Role of Brain Macrophages in the Pathogenesis and Treatment of Globoid Cell Leukodystrophy

脑巨噬细胞在球状细胞脑白质营养不良的发病机制和治疗中的作用

• 批准号: 10599167
• 负责人: Frederick Bennett
• 金额: $ 46.85万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-03 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599167
• 关键词: Adopted; Appearance; Astrocytes; Birth; Brain; Brain Diseases; CSF1R gene; Cell Therapy; Cells; Central Nervous System; Childhood; Data; Disease; Donor person; Effectiveness; Embryo; Engineering; Engraftment; Future; Genetic; Globoid cell leukodystrophy; Hematopoietic Stem Cell Transplantation; Heterogeneity; Immune; Infiltration; Injections; Knowledge; Label; Ligands; Lysosomal Storage Diseases; Macrophage; Maps; Methods; Microglia; Modeling; Mus; Names; Neurodegenerative Disorders; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway interactions; Peripheral; Population; Regulation; Resistance; Role; Synapses; Testing; Therapeutic; Tissues; Transplantation; Treatment Efficacy; Variant; Work; brain cell; brain tissue; cellular engineering; disease-causing mutation; disorder risk; improved; infancy; inhibitor; innovation; leukodystrophy; myelination; nervous system disorder; nervous system transplantation; neuropathology; new therapeutic target; novel strategies; preconditioning; receptor; reconstitution; risk variant; single cell sequencing; small molecule inhibitor; targeted treatment; tool; transcriptomics; translational potential; transplantation therapy; unpublished works

Globoid cell leukodystrophy (GLD), or Krabbe, is a fatal pediatric neurodegenerative disease caused by mutations in GALC. It is so-named due to the appearance of globoid cell macrophages. The major hurdle to curing GLD is treatment of central nervous system (CNS) pathology. Hematopoietic stem cell transplant (HSCT) is the only treatment, but is not curative, and must be administered presymptomatically in early infancy. HSCT is thought to work by therapeutic engraftment of donor macrophages and replacement of globoid cells, but in the brain, does so inefficiently. Despite being pathognomonic for GLD, little is known about globoid cells in the brain - their function, origin, and formation. It is unknown if globoid cells arise from embryonically-derived tissue resident microglia or HSC-derived infiltrating macrophages, the degree to which they are pathogenic, and if their replacement is key to GLD treatment. This is a critical knowledge gap that has limited the advancement of more effective GLD therapies and is the focus of this proposal. Our central hypothesis is that globoid cells are unique reactive microglia and that robust replacement by “true” microglia is sufficient to treat GLD CNS neuropathology. We are experts in the study of brain macrophages by direct CNS transplantation in mice. The twitcher (GALCKO) mouse is a widely accepted model of GLD. We created new methods to 1) distinguish microglia, infiltrating macrophages, and transplanted donor macrophages from each other and 2) replace host brain macrophages with directly injected cells at high efficiency without HSCT, including by engineering the first small molecule inhibitor-resistant variant of CSF1R, a survival receptor for brain macrophages. In this proposal, we will apply these new methods in the GALCKO model to determine the role of brain macrophages in GLD pathogenesis and treatment. In Aim 1, we will define the origin and transcriptomic identity of all reactive brain macrophages, including globoid cells, in GALCKO, including after HSCT. This knowledge promises to reveal new therapeutic targets for GLD. In Aim 2, we will test the hypothesis that direct replacement of GALCKO microglia with healthy surrogates eliminates globoid cells and drives the neurotherapeutic effects of HSCT. If true, this approach has great translational potential to maximize engraftment efficiency and broaden the therapeutic window for cell therapy. Finally in Aim 3, we will determine if HSC-derived cells are effective microglial surrogates, given the distinct functions of non-microglial macrophages in the CNS. This will guide future work to enhance the efficacy of cell therapies for brain diseases. Completion of these aims will fill longstanding knowledge gaps about the role of microglia and other macrophages in the pathogenesis and treatment of pediatric neurodegenerative diseases.

Globoid cell leukodystrophy (GLD)，简称Krabbe，是一种致命的小儿神经退行性疾病