Regeneration of the Lower Urinary Tract in Nonhuman Primates

描述(由申请人提供)：尿失禁影响全球2亿多患者，并与生活质量显著下降有关，目前的治疗方案存在局限性，需要选择。在临床前研究和临床试验中，细胞疗法治疗女性尿括约肌缺乏症相关的压力性尿失禁仍在进行中。这是RO1的更新应用，其最初目标是建立稳定的UDS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，横断阴部神经支配到女性NHP的尿括约肌复合体产生稳定的(伤后12个月)UU，括约肌注射skMPC产生同样稳定的结构和功能改善。续签申请将利用美国大学的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，至少在一定程度上，注射的CEL主动整合到括约肌组织中，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” 作为注射细胞再生括约肌组织的中心作用模式，“整合与刺激细胞迁移”。2)细胞疗法对已建立/稳定的美元的有效性--通常的临床图景--仍不清楚，现在将在该模型中进行测试。)研究将比较直接括约肌注射和静脉注射的疗效--后者可能会得到更广泛的临床接受。自体标记骨髓祖细胞(BMC)移植后，在去括约肌6周或去神经支配6个月后静脉或直接向括约肌复合体内注射自体标记skMPC。目的1.检测和比较skMPC治疗途径和治疗时机对尿失禁大鼠尿括约肌复合体结构的影响。假设刺激自然细胞迁移是一个重要的过程，注射的细胞通过这个过程有助于括约肌复合体的再生。因此，结构性的 在局部细胞治疗组，括约肌的再生将更大(无论 时机)，因为与全身注射相比，最初的细胞-细胞直接内容物增强了趋化旁分泌活性，并增加了天然细胞(BMC)向括约肌的迁移。目的2比较skMPC治疗的途径和时机对尿括约肌功能(躯体和肾上腺素能反射对括约肌压力和血流的控制)的影响。假设功能性再生将反映对括约肌复合体的结构、血管和肌肉成分的治疗效果。预计拟议研究的结果将有助于更好地确定细胞治疗的机会窗口， 在一个位于临床翻译结点的肛门模型中，细胞疗法可能有效的给药途径和作用模式。

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.