Each year in the U.S. 200,000 people are diagnosed with abdominal aortic aneurysm (AAA) and 15,000 will inevitably die from rupture due to unrelenting expansion of the aneurysm sac. Consequently 40,000 elective endovascular or open surgeries are performed annually with morbidity rates as high as 23% and two-year costs up to $116K per patient treated in the Veterans Administration medical system. The risk of rupture accelerates with AAA diameter thus an effective therapy that could suppress AAA expansion would have a significant impact on patient survival, quality of life, and health care costs. Randomized, controlled trials with doxycycline, statins, and beta-blockers have failed to decrease AAA expansion rates and thus pharmacologic inhibition of AAA remains an unmet medical need. There is accumulating evidence that AAA is an autoimmune disease characterized by activation of the innate and adaptive immune systems. In patients with AAA we and others have demonstrated that circulating CD4+CD25+FoxP3+ T-regulatory cells (Treg) are significantly diminished in frequency and immune suppressor function whereas CD4+/CD8+CD28- T-cells and activated monocytes are increased in number and cytoxicity. In mouse models we have demonstrated that human mesenchymal stromal cells (MSC) increase Treg frequency, promote their immune suppressor function by inducing expression of the transcription factor FoxP3, and inhibit AAA expansion. Our central objective in this Phase I randomized, placebo controlled clinical trial is t determine if the pathogenic immune responses implicated in AAA formation can be favorably modulated by administering MSCs in patients with small AAA (35-45. mm. diameter). The primary endpoint of Aim 1 is to assess the dose effect of allogeneic MSCs (1 or 3 million MSCs/kg) on circulating Treg number and immune suppressor function as compared to a placebo treated control group. The secondary endpoints are changes in frequency of Tr1 regulatory cells, CD4+CD8+/CD28- T-cells, changes in cytotoxic function (perforin and IFN-? activity), and frequency of activated CD45+CD14dim/-CD16++ monocytes. The primary endpoint of Aim 2 is to characterize the MSC secretome produced in response to patient specific signals in vitro and in vivo, specifically focusing on IL-10.
Aim 3 will assess the effectof MSC administration on aortic inflammation by measuring 18-flurodeoxyglucose uptake with PET/CT and serum levels of matrix metalloproteinase-2 and -9 activity. Completion of this proposal will allow us to develop statistical power to calculate the sample sizes needed to execute a larger clinical study that will test the efficacy of MSCs in suppressing AAA expansion. Equally important, this proposal will be plenary in its definition of the mechanisms by which MSCs modulate immune responses in human disease and facilitate bedside to bench experiments that may yield more effective therapeutic strategies for AAA in the future.

Public Health Relevance

Abdominal aortic aneurysm (AAA) is an inflammatory disease resulting in over 15,000 deaths each year and is characterized by diminished function and number of immune suppressor T-regulatory (Treg) cells. Mesenchymal stem cells (MSC) have the unique ability to induce Tregs and suppress AAA expansion in animal models. The purpose of this clinical investigation is to assess the efficacy of MSCs in increasing Tregs and their immune suppressor function in patients with small AAA and characterize the downstream impact on pathogenic inflammatory pathways.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Clinical Trials - B (CLNB)
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Rlr VA Medical Center
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Wang, S Keisin; Murphy, Michael P (2018) Immune Modulation as a Treatment for Abdominal Aortic Aneurysms. Circ Res 122:925-927
Wang, S Keisin; Green, Linden A; Gutwein, Ashley R et al. (2018) Osteopontin may be a driver of abdominal aortic aneurysm formation. J Vasc Surg 68:22S-29S
Wang, S Keisin; Green, Linden A; Gutwein, Ashley R et al. (2018) Rationale and Design of the ARREST Trial Investigating Mesenchymal Stem Cells in the Treatment of Small Abdominal Aortic Aneurysm. Ann Vasc Surg 47:230-237
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