AMD-FCRx to Restore Damaged Pigment Epithelium

描述(申请人提供)：老年性黄斑变性(AMD)是西方世界导致失明的主要原因。该病的特点是视网膜色素上皮(RPE)功能障碍，随后黄斑中心凹感光细胞死亡。造血干细胞(HSC)已被证明在选定的条件下可以修复受损的组织，包括心脏、肌肉和神经。同种异体RPE移植已尝试修复受损的RPE。然而，同种异体RPE细胞不能有效地附着在衰老的Bruch膜上，也不能有效地修复缺陷。 此外，同种异体成人RPE移植后发生排斥反应，除非使用免疫抑制。因此，开发一种同基因的HSC产品(AMD-FCRx)来治疗AMD并避免全身免疫抑制的需要将是一个重大进展。我们是第一个发现CD8+/TCR移植促进细胞(FC)的人，这是一种在骨髓中显著增强同基因受者HSC植入的新细胞。Fc表达SDF-1和CXCR4，SDF-1是HSC归巢的关键趋化因子，CXCR4也存在于HSC上。我们有强有力的初步数据表明，Fc增强了HSC对受损RPE的归巢。因此，Fc可能在HSC介导的RPE损伤修复中起关键作用。在本申请的第一阶段，我们将确定用于移植的HSC和FC的最佳组成，以取代受损的RPE。具体地说，我们将优化策略，促进HSC归巢到RPE损伤或丢失的区域，附着在正常的Bruchs膜上，增殖并填充造成的缺损区，并分化为成熟的RPE细胞。这些研究将为第二阶段奠定基础，在第二阶段，AMD-FCRx产品将在更严格的AMD模型中进行测试，然后转化为第一阶段临床方案。 Regenerex，LLC已被合并，将骨髓移植工程技术的好处商业化，用于治疗血液疾病和组织修复。我们组建了一支才华横溢的团队，拥有眼科、干细胞生物学和移植方面的专业知识。路易斯维尔医疗中心发展公司、犹太医院、肯塔基州和路易斯维尔大学之间独特的合作开发生物医学孵化器使Regenerex，LLC得以搬进位于东杰斐逊街201号的办公空间。我们的长期目标是通过销售一种定义明确的HSC细胞治疗产品来开发促进细胞的潜力，用于治疗AMD。Regenerex是一家由女性拥有的企业，位于EPSCoR州肯塔基州。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is the leading cause of blindness in the Western world. The hallmark of the disease is retinal pigment epithelial (RPE) dysfunction with subsequent death of the foveal photoreceptors. Hematopoietic stem cells (HSC) have been demonstrated to repair damaged tissues including heart muscle and nerve under selected conditions. Allogeneic RPE transplantation has been attempted to restore the damaged RPE. However, allogeneic RPE cells do not attach to senescent Bruch's membrane efficiently, and do not efficiently repair the defect. Furthermore, rejection occurs after allogeneic adult RPE transplantation unless immunosuppression is employed. Thus, the development of a syngeneic HSC product (AMD-FCRx) to treat AMD and avoid the need for systemic immunosuppression would be a major advance. We were the first to discover CD8+/TCR- graft facilitating cells (FC), a novel cell in bone marrow that significantly enhances HSC engraftment in syngeneic recipients. FC express SDF-1, a critical chemokine for HSC homing, and CXCR4, its unique receptor that is also present on HSC We have strong preliminary data to show that FC enhance homing of HSC to damaged RPE. As such, FC may play a critical role in HSC-mediated repair of damaged RPE. In phase I of this application we will define the optimal composition of HSC and FC for transplantation to replace damaged RPE. Specifically, we will optimize strategies to promote homing of HSC to areas of RPE damage or loss, attach to normal Bruch's membrane, proliferate and fill in the defect created, and differentiate into mature RPE cells. These studies will lay the groundwork for Phase II in which the AMD-FCRx product will be tested in a more rigorous model of AMD and then translated into a phase I clinical protocol. Regenerex, LLC has been incorporated to commercialize the benefits of bone marrow graft engineering technologies for treatment of blood disorders and tissue repair. We have assembled a highly talented team with expertise in ophthalmology, stem cell biology, and transplantation. A unique collaboration between the Louisville Medical Center Development Corporation, Jewish Hospital, the State of Kentucky, and the University of Louisville to develop a biomedical incubator has allowed Regenerex, LLC to move into office space located at 201 East Jefferson Street. Our long-term goal is to exploit the potential of the facilitating cell by marketing a well-defined HSC cellular therapeutic product for worldwide distribution to treat AMD. Regenerex is a woman-owned business in Kentucky, an EPSCoR state.