Autologous Lung Multipotent Stromal Cell Therapy for Emphysema

描述（由申请人提供）：正在探索使用干细胞的再生疗法用于治疗晚期肺部疾病，如肺气肿。我们最近从肺组织中鉴定出一种未分化的“成纤维细胞样”多能基质细胞（LMSC），其表达与多能骨髓基质细胞相同的表面标志物（CD44、CD73、CD90、CD105），并在移植到患有实验性肺气肿的小鼠和绵羊体内后显示出再生能力。来自成人肺组织的LMSC在体外具有弹性生成能力，在基质胶中自发形成肺泡样结构，并分泌可促进重塑的生长因子，包括FGF 2、FGF 7、FGF 10和HGF。与Dana Farber癌症研究所的细胞治疗生产辅助（PACT）小组合作，我们开发了从活检标本中生产临床级LMSC的程序，并设计了一种生物聚合物支架，以促进支气管内给药后LMSC的肺植入。这些技术进步使得自体LMSC移植对于人类应用是可行的，解决了与同种异体移植相关的排斥和免疫抑制的需要的问题。本项目的目标是：1）完成开始人体试验所需的临床前药物毒理学试验。 2)在等待肺移植的肺气肿患者中启动自体LMSC移植的I期试验。这项试验设计将使我们能够恢复LMSC治疗的 器官进行组织学分析，以表征在细胞水平上对LMSC治疗的反应。

DESCRIPTION (provided by applicant): Regenerative therapies using stem cells are being explored for treatment of advanced lung diseases such as emphysema. We recently identified an undifferentiated "fibroblast-like" multipotent stromal cell (LMSC) from lung tissue that expresses the same surface markers (CD44, CD73, CD90, CD105) as multipotent bone marrow stromal cells and displays regenerative capacity following transplantation in mice and sheep with experimental emphysema. LMSCs from adult human lung tissue have elastogenic capacity in vitro, spontaneously form alveolar-like structures in matrigel and secrete growth factors including FGF2, FGF7, FGF10, and HGF that can promote remodeling. In collaboration with the Production Assistance for Cellular Therapies (PACT) group at the Dana Farber Cancer Institute, we have developed procedures for manufacturing clinical grade LMSCs from biopsy specimens, and designed a biopolymer scaffold to promote lung engraftment of LMSCs following endobronchial administration. These technological advances make autologous LMSC transplantation feasible for human applications, addressing problems of rejection and the need for immunosuppression that are associated with allogeneic transplantation. The objectives of this project are: 1) to complete the preclinical pharmacotoxicology testing required to begin human trials. 2) Initiate Phase 1 trials of autologous LMSC transplantation in emphysema patients awaiting lung transplantation. This trial design will allow us to recover the LMSC-treated organ for histological analysis to characterize responses to LMSC treatment at the cellular level.