# Restoring Tolerance with an Oral AMPK Agonist Nanomedicine Targeting Intestinal Dendritic Cells as a Preventative Therapy for Type 1 Diabetes > **NIH NIH R41** · QRONO, INC · 2024 · $306,500 ## Abstract PROJECT SUMMARY In the United States alone, an estimated 1.45 million people suffer from Type 1 Diabetes (T1D), a chronic autoimmune disease resulting from immune-mediated destruction of insulin- producing pancreatic b cells. Autoimmune recognition of b cells leads to significant loss of b cell mass, resulting in impaired control of blood glucose levels and hyperglycemia. Standard care involves continuous blood glucose monitoring and daily insulin replacement. However, the life expectancy of T1D patients is reduced by ~ 20 years compared to the general population, highlighting an urgent need to develop novel therapies that prevent b cell destruction. A long pre-clinical period marked by the appearance of immunological abnormalities, including functional loss of intestinal homeostasis, precedes disease onset in T1D mouse models and patients. A failure to develop immunological tolerance is centered around a reduced number and function of tolerogenic dendritic cells (tolDCs) in the small intestinal mucosa, which are critical to the maintenance of GI homeostasis by promoting regulatory T cell (Treg) induction. Although aberrant APC activity is critical for T1D pathogenesis, there have been no DC- targeted therapies developed to date for the treatment of T1D. Qrono Inc is developing QR402, a first-in-class, oral, DC-specific AMPK pathway agonist as a preventative therapy for T1D. QR402 uses custom nanoparticles to directly promote an AMPK-induced tolDC phenotype. This work is inspired by studies demonstrating 1) that the AMPK pathway is downregulated by intestinal DCs in T1D patients and 2) that activation of the AMPK pathway via systemic administration of AMPK pathway agonists can successfully alleviate disease severity in preclinical mouse studies. While AMPK has long been a target of interest for T1D, clinical development of AMPK agonists has been limited by severe adverse effects associated with systemic administration including metabolic complications (i.e. lactic acidosis) and cardiac hypertrophy. Thus, approaches like the ones proposed herein capable of targeting AMPK agonists to intestinal DCs are vital to safely activating the AMPK pathway that’s dampened in T1D, and restoring tolerance. Our preliminary data identify the AMPK agonist PF-739 as having tolerogenic activity, marked by a dampening of pro-inflammatory IL-12p70 production coupled with a significant increase in anti-inflammatory IL-10 secretion in LPS stimulated DCs, features that promote Treg induction. We hypothesize that a treatment targeting AMPK-activating compounds to intestinal DCs will restore intestinal tolerance and protect against T1D onset. Accordingly, we will prepare and characterize enteric- coated nanoparticles of PF-739 (QR402) that we can then use for the proposed in vitro and in vivo studies. Successful completion of this project will establish proof-of-concept for a first-in-class DC-targeted preventative therapy for T1D. Data will be leveraged to support a Phase... ## Key facts - **NIH application ID:** 11007750 - **Project number:** 1R41AI186895-01 - **Recipient organization:** QRONO, INC - **Principal Investigator:** Christina Paige Cargill - **Activity code:** R41 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $306,500 - **Award type:** 1 - **Project period:** 2024-07-22 → 2025-06-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/11007750 ## Citation > US National Institutes of Health, RePORTER application 11007750, Restoring Tolerance with an Oral AMPK Agonist Nanomedicine Targeting Intestinal Dendritic Cells as a Preventative Therapy for Type 1 Diabetes (1R41AI186895-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/11007750. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*