Imaging and Image-guided Therapies in Diabetes
The importance of early diabetes detection by non-invasive imaging is underscored by the emerging technologies for preventing and potentially curing diabetes. Establishment of clinically viable approaches for imaging beta cell mass and assessing islet function would allow at-risk individuals to be monitored prior to the onset of diabetes. Besides developing tools for imaging various events during diabetes progression, this Program is focused on investigating image-guided approaches for therapy delivery (theranostics). Specific projects are listed below.
- Developing of beta-cell specific imaging agents. This project investigates the possibility of imaging beta-cell mass using target-specific imaging probes. These probes are directed to specific antigens on beta-cell surface and include known targets (i.e. glucagon-like peptide receptor, GLP-1R) and targets under discovery in Dr. Moore’s laboratory (sphongomyelin-based patches,). Imaging modalities include magnetic resonance imaging (MRI), positron emission tomography (PET) and optical imaging.
- Imaging of islet inflammation. Autoimmune destruction of beta cells in type 1 diabetes is caused by infiltrating lymphocytes. Dr. Moore’s laboratory was the first to develop a strategy to detect the accumulation of these cells in the pancreas prior to the onset of the disease. This strategy is based on targeting a prevalent subset of diabetogenic lymphocytes responsible for beta-cell destruction using iron oxide nanoparticles conjugated to an MHC class 1- autoantigenic peptide complex that recognizes the T cell receptor (TCR) on these cells. Tracking of these labeled cells to the pancreas is performed by MRI.
Changes in islet vasculature is another prominent feature of diabetic inflammation, and this has implications for early diagnosis since it occurs long before the onset of the disease. Dr. Moore’s laboratory developed a method to monitor vascular changes in a variety of type 1 diabetes models using in vivo magnetic resonance imaging. This approach is based on the notion that a long circulating blood pool agent protected graft copolymer (PGC) accumulates in the areas of compromised vasculature after passing through the endothelial gaps. This can now be developed as a surrogate non-invasive biomarker of early diabetes progression. Similarly, this approach was applied for imaging leaky vasculature in transplanted islets during the course of immune rejection.
- Imaging of islet transplantation. Since islet transplantation has emerged as one of the most promising therapies to treat type 1 diabetes patients, there is a tremendous need to monitor the viability and function of islet grafts non-invasively over time. Dr. Moore’s laboratory is investigating methods of labeling pancreatic islets with contrast agents prior to transplantation with the goal of longitudinal non-invasive monitoring of transplanted islet grafts by imaging.
- Theranostic approach for islet transplantation (siRNA therapy). Dr. Moore’s laboratory is developing a theranostic approach for islet transplantation by combining in vivo imaging and siRNA therapy. With the ultimate goal of protecting islets prior to transplantation serioes of studies have demonstrated the utility of theranostic iron oxide nanoparticles carrying siRNA-targeting genes responsible for islet damage. In a clinical scenario this could create a window of opportunity for further therapeutic intervention and graft preservation.
1. Wang P, Yoo B, Yang J, Zhang X, Ross A, Pantazopoulos P, Dai G, Moore A. GLP-1-targeting magnetic nanoparticles for pancreatic islet imaging. Diabetes, 2014, Jan. 23 [Epub ahead of print].
2. Moore A, Bonner-Weir S, Weissleder R. Non-invasive in vivo measurement of beta-cell mass in mouse model of diabetes. Diabetes, 2001, 50:2231-2236.
3. Kavishwar A, Medarova Z, Moore A. Unique sphingomyelin patches are targets of a beta cell specific antibody, J Lipid Res, 2011, 52:1660-1671. PMCID: PMC3151686
4. Medarova Z, Greiner DL, Ifediba M, Dai G, Bolotin E, Castillo G, Bogdanov A, Kumar M, Moore A. Imaging the pancreatic vasculature in diabetes models. Diab Metab Res Rev, 2011, 27:767-772.PMCID:PMC3721374
5. Wang P, Schuetz C, Ross A, Dai G, Markmann J, Moore A. Immune rejection after pancreatic islet cell transplantation: in vivo dual contrast-enhanced MR imaging in a mouse model. Radiology 2013; 266:822-830. PMCID:PMC3579171
6. Evgenov N, Medarova Z, Dai G, Bonner-Weir S, Moore A. In vivo imaging of islet transplantation. Nature Med, 2006, 12:144-148.
7. Medarova Z, Vallabhajosyula P, Tena A, Evgenov N, Pantazopoulos P, Tchipashvili V, Weir G, Sachs D, Moore A. In vivo imaging of autologous islet grafts in the liver and under the kidney capsule in non-human primates. Transplantation, 2009, 87(11):1659-1666. PMCID: PMC2746764
8. Medarova Z, Kumar, M, Ng, SW, Junzheng, Y, Barteneva N, Evgenov N, Petkova V, Moore A. Multifunctional magnetic nanocarriers for image-tagged siRNA delivery to intact pancreatic islets. Transplantation, 2008, 86:1170-1177. PMCID: PMC2678246
9. Wang P, Yigit MV, Medarova Z, Wei L, Dai G, Schuetz C, Moore A. Combined siRNA therapy and in vivo MRI in islet transplantation, Diabetes, 2011, 60:565-571. PMCID: PMC3028356
10. Wang P, Yigit M, Ran C, Ross A, Wei L, Dai G, Medarova Z, Moore A. A theranostic siRNA nanoprobe protects pancreatic islet grafts from adoptively transferred immune rejection. Diabetes, 2012, 61:3247-3254 PMCID:PMC3501867