{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE324nnn/GSE324575/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE324575"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Engineering the insulin signal peptide to protect human pancreatic beta cells from autoimmune destruction","description":"The autoreactive T cells that destroy beta cells in type 1 diabetes are largely targeting insulin signal peptide fragments. 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. Crucially, beta-cells expressing insulin with chromogranin-A signal peptide evaded recognition and killing by autoreactive T cells without inducing ER stress or compromising cellular identity. This approach may offer a targeted alternative to systemic immunosuppression to be used in stem-cell-derived therapies by engineering endogenous insulin locus.","dates":{"publication":"2026/08/13"},"accession":"GSE324575","cross_references":{"GSM":["GSM9579649","GSM9579647","GSM9579648","GSM9579645","GSM9579646","GSM9579644"],"GPL":["18573"],"GSE":["324575"],"taxon":["Homo sapiens"]}}