Matrix Regenerative Nanotherapeutic Platform for Pelvic Organ Prolapse

The goal of this research is to slow POP progression by treating early-stage pelvic organ prolapse (POP) with our novel elastogenic functionalized Nanomaterial-Drug Complexes (fNDCs). POP involves the bulging or herniation of pelvic organs and reduces quality of life for many women. POP worsens with time and surgical treatments can fail since the underlying proteolytic processes continue to degrade tissues. No existing treatment reverses this proteolytic pathophysiology. Specifically, POP pathophysiology has been linked to naturally irreversible proteolytic disruption and loss of elastic fibers. Since elastic fibers provide tissue stretch and recoil, their dysfunction can result in POP. Our novel fDNC technology offers a comprehensive solution to restore ECM homeostasis by targeting pathways involved in elastic fiber breakdown, new fiber assembly, and tissue fibrosis. They therefore have the potential to prevent or slow POP progression. Our biodegradable polymer fNDCs are designed to ‘stick’ to disrupted elastic fibers and to locally provide pro-elastogenic and anti- matrix metalloprotease stimuli independent of the regenerative effects of a released drug, doxycycline (Dox). In this study, we will first modify our novel first generation fNDC design for application to POP and will perform a comprehensive investigation of the mechanistic basis for the additive regenerative effect of Dox and fNDCs. Recent research links upregulated MAPKs (JNK, ERK1/2, and AkT) in POP to ECM issues like collagen buildup and elastin loss. Dox has been shown to inhibit these MAPKs, and our findings suggest MAPK attenuation promotes anti-MMP effects and elastin repair. We will thus investigate MAPKs as therapeutic targets and expand studies on the combined regenerative effects of Dox and fNDCs, demonstrating their additive impact on matrix regeneration to alleviate POP. We will also investigate fNDCs in vivo in an animal model of POP to develop a fNDC-based therapy to slow progression of early-stage POP. Our aims will test the hypothesis that fNDCs are retained locally and act additively with Dox primarily by inhibiting MAPK pathways to restore elastic matrix homeostasis and delay progression of POP. We will use 3 model systems: 1) cultured nonepithelial vaginal cells (NEVCs) from human vaginal tissues of women with POP and from LOXL1 KO mice with POP, 2) ex vivo tissue cultures of human vaginal tissue, and 3) in vivo testing in LOXL1 KO mice with POP. Aim 1 will investigate mechanisms of ECM restorative effects of Dox and demonstrate additive matrix regenerative benefits of Dox and application specific fNDCs in cell culture. Aim 2 will determine the mechanistic correlates of the ECM modulatory effects of Dox-fNDCs in human vaginal tissue cultures ex vivo. Aim 3 will evaluate ECM restorative effects of Dox-fNDCs in vivo in LOXL1 KO mice with early-stage POP. The significance of this research lies in advancing understanding of mechanisms to mitigate the effects of POP and developing a novel technology to slow progression of POP pathophysiology. Project Number: 1R01HD119910-01 | Fiscal Year: 2025 | NIH Institute/Center: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) | Principal Investigator: MARGOT DAMASER (+1 co-PI) | Institution: CLEVELAND CLINIC LERNER COM-CWRU, CLEVELAND, OH | Award Amount: $688,436 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 KUDS-H (05)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HD11991001