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Enhancing the Engraftment of Microglia for the Treatment of Neurological Disease

增强小胶质细胞的植入以治疗神经系统疾病

基本信息

批准号：
10382086
负责人：
Sunil Gandhi
金额：
$ 39.99万
依托单位：
NOVOGLIA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382086
关键词：
Adult Alzheimer&apos s Disease Animals Basic Science Biological Assay Brain CSF1R gene Cell Line Cell Survival Cells Chimerism Complex Corpus striatum structure Couples Data Development Dimethyl Sulfoxide Disease Dose Drug resistance Engineering Engraftment Excision Flow Cytometry Frontotemporal Dementia Genes Genomics Hippocampus (Brain)Homeostasis Human Immune Immunohistochemistry In Vitro Injections Legal patent Licensing Lipopolysaccharides Lysosomal Storage Diseases Measures Microglia Mouse Cell Line Mucopolysaccharidosis III Mus Mutation Neoplasms Neurodegenerative Disorders Oral Pathology Patients Pharmaceutical Preparations Phase Phosphorylation Play Population Production Prosencephalon Receptor Signaling Research Resistance Role Saline Supportive care Technology Therapeutic Tissues Transplantation Tyrosine Ursidae Family Work base brain cell brain tissue cellular engineering density drug discovery effective therapy experimental study frontal lobe genetically modified cells human pluripotent stem cell in vivo induced pluripotent stem cell inhibitor loss of function nervous system disorder novel novel strategies novel therapeutics pathogen postnatal preclinical safety precursor cell preservation response to injury small molecule inhibitor standard of care success transcriptome transcriptomics treatment strategy

项目摘要

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.

目前还没有有效的治疗方法来治疗小胶质疾病，这是一种由由于大脑中特殊细胞的缺失或功能失常，这种细胞被称为小胶质细胞。一种潜在的治疗策略患有小胶质细胞病的患者将用新的细胞取代他们患病的小胶质细胞。诺和格利亚的技术 Platform使用诱导的多能干细胞来高规模、高纯度地生成新的小胶质细胞。 NovoGlia细胞可以安全有效地移植到幼鼠的脑内，其中内源性小胶质细胞仍在发育中，但在成人大脑中实现高水平的小胶质细胞嵌合体的策略有一个完全占据的利基市场还没有开发出来。这项建议的目标是证明一种新的方法的可行性结合内源性小胶质细胞的耗竭使用商业可用于NovoGlia细胞移植的药物，这些细胞被设计为对小分子具有抵抗力抑制剂。NovoGlia开发了两种新的细胞系，它们携带突变，使其对药物产生抗药性，以及在基于细胞的实验中证明了它们的生存能力，确认了它们的小胶质细胞转录图谱，以及在基于细胞的检测中显示了耐药性。目标1将确认体内转录和功能保存新的细胞系。目标2将在存在的情况下衡量NovoGlia细胞替换的成功率不同剂量的抑制剂在体内的应用，目标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。小胶质疾病和潜在的其他神经退行性疾病。第一阶段的结果将证明- 支持NovoGlia治疗小胶质疾病和其他疾病的持续发展的概念数据神经退行性疾病。