Stem Cell-Based Clinical Trials for Diabetes Mellitus.
Stem Cell-Based Clinical Trials for Diabetes Mellitus.
复制标题
干细胞治疗糖尿病的临床试验。
DOI：
10.3389/fendo.2021.631463
复制
发表时间：
2021
影响因子：
5.2
通讯作者：
Hebrok M
中科院分区：
文献类型：
--
作者：
de Klerk E;Hebrok M
自二十多年前引入以来，门静脉内同种异体尸体胰岛移植已被证明是I型糖尿病（T1D）患者的有希望的治疗方法。尽管其积极的结果，胰岛移植的影响有限，由于一些混淆的问题，包括有限的可用性尸体胰岛，免疫抑制药物的典型终身依赖，以及缺乏由健康保险公司在一些国家的移植费用的覆盖。尽管免疫抑制方案有所改进，但所需胰岛的数量仍然很高，每个患者通常需要两个或更多个供体。胰岛素依赖性通常在胰岛移植后实现，但平均只有25%的患者在五年后不需要外源性胰岛素注射。由于这些原因，胰岛移植的实施几乎仅限于脆性T1D患者，尽管优化了胰岛素治疗，但这些患者仍无法避免低血糖事件。为了改善T1和T2糖尿病患者的C肽水平，许多临床试验已经探索了间充质干细胞（MSC）的功效，既可以作为保护现有β细胞的支持细胞，也可以作为新生成β细胞的来源。发现MSC的移植对于T2D患者是有效的，但是其在T1D中的功效是有争议的，因为MSC在体外分化成功能性β细胞的能力差，并且在体内转分化似乎不发生。相反，为了解决与供应相关的限制，正在探索人胚胎干细胞（hESC）衍生的β细胞作为尸体胰岛的替代物。同种异体hESC衍生的产生胰岛素的类器官的移植最近已进入I期和II期临床试验。干细胞替代疗法克服了有限可用性的障碍，但它们仍然面临免疫排斥。正在测试免疫保护策略，包括将hESC衍生的产生胰岛素的类器官与大胶囊化装置和微胶囊化技术偶联，以平衡免疫保护的必要性与血管化的需要。在这里，我们比较了不同的人类干细胞方法和最近完成和正在进行的临床试验的结果，并讨论了为克服移植干细胞衍生的β细胞所面临的最重大挑战而开发的创新策略。
Since its introduction more than twenty years ago, intraportal allogeneic cadaveric islet transplantation has been shown to be a promising therapy for patients with Type I Diabetes (T1D). Despite its positive outcome, the impact of islet transplantation has been limited due to a number of confounding issues, including the limited availability of cadaveric islets, the typically lifelong dependence of immunosuppressive drugs, and the lack of coverage of transplant costs by health insurance companies in some countries. Despite improvements in the immunosuppressive regimen, the number of required islets remains high, with two or more donors per patient often needed. Insulin independence is typically achieved upon islet transplantation, but on average just 25% of patients do not require exogenous insulin injections five years after. For these reasons, implementation of islet transplantation has been restricted almost exclusively to patients with brittle T1D who cannot avoid hypoglycemic events despite optimized insulin therapy. To improve C-peptide levels in patients with both T1 and T2 Diabetes, numerous clinical trials have explored the efficacy of mesenchymal stem cells (MSCs), both as supporting cells to protect existing β cells, and as source for newly generated β cells. Transplantation of MSCs is found to be effective for T2D patients, but its efficacy in T1D is controversial, as the ability of MSCs to differentiate into functional β cells in vitro is poor, and transdifferentiation in vivo does not seem to occur. Instead, to address limitations related to supply, human embryonic stem cell (hESC)-derived β cells are being explored as surrogates for cadaveric islets. Transplantation of allogeneic hESC-derived insulin-producing organoids has recently entered Phase I and Phase II clinical trials. Stem cell replacement therapies overcome the barrier of finite availability, but they still face immune rejection. Immune protective strategies, including coupling hESC-derived insulin-producing organoids with macroencapsulation devices and microencapsulation technologies, are being tested to balance the necessity of immune protection with the need for vascularization. Here, we compare the diverse human stem cell approaches and outcomes of recently completed and ongoing clinical trials, and discuss innovative strategies developed to overcome the most significant challenges remaining for transplanting stem cell-derived β cells.
登录
查看更多内容
影响因子：
5.6
作者：
Zhu K;Dong L;Wang J;Li D;Chen M;Jiang C;Wang J
通讯作者：
Wang J
影响因子：
16.2
作者：
Cryer PE
通讯作者：
Cryer PE
影响因子：
4.6
作者：
Dave, S. D.;Vanikar, A. V.;Chandra, T.
通讯作者：
Chandra, T.
影响因子：
16.2
作者：
Foster, Eric D.;Bridges, Nancy D.;Alejandro, Rodolfo
通讯作者：
Alejandro, Rodolfo
影响因子：
7.7
作者：
Carlsson, Per-Ola;Schwarcz, Erik;Le Blanc, Katarina
通讯作者：
Le Blanc, Katarina