Treatment of venous ulcers with autologous cultured bone marrow stem cells

自体培养骨髓干细胞治疗静脉性溃疡

• 批准号: 8790865
• 负责人: Vincent Falanga
• 金额: $ 23.92万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8790865
• 关键词: Treatment; venous; ulcers; autologous; cultured

DESCRIPTION (provided by applicant): Venous leg ulcers and other severe chronic wounds affect 5-7 million Americans, and are responsible for a direct cost of at least $20 billion annually. Patients with venous ulcers experience poor quality of life, frequent infections, and loss of work and independence. Clinical outcomes have improved in recent years because of better conventional care and new advanced therapies, such as the use of living bioengineered skin. However, the underlying problem of venous hypertension leads to severe secondary changes, such as tissue fibrosis, propensity for infection, and an increasingly recognized set of phenotypic changes in resident wound cells that impair dermal repair and epidermal resurfacing. Venous ulcers can become very difficult to heal. Indeed, even advanced therapies heal less than 50% of venous ulcers that have been present for more than a year. We have recently developed evidence that the topical application of autologous bone marrow-derived mesenchymal stem cells (MSCs), grown from the patients' own bone marrow aspirate and cultured and expanded in vitro, can lead to dramatic acceleration of healing in chronic wounds, including venous ulcers. During our preliminary work, we have developed a novel fibrin polymer construct for delivering the cultured MSCs to the wound in a spray system. In doing so, we modified an existing fibrin glue construct by decreasing the fibrinogen/thrombin concentrations required for polymerization and by eliminating aprotenin as the protease inhibitor component. Once sprayed into the wound, the MSCs are in a thin fibrin gel that does not affect their viability and is endogenously eliminated, thus releasing the cells to the wound. We are now ready to move forward with a clinical trial that will test the hypothesis that the patients' own MSCs can accelerate the healing of their wounds. We have developed a GMP facility for handling the the growth of MSCs, and we have received an IND from the FDA for our clinical trial. We plan the following two specific aims: 1) Determine the effect of MSCs on the healing of venous ulcers in a three-arm randomized controlled blinded clinical trial. All patients will be treated with conventional leg compression bandages. Cultured autologous MSCs will be delivered to the wound in a fibrin spray, and this group will be compared to control patients receiving leg compression treatment alone or the fibrin spray only. Healing will be assessed by computerized planimetry for wound edge migration and healing rate, wound size reduction, and complete closure; 2) Characterize and closely correlate the expression of wound edge molecular markers of impaired healing and epithelial migration in response to treatment. Baseline and sequential biopsies from the edges of venous ulcers treated in specific aim 1 will be used to determine the epidermal expression of c-myc, 2-catenin, and keratins 6/16 and 17 at the wounds' edges. These measurements, closely correlated with wound size and edge migration, will help us establish promising molecular markers involved in impaired healing and whether the MSCs may work by affecting the expression and localization of these specific molecular markers.

描述（由申请人提供）：静脉腿溃疡和其他严重的慢性伤口影响5-7万美国人，并负责每年至少达到200亿美元的直接成本。静脉溃疡患者的生活质量较差，经常感染以及失去工作和独立性。近年来，临床结果有所改善，因为使用了更好的常规护理和新的先进疗法，例如使用生物工程的皮肤。然而，静脉高血压的潜在问题会导致严重的次要变化，例如组织纤维化，感染倾向以及越来越认识的居民伤口细胞的表型变化，这些变化会损害皮肤修复和表皮重新外观。静脉溃疡可能很难治愈。确实，即使是先进的疗法也不到50％的静脉溃疡，这些静脉溃疡已经存在了一年以上。 我们最近开发了证据表明，自体骨髓衍生的间充质干细胞（MSC）的局部应用是由患者自身的骨髓抽吸和培养和扩展的体外培养和扩展的，可导致慢性伤口愈合的急剧加速，包括静脉溃疡。在初步工作中，我们开发了一种新型的纤维蛋白聚合物构建体，用于将培养的MSC传递到喷雾系统中的伤口。在这样做时，我们通过降低聚合所需的纤维蛋白原/凝血酶浓度并消除脱核酸蛋白酶作为蛋白酶抑制剂成分来修饰现有的纤维蛋白胶构建体。一旦喷洒到伤口中，MSC就处于薄纤维蛋白凝胶中，不会影响其生存能力并被内源消除，从而将细胞释放到伤口上。现在，我们准备进行一项临床试验，该试验将测试患者自己的MSC可以加速伤口的假设。我们已经开发了用于处理MSC增长的GMP设施，并收到了FDA的IND进行临床试验。我们计划以下两个具体目的：1）确定MSC在三臂随机对照盲目临床试验中对静脉溃疡治愈的影响。所有患者将接受常规的腿部压缩绷带治疗。培养的自体MSC将在纤维蛋白喷雾剂中输送到伤口，该组将与仅接受腿部压缩治疗或仅接受纤维蛋白喷雾的对照患者进行比较。愈合将通过计算机化平面图来评估伤口边缘迁移和愈合率，降低伤口大小和完全闭合； 2）表征并密切相关，以响应治疗而受损的愈合和上皮迁移的伤口边缘分子标记的表达。在特定目标1中处理的静脉溃疡边缘的基线和顺序活检将用于确定伤口边缘的C-Myc，2-catenin和角蛋白6/16和17的表皮表达。这些测量值与伤口大小和边缘迁移密切相关，将有助于我们建立有希望的分子标记，涉及损害的愈合，以及MSC是否可以通过影响这些特定分子标记的表达和定位来起作用。