Cell-based Therapy for Neurogenic Bladder following Spinal Cord Injury

脊髓损伤后神经源性膀胱的细胞疗法

• 批准号: 8399231
• 负责人: MATTHEW O FRASER
• 金额: --
• 依托单位: DURHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8399231
• 关键词: Address; Adipocytes; Adrenal Glands; Adrenal Medulla; Adrenergic Agents; Adrenergic Antagonists; Adrenergic beta-Agonists; Adverse effects; Agonist; Allogenic; American; Animals; Ataxia; Autologous; Autonomic Dysreflexia; Biological; Bladder; Cardiovascular system; Catecholamines; Cell Survival; Cell Therapy; Cell Transplants; Cells; Cessation of life; Chromaffin Cells; Chronic; Contracts; Control Animal; Control Groups; Culture Media; Data; Development; Disease; Drug Costs; Environment; Epinephrine; Evaluation; Exhibits; FDA approved; Functional disorder; Future; Genes; Goals; Growth; Harvest; Health; Histologic; Histology; Homologous Transplantation; Human; Hydronephrosis; Hyperreflexia; Immunosuppression; Inbred Lew Rats; Inbred Strains Rats; Inbreeding; Individual; Infection; Injection of therapeutic agent; Injury; Interruption; Intravesical Instillation; Investigation; Kidney Failure; Left; Life; Lower urinary tract; Measurement; Mediating; Medical Device; Methods; Molecular; Muscle; Neuraxis; Neurogenic Bladder; Neurotoxins; Neurotransmitters; Norepinephrine; Operative Surgical Procedures; Outcome; Paraplegia; Patient Noncompliance; Patients; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Plague; Production; Pyelonephritis; Quadriplegia; Quality of life; Rat Strains; Rattus; Receptors, Adrenergic, beta-3; Reflex action; Reflux; Rehabilitation therapy; Relaxation; Research; Residual state; Risk; Role; Smooth Muscle; Smooth Muscle Myocytes; Soldier; Sphincter; Spinal Cord; Spinal cord injury; Spinal cord injury patients; Stem cells; Striated Muscles; Suspension substance; Suspensions; Techniques; Testing; Therapeutic; Time; Toxin; Transplantation; Treatment Efficacy; Urethane; Urethra; Urethral sphincter; Urination; Urine; Urodynamics; Veterans; adrenergic; awake; base; beta-adrenergic receptor; bladder dome; cell type; indexing; injured; insight; intravesical; pressure; public health relevance; receptor; response; urinary

DESCRIPTION (provided by applicant): Suprasacral spinal cord injury (SCI) can result in an interruption of descending inhibitory control of the urinary bladder and the urethral sphincters. This results in a condition in which the bladder reacts to filling by contraction rather than relaxation throughout the filling cycle, a condition known as detrusor hyperreflexia. Detrusor hyperreflexia is very often associated with external (striated muscle) and internal (smooth muscle) urethral sphincter dyssynergia, such that the urethral outlet contracts in response to high pressure bladder contractions, rather than relaxing as is normal during a normal voiding. The combined effect of a hyperreflexic bladder contracting against a dyssynergic outlet is frequent high pressure bladder contractions with little or no ability to empty, a condition referred to as neurogenic bladder with detrusor-sphincter dyssynergia (DSD). This condition, if left unchecked, can be life threatening, causing autonomic dysreflexia, ureteral reflux and hydronephrosis/renal failure, and, because of poor emptying providing a safe-harbor reservoir of residual urine for bacterial growth, uncontrolled urinary trac infections and pyelonephritis. The goal of the proposed research is to provide proof of concept for a cell-based therapeutic strategy which will treat the lower urinary tract (LUT) dysfunction following suprasacral SCI with high efficacy while eliminating the side effect/surgical burden associated with the current pharmaceutical, medical device and/or surgical treatments. Briefly, the strategy is to inject cells, which produce the sympathetic neurotransmitters norepinephrine and epinephrine, into the walls of the bladder body. These transmitters are known to quiet bladder body smooth muscle via stimulation of beta-3 adrenergic receptors, and thus reduce the number and force of hyperreflexic bladder contractions. Pharmacological approaches to utilization of beta adrenergic receptors for this therapeutic goal in patients have suffered due to lack of selectivity for the bladder over the cardiovascular (CV) system. Happily, this CV concern may be overcome in the near future by truly beta-3 specific agonists. However, at this time, no beta 3 agonist has been approved by the FDA for use in humans. Regardless, the systemic administration of any pharmacological agent is likely to have side effects and requires daily or more often dosings, making this approach costly over the long term and a risk for patient noncompliance due to systemic side effects, drug costs and inconvenience. Other approaches with local injections or intravesical instillations of neurotoxins appear(ed) promising, but these are also confounded by the need for repeated treatments as the effect of the toxins wear off. The proposed approach has the potential to develop into a single treatment cure for the hyperreflexia seen in SCI patients. Cells from the patient's adrenal medulla may be harvested directly, or other cell types harvested and made to secrete adrenergic catecholamines by molecular biological techniques. The latter is beyond the scope of the initial proof of concept studies outlined in this proposal. In this case, adrenal chromaffin cells will be harvested from normal donor rats and injected into the bladder walls of chronic SCI rats. The ability of the cells to survive in the new environment as well as the efficacy of their catecholamine secretions will be determined physiologically, pharmacologically and histologically first in spinal cord intact animals at 1, 2 and 4 weeks post transplantation. At the optimal time after adrenal chromaffin cell or fat cell transplant, or cell suspension vehicle only injection, as determined by the aforementioned studies in intact animals, chronic SCI rats will undergo cystometric urodynamic evaluation. Following a control period of cystometry in which the efficacy of the cell therapy should be evident in comparison to control animals, the animals will be challenged by pharmacological means to determine the level of beta receptor stimulation. In this way determination of the efficacy of the treatments can be made, as well as the role of adrenergic catecholamines in the response. PUBLIC HEALTH RELEVANCE: Greater than 250,000 Americans are spinal cord injured. 52% of spinal cord injured individuals are considered paraplegic and 47% quadriplegic. Approximately 11,000 new injuries occur each year. Of the more than 250,000 Americans with serious spinal cord injuries and disorders, about 42,000 are Veterans. Thus, any insights into enhancing the general health of SCI patients will greatly impact a large number of veterans as well as soldiers who may be injured in the future. Lower urinary tract (LUT) dysfunction associated with suprasacral SCI can be life threatening at its worst and socially debilitating at its least for these patients. Moreover, SCI patients themselves rank their LUT dysfunctions as primary concerns, even greater than mobility. Successful rehabilitation for the SCI patient must address not only the important health concerns associated with LUT dysfunction, but also the deleterious effects that it has on the patient's quality of life. Additionally, this research would provide proof of concept evidence for the use of cell therapy to treat LUT dysfunction in SCI .

描述（由申请人提供）： 骶上脊髓损伤（SCI）可导致下行抑制控制中断 膀胱和尿道括约肌这导致膀胱在整个充盈周期中通过收缩而不是松弛来对充盈作出反应的状况，这种状况称为逼尿肌反射亢进。逼尿肌反射亢进通常与外部（横纹肌）和内部（平滑肌）尿道括约肌协同失调相关，使得尿道出口响应于高压膀胱收缩而收缩，而不是在正常排尿期间正常地松弛。反射亢进的膀胱收缩对抗协同失调的出口的组合效应是频繁的高压膀胱收缩， 或没有排空能力，这是一种被称为逼尿肌-括约肌协同失调（DSD）的神经性膀胱的病症。这种情况，如果不加以控制，可能危及生命，导致自主神经反射异常，输尿管反流和肾盂积水/肾功能衰竭，并且由于排空不良为细菌生长提供了残余尿的安全港水库，不受控制的尿路感染和肾盂肾炎。 拟议研究的目标是为基于细胞的治疗策略提供概念验证，该策略将以高疗效治疗骶上SCI后的下尿路（LUT）功能障碍，同时消除与当前药物，医疗器械和/或手术治疗相关的副作用/手术负担。简言之，该策略是将产生交感神经递质去甲肾上腺素和肾上腺素的细胞注射到膀胱体的壁中。已知这些递质通过刺激β-3肾上腺素能受体使膀胱体平滑肌安静，从而减少反射亢进膀胱收缩的次数和力量。在患者中利用β肾上腺素能受体用于该治疗目标的药理学方法由于以下原因而受到影响： 对膀胱缺乏对心血管（CV）系统的选择性。令人高兴的是，在不久的将来，真正的β-3特异性激动剂可能会克服这种CV问题。然而，在这个时候，没有β 3激动剂已被FDA批准用于人类。无论如何，任何药理学试剂的全身给药都可能具有副作用，并且需要每天或更频繁地给药，使得这种方法在长期内成本高昂，并且由于全身副作用、药物成本和不便而存在患者不依从的风险。局部注射或膀胱内滴注神经毒素的其他方法似乎（艾德）有希望，但这些方法也因需要重复治疗而混淆，因为毒素的作用逐渐消失。 所提出的方法有可能发展成为一个单一的治疗治愈反射亢进看到SCI患者。可以直接从患者的肾上腺髓质收获细胞，或者收获其他类型的细胞并通过分子生物学技术使其分泌肾上腺素能儿茶酚胺。后者超出了本提案中概述的初步概念验证研究的范围。在这种情况下，将从正常供体大鼠中收获肾上腺嗜铬细胞并注射到慢性SCI大鼠的膀胱壁中。细胞的能力 首先在移植后1、2和4周在脊髓完整动物中从生理学、病理学和组织学上确定它们在新环境中存活的能力以及它们的儿茶酚胺分泌物的功效。在肾上腺嗜铬细胞或脂肪细胞移植或仅注射细胞悬液载体后的最佳时间，如在完整动物中的上述研究所确定的，慢性SCI大鼠将进行膀胱测压尿动力学评价。在膀胱测压的对照期（其中与对照动物相比，细胞疗法的功效应该是明显的）之后，将通过药理学方法激发动物以确定β受体刺激的水平。以这种方式，可以确定治疗的功效，以及肾上腺素能儿茶酚胺在反应中的作用。 公共卫生关系： 超过250，000美国人脊髓受伤。52%的脊髓损伤患者被认为是截瘫，47%是四肢瘫痪。每年约有11，000起新的伤害发生。在超过25万名患有严重脊髓损伤和疾病的美国人中，约有42，000人是退伍军人。因此，任何提高SCI患者整体健康的见解都将极大地影响大量退伍军人以及未来可能受伤的士兵。与骶上脊髓损伤相关的下尿路（LUT）功能障碍在最坏的情况下可能危及生命，至少对这些患者来说是社会衰弱。此外，SCI患者自己将他们的LUT功能障碍列为主要关注点，甚至比移动性更重要。SCI患者的成功康复不仅要解决与LUT功能障碍相关的重要健康问题，还要解决其对患者生活质量的有害影响。此外，这项研究将为使用细胞疗法治疗SCI中的LUT功能障碍提供概念证据。