Genetically engineered allogeneic islet cells restored insulin secretion in a patient with type 1 diabetes without triggering an immune response or requiring immunosuppressive therapy, according to a recent brief report.
In a first-in-human, open-label trial researchers investigated the survival and function of genetically modified allogeneic islet cells transplanted into a patient with long-standing type 1 diabetes mellitus without the use of immunosuppression. The study, published in The New England Journal of Medicine, aimed to overcome the limitations of current transplantation approaches, which require lifelong immunosuppressive therapy and are associated with substantial morbidity.
The research team, led by Per-Ola Carlsson of the Department of Medical Cell Biology at Uppsala University in Uppsala, Sweden, employed clustered regularly interspaced short palindromic repeats–CRISPR-associated protein 12b to inactivate the B2M and CIITA genes—key regulators of human leukocyte antigen (HLA) class I and II expression, respectively. Lentiviral transduction was used to overexpress CD47 complementary DNA. Of the final islet-cell product (UP421), 86% of cells lacked HLA class I expression, 100% lacked HLA class II, and 46% exhibited high CD47 expression. Approximately 66% of cells were insulin-producing beta cells.
The engineered cells—nearly 80 million in total—were injected into the participant’s left brachioradialis muscle through 17 intramuscular injections. The 42-year-old male participant, who had a 37-year history of type 1 diabetes, a baseline glycated hemoglobin level of 11% (96 mmol/mol), and undetectable C-peptide levels, received no immunosuppressive, anti-inflammatory, or glucocorticoid medications.
Throughout the 12-week follow-up, wild-type and double-knockout islet-cell subpopulations elicited robust immune responses, including T-cell activation, IgM and IgG antibody production, and complement- and antibody-dependent cytotoxicity. In contrast, the gene-edited hypoimmune islet cells triggered no detectable immune activation or antibody response and were not killed in ex vivo assays using the patient's serum and peripheral blood mononuclear cells.
C-peptide levels, undetectable at baseline, became measurable and glucose-responsive at weeks 4, 8, and 12 during mixed-meal tolerance testing. These values remained stable from day 7 to week 12. The participant’s glycated hemoglobin decreased by approximately 42% during follow-up. Imaging with positron-emission tomography–magnetic resonance imaging demonstrated localized radiotracer uptake consistent with viable, functional grafts.
Four mild adverse events were reported, none of which were related to cellular therapy. The results were consistent with immune evasion by HIP islet cells and with stable beta-cell function in the absence of systemic immunosuppression.
Full disclosures can be found in the published brief report.