Adipose vs Bone Marrow Derived Stromal cells for Treatment of Stroke in the Aged

描述（由申请人提供）：中风是导致长期残疾的主要原因，大多数中风发生在老年人中。非常需要可以减少中风引起的神经功能缺损并延长受影响患者健康、活跃的生命年数的疗法。因此，本建议的长期目标是开发一种细胞治疗产品，其可以在中风后的急性期之后施用，以恢复神经功能。成人骨髓来源的基质/干细胞（BMSC）已被证明可以改善中风动物模型和最近的小型临床试验中的神经功能，即使细胞的给药时间远远超过目前批准的中风患者治疗所需的3小时窗口。脂肪来源的基质/干细胞（ASC）在某些方面与BMSC相似，但在其他方面是独特的，并且可以很容易地从选择性吸脂手术期间获得的脂肪抽吸物中大量分离。Theradigm已经获得了生产和使用BMSC和ASC治疗神经系统疾病的知识和知识产权。我们假设，相对于BMSC，ASCs在治疗中风方面将显示出更大的功效。在该I期提案中，将从表达人碱性磷酸酶（AP）标志物的转基因大鼠中分离ASC和BMSC。这些细胞将通过静脉输注给中风的老年大鼠，以确定哪种细胞类型在改善中风后的神经功能方面更有效。将使用AP标记物在组织学上评估移植细胞在脑中的分布。此外，将在体外测量ASC或BMSC向在中风后的不同时间点从大鼠获得的缺血性脑组织的组分的迁移，以确定递送细胞的最佳治疗窗口，其随后可以在具有所选细胞类型的大鼠中风模型中确认。该I期研究的结果将用于II期研究，以在适当的动物模型中进一步研究人ASC或人BMSC的有效性和安全性，沿着生产大规模临床级人细胞的工艺开发。免疫惰性的成体衍生细胞（如ASC和BMSC）可能会被开发成一种现成的产品，可以改善数百万患有广泛神经功能缺损的中风幸存者的生活质量。

DESCRIPTION (provided by applicant): Stroke is the leading cause of long term disability with majority of strokes occuring in the aged. There is a great need for therapies that can reduce neurological deficits from stroke and extend the healthy, active years of life of the affected patients. Thus the long term objective of this proposal is to develop a cellular therapeutic product that can be administered beyond the acute period after stroke for the purpose of restoring neurological function. Adult Bone Marrow derived Stromal/Stem Cells (BMSCs) have been shown to improve neurological function in animal models of stroke and a recent small clinical trial, even when the cells were administered well beyond the 3 hour window mandated for currently approved treatments of stroke patients. Adipose derived Stromal/Stem cells (ASCs) are similar to BMSCs in some ways but unique in other ways, and can be easily isolated in large quantities from lipoaspirates obtained during elective liposuction procedures. Theradigm has gained both the knowledge and intellectual property to produce and use both BMSCs and ASCs for the treatment of neurological diseases. We hypothesize that ASCs will display greater efficacy relative to BMSCs for treatment of stroke. In this Phase-1 proposal ASCs and BMSCs will be isolated from transgenic rats expressing a human alkaline phosphatase (AP) marker. The cells will be delivered intravenously to aged rats subjected to stroke to determine which cell type is more efficacious in improving neurological function after stroke. The distribution of the transplanted cells in the brain will be assessed histologically using the AP marker. Additionally, migration of ASCs or BMSCs towards components of ischemic brain tissue obtained from rats at various time points after stroke will be measured in vitro to determine the optimal therapeutic window for delivering the cells, which can be subsequently confirmed in the rat stroke model with the chosen cell type. Results from this Phase-1 study will be used in Phase-2 to further investigate either human ASCs or human BMSCs in suitable animal models in terms of both efficacy and safety, along with process development for manufacture of large scale clinical grade human cells. Adult derived cells such as ASCs and BMSCs that are immunologically inert could potentially be developed into an off the shelf product that can improve the quality of life of millions of stroke survivors living with a wide range of neurological deficits.