Precision genome editing in macrophage and CD8+ human primary T cells for immuno

Presented by

Laura Daley, PhD

About this talk

Innate immune cells play a critical role in cell-mediated immunity and have the potential to serve as cell-based therapies to treat a broad spectrum of immune diseases such as cancer and autoimmune disorders. Modified immune cells, such as genetically engineered CAR-T cells, have proven to be critical in developing new cell-based therapies for these diseases. However, immune cell biology creates challenges during the gene-editing process that lead to hyper-regulated RNA and DNA sensing pathways and enhanced cell death upon introduction of exogenous ribonucleotides. Further, engineering in primary immune cells is often restricted due to their limited expansion capacity. Genetic engineering in immune cells has traditionally relied on random integration of gene-editing components using viral delivery systems. In contrast, genome editing mediated by nucleases, such as CRISPR/Cas9-single guide RNPs, provide a platform for precision editing, and alleviate the potential side effects caused by randomly integrated viral DNA. While RNP gene editing in immune cells is just beginning to be considered by the immune-therapeutics field, our recent advances demonstrate that this approach can be used to create targeted modifications in two key cell types, the macrophage and the CD8+ primary T-cell. In an effort to circumvent challenges with the finite lifespan of primary T-cells, we targeted genes to edit that rendered this cell type “pseudo-immortalized”, allowing additional passages for further downstream genome editing and propagation. In addition, we demonstrated that precision editing can be used to introduce disease relevant SNPs into the macrophage genome, which resist introduction of exogenous ribonucleotides due to the induction of apoptotic pathways. Advances such as these overcome many of the obstacles currently faced with immune cell editing and offer improved gene stability and expression in immune cells and will transform the Immuno-Oncology and Gene Therapy fields.

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