the longevity of the cell.
• Conditional deletion of the de novo methyltransferase Dnmt3a at an early stage of effector differentiation resulted in reduced methylation and faster re-expression of naive-associated genes, thereby accelerating the development of memory cells.
• Longitudinal phenotypic and epigenetic characterization of the memory-precursor effector subset of virus-specific CD8 T cells transferred into antigen-free mice revealed that differentiation to memory cells was coupled to erasure of de novo methylation programs and re-expression of naïve associated genes.
• Epigenetic repression of naive-associated genes in effector CD8 T cells can be reversed in cells that develop into long-lived memory CD8 T cells while key effector genes remain demethylated, demonstrating that memory T cells arise from a subset of fatepermissive effector T cells.
US20210275592A1
Effector CD8 T cells dedifferentiate into long-lived memory cells. Nature, (2017)
