Preclinical development of an immune evasive islet cell replacement therapy for type 1 diabetes

ViaCyte is a regenerative medicine company focused on the discovery, development, and commercialization of cell replacement therapies for type 1 and insulin-requiring type 2 diabetes. To produce the cells for ViaCyte’s product candidates, pluripotent stem cells are differentiated to pancreatic endoderm cells (also known as pancreatic precursor cells; PEC-01 cells). Once implanted in animals, PEC-01 cells engraft and mature into glucose-sensing insulin-secreting beta cells. In patients however, PEC-01 cells would be attacked by the immune system as would an allogenic organ transplant. Further, with type 1 diabetes, an autoimmune condition, the misdirected immune response to beta cells would compromise the therapeutic cells. Therefore, PEC-01 cells must be protected from allogeneic and autoimmune responses in order to have the potential to treat diabetic patients. Approaches for immune evasion include implantation within a protective device, immunosuppressive drug treatment, and gene editing to prevent rejection by the host immune system.

ViaCyte and CRISPR Therapeutics, a leading company in the gene-editing space, are collaborating to use CRISPR/Cas9 to edit immune-modulatory genes in ViaCyte’s CyT49 pluripotent stem cell line that is used to produce PEC-01 cells. The gene edits introduced into the CyT49 cell line result in the absence of HLA class 1 proteins, which are major determinants of allo- and auto-immunity, from the cell surface, and the addition of cell-surface molecules that downregulate immune cells. This cell line, VCTX210, passed all tests for proper editing, lack of off-target editing, and genomic stability. Animal tests with VCTX210 PEC-01 showed a robust insulin-secretion response to injected glucose, as with unedited CyT49 PEC-01. Further studies are ongoing to enable clinical testing of VCTX210 over the next few years.