Polymeric Nanocarriers Delay the Onset of Type 1 Diabetes in Mice

Introduction:: In type 1 diabetes (T1D), autoreactive lymphocytes target and destroy the insulin-secreting islet beta cells in the pancreas. Rapamycin is an immunosuppressant and selective inhibitor of the mTOR signaling pathway that is commonly used to prevent rejection in transplant patients. We previously demonstrated that rapamycin-loaded polymersome nanoparticles (rPS) switches the rapamycin immunomodulation from suppression to tolerance during allogeneic islet cell transplantation in mice.¹ Mice treated with a low dose of rPS over 14 days had increased regulatory T cells, remained normoglycemic for 100 days post-transplant, and experienced less adverse effects compared to chronic immunosuppression. To assess whether this strategy protects innate beta cell mass at T1D onset, we benchmarked rPS against Liraglutide, an FDA-approved therapy for type 2 diabetes and a potential therapy to delay T1D via beta cell regeneration.


Materials and Methods:: rPS was fabricated with the block copolymer poly(ethylene) glycol and polypropylene sulfide (PEG₁₇-b-PPS₃₀) as previously described.¹ Prediabetic (8-week-old) female nonobese diabetic (NOD) mice received either three injections of rPS (1 mg/kg of 0.125 mg/mL rPS) or three injections of 1 mg/kg Liraglutide (6 mg/mL,Victoza Flex Pens, Nova Nordisk) all in equal injection volumes. All mice were monitored three times per week for T1D onset along with a non-treated (NT) group (n=6 mice per group) for 31 weeks. T1D onset was determined by two consecutive, random blood glucose readings above 250 mg/dL. Upon onset, mice were removed from the study and their pancreas were excised for histology. Staining for insulitis scoring was completed by the Northwestern Mouse Histology and Phenotyping laboratory. Additionally, beta cell secretion was measured by weekly C-peptide concentration (C-peptide ELISA Raybiotech) and an oral glucose tolerance test (OGTT) was performed on the remaining mice at the age of 30 weeks.

Results, Conclusions, and Discussions:: Results: After 31 weeks, rPS delayed the median age of onset of T1D in comparison to the NT and Liraglutide group by 12 and 4 weeks, respectively (Figure 1). In addition, mice that received rPS maintained a significantly lower random C-peptide secretion than Liraglutide and NT after treatment (Figure 2). The OGTT showed that mice treated with rPS had a slower insulin response to the change in glucose load, but still returned to normoglycemia.
Conclusion: rPS is a promising early-intervention therapy to delay the onset of T1D. The c-peptide results suggest rPS may cause a decrease in glucose sensitivity and a modulated insulin secretory response to maintain normoglycemia. The nonimmunogenic PEG-b-PPS platform allows for safe and effective delivery of rapamycin that could prolong insulin-independence for the T1D community.
Discussions: During this study, the FDA approved Teplizumab (Tzield) which delays the onset of T1D for 2 years in some individuals. Tzield is an anti-CD3 monoclonal antibody that targets the autoreactive T lymphocytes directly. Based on our prior work, we propose that rPS may act via a distinct mechanism to Tzield by instead leveraging antigen presenting cells to indirectly reprogram T cells. Future studies will further benchmark rPS to the new standard in the field.


Acknowledgements (Optional): :

References (Optional): : 1. Burke, J. A.; Zhang, X.; Bobbala, S.; Frey, M. A.; Bohorquez Fuentes, C.; Freire Haddad, H.; Allen, S. D.; Richardson, R. A. K.; Ameer, G. A.; Scott, E. A. Subcutaneous Nanotherapy Repurposes the Immunosuppressive Mechanism of Rapamycin to Enhance Allogeneic Islet Graft Viability. Nat. Nanotechnol. 2022, 17 (3), 319–330. https://doi.org/10.1038/s41565-021-01048-2.