Enhancing the Engraftment of Microglia for the Treatment of Neurological Disease

目前还没有有效的治疗方法来治疗小胶质细胞病，这是一类神经退行性疾病， 大脑中一种叫做小胶质细胞的特殊细胞的缺失或功能失调。一种潜在的治疗策略 患有小胶质细胞病的患者是用新细胞替换他们患病的小胶质细胞。NovoGlia技术 该平台使用诱导多能干细胞以高规模和高纯度产生新的小胶质细胞。 NovoGlia细胞可以安全有效地移植到年轻小鼠的大脑中，其中内源性 小胶质细胞仍在发展中，但在成人大脑中实现高水平小胶质细胞嵌合体的策略 尚未得到充分开发。本提案的目的是证明 一种新方法的可行性，该方法结合了使用商业化的 通过移植NovoGlia细胞（经工程改造可抵抗小分子药物）， 抑制剂. NovoGlia开发了两种新的细胞系，这些细胞系携带突变，使其对药物产生耐药性， 在基于细胞的实验中证明了它们的活力，证实了它们的小胶质细胞转录组学特征， 在基于细胞的测定中证明了耐药性。目的1将证实在体内转录组和功能 新细胞系的保存。目标2将衡量NovoGlia细胞替代的成功， Aim 3将优化NovoGlia细胞替代策略。成功 完成这些目标是开发新的商业治疗方法的必要的第一步 小胶质细胞病和其他潜在的神经退行性疾病。第一阶段的结果将提供证据- 支持NovoGlia治疗小胶质细胞病和其他疾病的持续开发的概念数据 神经退行性疾病

There are no effective treatments for microgliopathies, a class of neurodegenerative disorders that are caused by the absence or misfunction of specialized cells in the brain, called microglia. One potential strategy to treat patients with a microgliopathy is to replace their diseased microglia with new cells. The NovoGlia technology platform uses induced pluripotent stem cells to generate new microglia cells at high scale and with high purity. NovoGlia cells can be safely and effectively transplanted into the brains of young mice, in which endogenous microglia are still developing, yet strategies that enable high levels of microglial chimerism within adult brains with a fully occupied niche have yet to be developed. The objective of this proposal is to demonstrate the feasibility of a novel approach that combines the depletion of endogenous microglia using a commercially available drug with the transplantation of NovoGlia cells that are engineered to be resistant to the small molecule inhibitor. NovoGlia developed two novel cell lines that bear mutations making them resistant to the drug, and demonstrated their viability in cell-based experiments, confirmed their microglia transcriptomic profile, and demonstrated drug resistance in cell-based assay. Aim 1 will confirm the in vivo transcriptomic and functional preservation of the novel cell lines. Aim 2 will measure the success NovoGlia cell replacement in the presence of variable doses of inhibitor in vivo, and Aim 3 will optimize the NovoGlia cell replacement strategy. Successful completion of these Aims is a necessary first step in developing new commercial therapeutics for the treatment of microgliopathies and potentially other neurodegenerative diseases. Phase I results will provide proof-of- concept data to support the continued development of NovoGlia therapies for microgliopathies and other neurodegenerative diseases.