BioSphincter to Treat Fecal Incontinence. Phase 1/2 Clinical Trial. SBIR Phase IIB

项目摘要/摘要： 大便失禁(FI)，即不由自主地弄脏不同数量的液体和固体大便，通常是 从社会、心理和卫生的角度来看，这是毁灭性的。男性和女性同样患有FI 在20-30岁的人群中，这一比例为2%-6%。在70岁以上的人中，患病率上升到15%以上 年1.FI可能是由于单独或联合丧失平滑肌功能(IAS)、骨骼肌 功能(EAS)、肛门直肠感觉机制或神经控制。 FI的治疗最初是保守的，试图使大便变大，调整或停止引起 腹泻或便秘，以及生物反馈2，3。虽然这些保守的措施可能会改善 FI的严重程度，需要额外的治疗才能完全控制症状。注射各种生物材料 也曾尝试过扩大肛门内括约肌，但结果多种多样且有限。 有效时的持续时间。在过去，曾尝试过前/后手术修复的手术尝试。 例如股薄肌成形术和骶神经刺激5，6，但长期效果令人失望6。 迫切需要新的治疗方法来解决FI，特别是对患有严重 被动性大小便失禁和低IAS压力。再生医学方法，其中一种新的IAS BioSphincter™是从患者自己的细胞中生物工程出来的，并被植入以恢复结构和 IAS的功能和治疗FI代表了一种理性和新颖的方法来治疗这种衰弱的疾病。 腹主动脉“生物括约肌™”的再生和植入可以恢复腹主动脉的生理功能， 改善或解决FI，提高生活质量。在啮齿动物体内植入后，工程化括约肌 形成了血管化，并保持了它们的表型和功能7，8。进一步在我们的大型动物研究中， 所开发的iAS BioSphincter™被验证用于治疗FI并成功地重建肛门直肠 兔9，10和非人灵长类11的功能。IAS BioSphincter™是在普洛斯条件下研制的 根据GMP指南进一步扩大生产规模，并组装成FDA应用程序。根据 根据NIDDK，NIH，每三个人中就有一个因为大便失禁而向医疗保健提供者报告，因此， IAS“Bispincter™”的再生和植入将使一大部分社会痛苦的人受益 通过恢复IAS的生理功能，解决FI，提高生活质量。 I期临床试验研究的主要目标是：1)确定植入的安全性 生物工程免疫吸附试验在严重FI患者中的应用2)分析数据以评估初步疗效 IAS植入术在减少重症患者尿失禁发作中的作用 菲尔。这种新的创新方法将为患者提供更好的生活质量，并恢复可控性， 通过提供一种从自身细胞中进行生物工程的内在神经内源性免疫球蛋白的添加剂。

Project Summary/Abstract: Fecal incontinence (FI), the involuntary soiling of various amounts of liquid and solid stool, is often devastating from a social, psychological, and hygiene perspective. Men and women suffer from FI equally with a range of 2 - 6% in people aged 20 - 30 years. The prevalence increases to over 15% in people older than 70 years1. FI may result from an isolated or combined loss of smooth muscle function (IAS), skeletal muscle function (EAS), anorectal sensory mechanisms or neural control. Treatment of FI is initially conservative with attempts to bulk the stool, adjust or stop drugs that cause either diarrhea or constipation, and biofeedback2,3. While these conservative measures may improve the severity of FI, additional therapies are needed for total symptom management. Injection of various biomaterials to augment the internal anal sphincter has also been attempted4, but results have been variable and of limited duration when effective. In the past, surgical attempts with anterior/posterior surgical repair have been tried such as graciloplasty and sacral nerve stimulation5,6, but long-term results have been disappointing6. There is a critical need for new therapies to address FI, particularly for patients who have severe passive incontinence and low IAS pressure. Regenerative medicine methods, wherein a new IAS BioSphincter™ is bioengineered from the patient's own cells and implanted to restore the structure and function of the IAS and treat FI, represents a rational and novel approach to this debilitating disease. Regeneration and implantation of the IAS “BioSphincter™” can restore physiological function of the IAS, improve or resolve FI, and improve quality of life. Following implantation in rodents, the engineered sphincters became vascularized and maintained their phenotype and functionality7,8. Further in our large animal studies, the developed IAS BioSphincter™ were validated to treat the FI and successfully restored anorectal functionality in rabbit9,10 and non-human primates11. The IAS BioSphincter™ was developed in GLP condition further scaled up for manufacturing following GMP guidelines and put together for FDA application. According to NIDDK, NIH, one out of three people report to health care providers owing to fecal incontinence, therefore, regeneration and implantation of the IAS “Biosphincter™” will benefit a large socially distressed segment of population via restoration of physiological function of the IAS, resolve FI, and improving quality of life. The primary objectives of the phase I clinical trial study are to: 1) determine the safety of the implanted bioengineered IAS in patients with severe FI and 2) to analyse the data in order to assess the initial efficacy potentials of the implanted IAS in decreasing the number of episodes of incontinence in patients with severe FI. This new innovative approach will provide the patients with a better quality of life, and reinstate continence, by providing an additive functional intrinsically innervated IAS bioengineered from their own cells.