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Abstract

Gene therapy targets diabetes pathophysiology rather than symptoms, yet clinical translation is slower than preclinical success. This review synthesizes 143 registered trials (ClinicalTrials.gov, 2010-2025) identifying systematic implementation barriers. Despite >15 years of development, 83% of trials remain in Phase I-II. Only zimislecel achieved Phase III outcomes (83% insulin independence at 12 months, n=12, requiring immunosuppression). VM202 for diabetic neuropathy failed Phase III despite positive extension results. Three systematic barriers emerged: (1) human transduction efficiency is 6-8.7-fold lower than preclinical models; (2) pre-existing immunity excludes 58-78% of candidates; (3) manufacturing capacity serves <2.5% of target population (40-400 years to treat at maximum capacity). These constraints explain why ex vivo cell therapies advanced to efficacy trials while in vivo gene delivery remains in Phase I despite longer development timelines. Research priorities should emphasize non-viral delivery systems offering scalable manufacturing and universal hypoimmune donor cells to address access barriers.

Article Type

Review

First Page

626

Last Page

652

Creative Commons License

Creative Commons Attribution-NonCommercial 4.0 International License
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License

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