High Biallelic CCR5 Gene Disruption Rates Using ZFN mRNA Delivery with Ability for Long-term Engraftment.
Researchers at Sangamo developed a CCR5- targeted zinc finger nuclease that they showed was active in a variety of CD4 T cells and HSPCs and that conferred resistance to HIV infection. This therapy was advanced to the clinic using adenoviruses to deliver the ZFN constructs. The phase I/II trials showed that CD4 cells with a disrupted CCR5 gene could be engrafted, were safe and persisted. Toxicity related to the adenoviral vector precluded the intended trials from progressing. To rescue the therapy, the company turned to mRNA delivery of the CCR5-specific ZFN using the MaxCyte GTxTM. The work published in Mol Ther. Methods Clin. Dev., 3, 2016 and summarized above demonstrate the rapid progression from process development of ZFN delivery, through manufacturing qualification runs, pre-clinical toxicity studies and initiation of clinical trial NCT02500849 using the MaxCyte GTxTM. See publication for detailed methods.