Peripheral arterial disease (PAD) affects approximately 8-12 million Americans. Many patients are not candidates for conventional treatments, e.g., surgical bypass or angioplasty, due to the extent and distribution pattern of their disease. Occlusive PAD may not only lead to pain at rest or with walking (claudication), but, if severe enough, may lead to distal limb ulceration and, ultimately, the need for amputation. Moreover, patients with critical limb ischemia have quality of life scores that are comparable to terminal cancer patient. Because the cues for new vessel formation are misplaced (due to the most ischemic areas occurring in the distal limb, i.e., foot, whereas the stenotic or occlusive artery is more proximal, i.e., iliac or femoral disease), exogenous cellular therapy offers a means to administer cells to the regions where they might be most helpful. This can be accomplished by either direct differentiation into blood vessels or by the release the appropriate cytokines to assist in neovascularization. Because patients'native stem cells are often dysfunction, allogeneic stem cells may offer the best choice of cellular products to provide off-the-shelf, high quality, cellular therapy for PAD patients. Clinical trials of cellular therapy will require methods to monitor delivery, engraftment, and therapeutic benefit in a non-invasive manner. In addition, current cellular therapies all suffer from extremely low engraftment primarily due to destruction of the cells in the first 24 hours after administration. Therefore, methods to protect stem cells from early destruction and also immunoprotect the patient from rejection of allogeneic cellular therapies that could be monitored non-invasively would be of tremendous benefit. In the current proposal, we will develop a novel method of combined radiopaque, MR-visible microencapsulation (XMRCap) of allogeneic mesenchymal stem cells (MSCs) that can be delivered and tracked non-invasively using x-ray fluoroscopy, computed tomography (CT), and magnetic resonance imaging (MRI). For the R21 phase of the application, we will focus on three specific aims: 1.) the formulation of an optimized XMRCap that maintains cellular viability, is biocompatible, and demonstrates sufficient sensitivity for non-invasive imaging for delivery;2.) demonstrate the ability to serially track XMRCaps with CT;and 3.) demonstrate that XMRCaps are immunoprotective and enhance cell survival. After achieving the R21 milestones, the R33 application will determine the degree of enhanced engraftment at 7 days post- administration and therapeutic efficacy by the ability to enhance arteriogenesis relative to naked MSCs in a relevant rabbit model of hindlimb ischemia. Because XMRCaps are composed of clinical grade products, we anticipate that these preclinical data will form the basis of safety and activity data for the FDA for translation of XMRCaps to therapeutic arteriogenesis clinical trials in PAD. Using a novel microencapsulation technique with clinical grade pharmaceuticals, the goal of the current application is to encapsulate stem cells from unrelated donors that can be seen by X-ray imaging and magnetic resonance imaging (MRI) for precise delivery and tracking in patients. The microencapsulation will: 1.) prevent the rejection of foreign cells;2.) enhance the survival of the cells compared to cells that are not encapsulated;and 3.) enable the stem cells to assist in the development of new vessels in patients whose arteries that are narrowed or occluded and who cannot be treated with conventional surgery or medical therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants Phase II (R33)
Project #
5R33HL089029-05
Application #
8096709
Study Section
Special Emphasis Panel (ZRG1-CB-B (52))
Program Officer
Buxton, Denis B
Project Start
2007-07-23
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$688,884
Indirect Cost
Name
Johns Hopkins University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Fu, Yingli; Azene, Nicole; Ehtiati, Tina et al. (2014) Fused X-ray and MR imaging guidance of intrapericardial delivery of microencapsulated human mesenchymal stem cells in immunocompetent swine. Radiology 272:427-37
Arifin, Dian R; Kedziorek, Dorota A; Fu, Yingli et al. (2013) Microencapsulated cell tracking. NMR Biomed 26:850-9
Kedziorek, Dorota A; Hofmann, Lawrence V; Fu, Yingli et al. (2012) X-ray-visible microcapsules containing mesenchymal stem cells improve hind limb perfusion in a rabbit model of peripheral arterial disease. Stem Cells 30:1286-96
Fu, Yingli; Azene, Nicole; Xu, Yi et al. (2011) Tracking stem cells for cardiovascular applications in vivo: focus on imaging techniques. Imaging Med 3:473-486
Barnett, Brad P; Ruiz-Cabello, Jesus; Hota, Partha et al. (2011) Fluorocapsules for improved function, immunoprotection, and visualization of cellular therapeutics with MR, US, and CT imaging. Radiology 258:182-91
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Link, Thomas W; Woodrum, David; Gilson, Wesley D et al. (2011) MR-guided portal vein delivery and monitoring of magnetocapsules: assessment of physiologic effects on the liver. J Vasc Interv Radiol 22:1335-40
Kraitchman, Dara L; Bulte, Jeff W M (2010) Magnetic nanoparticles and neurotoxins for treating atrial fibrillation: a new way to get burned? Circulation 122:2642-4
Fu, Yingli; Kraitchman, Dara L (2010) Stem cell labeling for noninvasive delivery and tracking in cardiovascular regenerative therapy. Expert Rev Cardiovasc Ther 8:1149-60
Kedziorek, Dorota A; Kraitchman, Dara L (2010) Superparamagnetic iron oxide labeling of stem cells for MRI tracking and delivery in cardiovascular disease. Methods Mol Biol 660:171-83

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