*Purpose: To study the prosecretory, prosurvival, and mitogenic effect of Lacripep™ and its analogs in enhancing islet viability, increasing insulin secretion and promoting long-term islet transplantation outcomes. *Background: Lacripep™ and its analogs are synthetic fragments of the multifunctional tear protein ‘lacritin’, that is currently in a phase II clinical trial (NCT03226444) for autoimmune dry eye disease. Islets are Lacritin/Lacripep™ responsive and prominently express known elements of the Lacripep™ receptor complex and signaling pathways.

*Methods: a) Human or mouse islets were cultured with 1 or 4µM Lacripep™ (N94-C6 or N94), N104, Tearpep3, Tearpep3/N-104, Tearpep3/C6 or negative control peptide C95, or left untreated for different time periods ranging from 1 to 20 days in DMEM at 37^oC. Viability of islets was scored by propidium iodide – fluorescein diacetate staining and Glucose stimulated Insulin secretion (GSIS) assay performed. b) C57BL/6 islets were pretreated with 4µM N94 Lacripep™ or C95 or saline for 24 hours followed by minimal islet mass transplantation into syngeneic diabetic recipients. Tail vein blood glucose was measured daily. c) Proliferation marker Ki67 was measured in islets cultured in the presence or absence of lacripep^TM.

*Results: Mouse islets cultured with Lacripep™ retained 61% viability at Day15 while islets cultured with C95 demonstrated only 20% viability (p<0.001). Lacripep™ and Tearpep3/ N-104 increased the GSIS by nearly 2.7 fold compared to untreated controls, while N-104 increased it by nearly 5.5-fold. The viability of human islets treated with Tearpep3/C-6, Tearpep3/N-104 and N94 was 74.4% and 80.6% and 69.6% at Day20 of culture, while that of islets treated with C95 or saline was 54.2% and 46.2%. GSIS on Day10 was increased by 2.3 fold with Tearpep3/N-104; by >2.1 fold with Tearpep3/C-6; by 1.5 fold with N94; and by 1.1 fold with C95 when compared to GSIS of untreated group. Incubation of mouse islets with Lacripep™ permanently returned transplanted mice to normoglycemia with glucoses below 200mg/dL within 9 days posttransplant with treatment efficacy continuing after 40 days post-transplant. With C95 treatment, the glucose at Day12 posttransplant was <250mg/dL. Average blood glucoses measured between Days 22 to 43 was 142.9±17.6mg/dL for Lacripep™ group compared to 275±34.8mg/dL for the C95 group. Higher percentage of Ki67 positive events was observed in lacripep^TM treated islets as compared to untreated islets.

*Conclusions: Lacripep™ and its analogs represent a novel class of interventional agents that can significantly enhance islet viability, increase insulin secretion, and promote long term longitudinal graft survival, indicating their immense potential for promoting clinical islet transplantation outcomes.

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