Engineering the insulin signal peptide to protect human pancreatic beta cells from autoimmune destruction

HLA knockout beta-cells have been proposed to create hypo-immune cells, but this strategy poses significant tumorigenic risks. As an alternative, we hypothesized that insulin signal peptide modification would give rise to beta-cells evading autoimmune recognition while maintaining insulin functionality.

Here, we developed human beta-cell lines lacking endogenous insulin that we complemented with insulin carrying signal peptides from different hormones including chromogranin-A. We evaluated insulin synthesis, processing, secretion, activity, and immune evasion. Chromogranin-A signal peptide substitution directed insulin expression, maturation and secretion, maintaining physiological proinsulin/insulin ratios. Secreted insulin remained functional.