1061-OR: N-104, Next-Gen Dual-Action Immunoregulatory and Regenerative Therapy for Type 1 Diabetes

Introduction and Objective: In type 1 diabetes, β-cell regeneration after inflammatory damage is limited. Lacritin, a plasma glycoprotein, is a potential dual immunoregulatory and regenerative factor. In NOD mouse studies, both activities reside in lacritin’s C-terminus as represented by the 15 amino acid synthetic peptide N-104. Here we explore whether the same is true in human pancreatic slices. Methods: Human pancreatic slices from healthy donors provided by the DRI, UM were cultured ex vivo with IL-1β, TNFα and INFγ plus the proliferation indicator BrdU. Multichannel immunofluorescence quantified β-cell proliferation, inflammatory signaling, and effects on α-cells and CK19+ ductal cells. Adult age- and gender-matched plasma from type 1 diabetics and normal controls were western blotted for lacritin. Supporting studies included GSIS and viability assays, CyTOF, islet transplantation, and NOD mouse treatment followed by IMC and scRNA-seq. Results: Human T1D plasma deficient (p0.001) in the active monomeric form of lacritin. In HPS, N-104 increased β-cell proliferation 3.6-fold and nearly prevented cytokine-induced HLA-I upregulation, indicating strong protection from inflammatory stress. β-cells showed the greatest proliferative benefit, followed by other endocrine and ductal cells. In supporting studies, N-104 treated mouse and human islets displayed improved GSIS and viability. N-104-pretreated islets restored normoglycemia in syngeneic and xenogeneic recipients. In NOD mice, PEGylated N-104 reduced insulitis, halted diabetes progression, preserved islet homeostasis, and suppressed pathogenic T- and B-cell populations for ≥23 weeks - the latter as determined by imaging mass cytometry. Per scRNA-seq of pancreatic draining lymph nodes, PEG-N-104 suppressed TCF7Hi stem-like progenitors of cytotoxic and helper T cell. Conclusion: N-104 directly promotes β-cell proliferation while suppressing inflammatory stress, supporting its potential as a dual immunoregulatory and regenerative therapy for restoring β-cell health in early onset T1D. Disclosure M. Ma: Other - Co-founder of the IsletRegen, LLC; Current; IsletRegen, LLC. P. Chhabra: None. J. Cook: None. J. Dominguez-Bendala: None. R. Pastori: None. G.W. Laurie: Other - Cofounder and CSO; Current; TearSolutions, Inc, IsletRegen, LLC. K. Brayman: Other - Cofounder and Chief Medical Officer; Current; IsletRegen, LLC. Funding UVA LaunchPad Grant Breakthrough T1D (2-SRA-2026-1796-S-B)