Translational Barriers to AAV and CRISPR Gene Therapy in Diabetes

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.