Urinary sphincter deficiency (ISD) is associated with stress urinary incontinence (SUI) in women and remains a major urological problem. Although good results of surgical therapy for SUI/ISD have been reported, complications are not infrequent, requiring almost 1/3 of patients requiring a second surgery and alternatives are needed. This has increased interest in cell therapy approaches to restore sphincter function. However, results of clinical studies using regenerative cell therapy have been only modest, with an average of 50% beneficial effects in around 50% of patients. As an alternative to cell therapy, this study will focus on the use of targeted chemokine CXCL12 (C-X-C motif chemokine 12) treatment for SUI/ISD using our established nonhuman primate (NHP) model of chronic ISD. The rationale for using CXCL12 is our published preliminary data reporting that local injection of CXCL12, but not cell therapy, restored urinary sphincter structure and function in the NHPs with chronic ISD. While these experiments provided proof-of-principle for this treatment approach, proposed experiments will not confirm and greatly expand this finding by exploring the mechanism underlying these beneficial effects. In addition, we will better define long-term functionality by assessing sphincter function and structure at increasing time points after injection. Proposed experiments will test the hypothesis that CXCL12-mediated cell mobilization to the urinary sphincter is a major underlying mechanism contributing to long-term regeneration of urinary sphincter structure and function in this LUTD. To address this hypothesis, we propose an in-depth assessment of the time-course changes in sphincter cell and matrix cellular and matrix composition for up to 12 months following local CXCL12 injections into the urinary sphincter of NHPs with chronic ISD. The aims are: 1) To assess the time-course effects of local CXCL12 injection on the cellular and structural development of the urinary sphincter. We will use novel multiplex/multispectral analysis of the urinary sphincter complex to test our working hypothesis that, after partial bone marrow transplantation with lenti-GFP transduced BMCs, CXCL12 will stimulate mobilization of GFP-BMCs to the urinary sphincter complex and that these cells provide continued production of chemokines associated with sustained nerve, vascular, muscle regeneration with native tissue-like architecture; and 2) To measure the time-course effects of CXCL12 on sphincter function. We will perform urodynamic measures resting and nerve-stimulated sphincter and bladder pressures, and quantify micturition patterns as functional correlates to the structural effects of CXCL12 therapy (Aim 1) to test our hypothesis that CXCL12 restores functional muscle and innervation that support innervated sphincter pressures; resting and nerve-stimulated sphincter blood flow; and normal micturition patterns. It is anticipated that this study will provide new data about a targeted chemokine therapy for late pre-menopausal chronic ISD. It will also provide new information about the cell mobilization capabilities of CXCL12, how these mobilized cells contribute to tissue regeneration and the long-term efficacy of this therapeutic approach.

R56DK121004

2019-09-23

2021-08-31