Mesenchymal Stem Cells for Treatment of Retinal Diseases

描述（由申请人提供）：许多疾病可能受益于长期内源性治疗分子的生产，包括蛋白质。我们建议研究使用转基因自体间充质干细胞（MSCs）植入具有治疗潜力的酶的持续递送的可能性。我们的总体目标是通过评估适当的MSCs植入眼睛的能力来测试这种治疗方法，以防止与溶酶体酶缺乏症相关的视网膜变性。这一目标将通过评估玻璃体植入的间充质干细胞延缓或预防神经元样脂褐变（NCL）（称为CLN1）小鼠模型视网膜变性的能力来实现。这种疾病是由一种编码可溶性溶酶体酶（PPT1）的基因突变引起的，这种酶通常在细胞之间交换。我们假设，如果供体间充质干细胞表达正常或高于正常水平的PPT1酶能够在眼睛中长期居住，它们将为宿主视网膜细胞提供足够的酶，以防止宿主细胞功能丧失和宿主细胞死亡。我们将通过实验来验证这一假设，以实现以下具体目标：(1)确定移植到CLN1敲除小鼠玻璃体中的正常间充质干细胞的长期命运。(2)确定供体间充质干细胞是否可以延缓或预防CLN1敲除小鼠视网膜的疾病相关表型变化。(3)确定供体间充质干细胞效应是否由于将PPT1蛋白转移到宿主小鼠视网膜细胞。通过在小鼠模型中评估这种方法，我们将更好地确定这种方法是否应该在人类中进行测试。小鼠研究将为指导我们未来人类临床研究的设计提供有价值的见解。这些研究的成功结果可以为将MSC植入作为治疗许多视网膜和其他眼部疾病的手段奠定基础。可能从这种方法中获益的条件包括眼病，其中通过植入细胞持续递送治疗剂将是有益的。如果成功，这种方法也可以扩展到治疗影响中枢神经系统其他部分的神经退行性疾病。公共卫生相关性：将进行研究，以确定从骨髓中分离出的转基因干细胞是否可以作为载体，长期、持续地向患有各种视网膜疾病的人的眼组织输送治疗剂。这种治疗方法将通过评估眼内植入适当修饰的骨髓干细胞来保护患有导致视网膜变性的遗传性疾病的动物的视网膜的能力来进行测试。这些研究的结果将与诸如老年性黄斑变性、糖尿病性视网膜病变、视网膜色素变性以及许多其他影响视网膜和其他组织的疾病的治疗有关。

DESCRIPTION (provided by applicant): Many diseases could benefit from long-term endogenous production of therapeutic molecules, including proteins. We propose to investigate the possibility of using implantation of genetically modified autologous mesenchymal stem cells (MSCs) for sustained delivery of enzymes with therapeutic potential. Our overall goal is to test this therapeutic approach by evaluating the ability of appropriate MSCs implanted in the eye to prevent retinal degeneration associated with lysosomal enzyme deficiencies. This goal will be achieved by assessing the ability of vitreally implanted MSCs to retard or prevent retinal degeneration in a mouse model of a form of neuronal ceroid lipofuscinosis (NCL), known as CLN1. This disease results from a mutation in a gene encoding a soluble lysosomal enzyme (PPT1) that is normally exchanged between cells. We hypothesize that if donor MSCs expressing normal or higher than normal levels of the PPT1 enzyme can take up long-term residence in the eye, they will supply enough of the enzyme to host retinal cells to prevent loss of host cell function and host cell death. We will test this hypothesis by conducting experiments to achieve the following specific aims: (1) Determine the long-term fate of normal MSCs transplanted into the vitreous of CLN1 knockout mice. (2) Determine whether donor MSCs can retard or prevent disease-related phenotypic changes in the CLN1 knockout mouse retina. (3) Determine whether the donor MSC effect is due to transfer the PPT1 protein to cells of the host mouse retina. By evaluating this approach in the mouse model, we will be in a better position to determine whether such an approach should be tested in humans. The mouse studies will provide valuable insights to guide the design of our future clinical studies in human patients. Successful outcomes of these studies could set the groundwork for using MSC implantation as a means of treating many retinal and other ocular diseases. Among the conditions that could potentially benefit from such an approach are eye diseases in which sustained delivery of a therapeutic agent by implanted cells would be beneficial. If successful, this approach could also be extended for treating neurodegenerative disorders that affect other parts of the central nervous system. PUBLIC HEALTH RELEVANCE: Studies will be undertaken to determine whether genetically modified stem cells isolated from the bone marrow can be used as vehicles for long-term, sustained delivery of therapeutic agents to eye tissues of people with a variety of retinal diseases. This approach to therapy will be tested be evaluating the ability of intraocular implantation of appropriately modified bone marrow stem cells to preserve the retina in animals with inherited diseases that cause retinal degeneration. The results of these studies will be relevant to the treatment of diseases such as age-related macular degeneration, diabetic retinopathy, retinitis pigmentosa, and many other disorders affecting the retina and other tissues as well.