Adenine Base Editor Targets SCID Mutation in New Study

Researchers from the University of California, Los Angeles, have used an adenine base editor to target a variant associated with CD3δ severe combined immune deficiency (SCID). SCID, an inborn error of immunity, is life-threatening, and CD3δ SCID is caused by biallelic mutations in CD3D gene that affect the CD3δ protein needed for CD3/T cell receptor formation. In a new paper appearing in Cell, the UCLA team used an adenine base editor that included a catalytically impaired Cas9 nickase fused to a DNA-modifying deaminase enzyme to change the CD3D c.202C>T mutation that leads to a premature stop codon to the wildtype version in a cell line disease model, in hematopoietic stem and progenitor cells (HSPCs) from a healthy individual that were transduced with the CD3D c.202C>T mutation, and in HSPCs from a patient with CD3δ SCID. This editing, they report, led to T lymphopoiesis. "Our results demonstrate that edited CD3δ SCID HSPCs produced functional T lymphocytes with diverse TCR repertoires in the [3D artificial thymic organoid system]," the authors write. "These data suggest an ABE-mediated autologous gene therapy is a promising treatment strategy for CD3δ SCID."