Regeneration of the Lower Urinary Tract in Nonhuman Primates

描述（由申请人提供）：尿失禁影响全球超过2亿患者，并与生活质量显著降低相关。目前的治疗方案有局限性，需要选择。细胞疗法治疗女性尿括约肌缺陷（USD）相关的压力性尿失禁继续在临床前研究和临床试验中进行测试。这是RO1的更新申请，其最初目标是开发稳定USD的非人灵长类动物（NHP）模型，然后测量自体骨骼肌前体细胞（skMPC）治疗对括约肌结构和功能的长期影响。结果表明，横切阴部神经支配至女性NHPs的尿括约肌复合体可产生稳定的（损伤后12个月）USD，而在括约肌注射skMPCs可产生同样稳定的结构和功能改善。续期申请将利用USD的NHP模型来解决关于这种治疗方法的剩余和额外的知识空白。1)初步研究提供的证据表明，注射细胞至少部分地主动融入括约肌组织，但它们也可能调节天然细胞向括约肌的迁移。因此，拟议的研究将更明确地探索“细胞”

DESCRIPTION (provided by applicant): Urinary incontinence affects more than 200 million patients worldwide, and is associated with significant reduction in quality of life Current treatment options have limitations and options are needed. Cell therapy for urinary sphincter deficiency (USD) - associated stress incontinence in women continues to be tested in preclinical studies and in clinical trials. This is a renewal application fo an RO1 whose initial goals were to develop a nonhuman primate (NHP) model of stable USD and then measure the long-term effects of autologous skeletal muscle precursor cell (skMPC) therapy on sphincter structure and function. Results indicate that transectin the pudendal innervation to the urinary sphincter complex of female NHPs produced stable (up to 12 months after injury) USD and that sphincteric injection of skMPCs produced equally stable structural and functional improvement. The renewal application will utilize the NHP model of USD to address remaining and additional gaps in knowledge concerning this therapeutic approach. 1) Initial studies provide evidence that, at least in part, injected cels actively incorporate into the sphincter tissue~ but that they may also modulate native cell migration to the sphincter. Thus, proposed studies will more definitively explore "cell incorporation vs. stimulation of cell migration" as central modes of action by which injected cells regenerate sphincter tissue. 2) The efficacy of cell therapy in established/stabl USD - the usual clinical picture - remains unclear and will now be tested in this model. ) Studies will compare the efficacy of direct sphincter vs. intravenous injection - which could afford wider clinical acceptance. Following bone marrow transplantation with labeled autologous labeled bone marrow progenitor cells (BMCs), autologous labeled skMPCs will be administered either 6 weeks post-sphincter denervation, or 6 months post-denervation, either intravenously, or directly into the sphincter complex. Aim 1. To measure and compare the route of skMPC treatment and the timing of skMPC treatment on structural changes of the urinary sphincter complex in the NHP model of USD. The hypothesis is that stimulation of native cell migration is an important process by whih injected cells contribute to regeneration of the sphincter complex. As such, structural regeneration of the sphincter will be greater in the local cell therapy groups (regardless of timing) because initial direct cell-cell content enhances chemotactic paracrine activity and increases migration of native cells (BMCs) to the sphincter compared to systemic injection. Aim 2 is to compare the route and timing of skMPC treatment on functional changes in the urinary sphincter (somatic and adrenergic reflex control of sphincter pressure and blood flow). The hypothesis is that functional regeneration will reflect treatment effects on te structural, vascular and muscular components of sphincter complex. It is anticipated that results of proposed studies will help better define the cell treatment window of opportunity, possible effective routes of administration and mode of action of cell therapy in an anial model that sits at the nexus of clinical translation.