First gene-edited islet transplant in a human passes functional trial

 Uppsala University Hospital-led investigators report that gene-edited donor islet cells survived 12 weeks inside a man with long-standing type 1 diabetes without any immunosuppressive medication.

Intensive insulin therapy can delay complications and improve life expectancy. Early-onset type 1 diabetes remains linked to reduced quality of life, serious cardiovascular risk, and shortened lifespan. Toxicity from lifelong immune suppression also drives morbidity and mortality in organ recipients.

In the study, "Survival of Transplanted Allogeneic Beta Cells with No Immunosuppression," published in the New England Journal of Medicine, researchers conducted a first-in-human open-label trial to test whether hypoimmune-engineered islet cells could evade rejection.

A single 42-year-old man with a 37-year history of type 1 diabetes formed the cohort.

Islets from an O-matched deceased donor pancreas were isolated, dissociated, edited with CRISPR-Cas12b to knock out B2M and CIITA, lentivirally transduced to overexpress CD47, reclustered, and injected in 17 tracks into the left brachioradialis muscle under general anesthesia. No glucocorticoids, anti-inflammatory agents, or immunosuppressants were given.

Serial assays over 84 days showed strong adaptive and innate immune attacks against residual wild-type and double-knockout cells.

Hypoimmune cells triggered no T-cell activation, antibody production, or cytotoxicity. High-sensitivity C-peptide remained near or above 10 pmol/L and rose during mixed-meal testing; glycated hemoglobin fell by roughly 42%. Magnetic resonance imaging and GLP-1 receptor-targeted PET confirmed viable grafts without inflammation. Four mild adverse events were recorded, none deemed drug-related.

Daily insulin therapy continued as only 7% of a full replacement dose of beta cells was implanted. The study authors therefore describe the trial as a proof-of-survival and proof-of-function validation.

Investigators conclude that hypoimmune gene editing may eventually lead to a curative beta-cell replacement for type 1 diabetes without systemic immune suppression, a prospect that could ease daily management and reduce long-term complications for millions.

More information: Per-Ola Carlsson et al, Survival of Transplanted Allogeneic Beta Cells with No Immunosuppression, New England Journal of Medicine (2025). DOI: 10.1056/NEJMoa2503822

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