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. Public Health Relevance Statement The objective of this work is to advance a novel approach that couples the removal of diseased microglia with NovoGlia cell replacement. This strategy has the potential to be developed into new therapies to treat patients with microgliopathies.
Project Terms: Adult ; 21+ years old ; Adult Human ; adulthood ; Alzheimer's Disease ; AD dementia ; Alzheimer ; Alzheimer Type Dementia ; Alzheimer disease ; Alzheimer sclerosis ; Alzheimer syndrome ; Alzheimer's ; Alzheimer's disease dementia ; Alzheimers Dementia ; Alzheimers disease ; Primary Senile Degenerative Dementia ; dementia of the Alzheimer type ; primary degenerative dementia ; senile dementia of the Alzheimer type ; Animals ; inhibitor/antagonist ; inhibitor ; Ursidae Family ; Bears ; Ursidae ; bear ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Brain ; Brain Nervous System ; Encephalon ; Cell Line ; CellLine ; Strains Cell Lines ; cultured cell line ; Cell Survival ; Cell Viability ; Cells ; Cell Body ; Corpus striatum structure ; Corpus Striatum ; Striate Body ; Striatum ; striatal ; Couples ; Dimethyl Sulfoxide ; DMSO ; Demasorb ; Demeso ; Dimethylsulphinyl ; Dimethylsulphoxide ; Domoso ; Dromisol ; Disease ; Disorder ; Drug resistance ; drug resistant ; resistance to Drug ; resistant to Drug ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Engineering ; Flow Cytometry ; Flow Cytofluorometries ; Flow Cytofluorometry ; Flow Microfluorimetry ; Flow Microfluorometry ; flow cytophotometry ; frontal lobe ; frontal cortex ; Genes ; Hippocampus (Brain) ; Ammon Horn ; Cornu Ammonis ; Hippocampus ; hippocampal ; Homeostasis ; Autoregulation ; Physiological Homeostasis ; Human ; Modern Man ; Immunohistochemistry Cell/Tissue ; Immunohistochemistry Staining Method ; Immunohistochemistry ; In Vitro ; Lipopolysaccharides ; HS-mucopolysaccharidosis ; MPS III ; Mucopolysaccharidosis 3 ; Polydystrophic Oligophrenia ; San Filippo's Syndrome ; Sanfilippo syndrome (A, B, C, D) ; Sanfilippo's Syndrome ; Sanfilippos Syndrome ; heparitinuria ; mucopolysaccharide storage disease III ; mucopolysaccharidosis (MPS) III (A, B, C, D) ; mucopolysaccharidosis type III ; Mucopolysaccharidosis III ; Mice ; Mice Mammals ; Murine ; Mus ; Genetic Alteration ; Genetic Change ; Genetic defect ; genome mutation ; Mutation ; neoplasia ; neoplastic growth ; Neoplasms ; Nervous System Diseases ; Neurologic Disorders ; Neurological Disorders ; neurological disease ; nervous system disorder ; Patents ; Legal patent ; Pathology ; Patients ; Protein Phosphorylation ; Phosphorylation ; Play ; Production ; Research ; social role ; Role ; Saline Solution ; Saline ; Technology ; Body Tissues ; Tissues ; transplant ; Transplantation ; Tyrosine ; Work ; Measures ; Lysosomal Enzyme Disorders ; inborn lysosomal enzyme disorder ; lysosome storage diseases ; Lysosomal Storage Diseases ; Fore-Brain ; Forebrain ; Prosencephalon ; base ; density ; Phase ; Hortega cell ; gitter cell ; mesoglia ; microglial cell ; microgliocyte ; perivascular glial cell ; Microglia ; Licensing ; Engraftment ; Therapeutic ; Chimerism ; Frontal Temporal Dementia ; front temporal dementia ; frontal lobe dementia ; fronto-temporal dementia ; fronto-temporal lobar dementia ; frontotemporal lobar dementia ; frontotemporal lobe degeneration associated with dementia ; Frontotemporal Dementia ; Supportive Therapy ; Supportive care ; Immunes ; Immune ; Complex ; Oral ; postnatal ; brain tissue ; Degenerative Neurologic Diseases ; Degenerative Neurologic Disorders ; Nervous System Degenerative Diseases ; Neural Degenerative Diseases ; Neural degenerative Disorders ; Neurodegenerative Diseases ; Neurologic Degenerative Conditions ; degenerative diseases of motor and sensory neurons ; degenerative neurological diseases ; neurodegenerative illness ; Neurodegenerative Disorders ; brain cell ; success ; novel ; Basic Research ; Basic Science ; Abscission ; Extirpation ; Removal ; Surgical Removal ; resection ; Excision ; cell engineering ; cellular engineering ; CD115 ; CD115 Gene ; CSF1R ; CSFMR ; Colony Stimulating Factor 1 Receptor Gene ; c-FMS ; c-fms Genes ; c-fms Proto-Oncogenes ; CSF1R gene ; Genomics ; drug discovery ; Dose ; Data ; Mouse Cell Line ; Receptor Signaling ; in vivo ; developmental ; Development ; novel strategies ; new approaches ; novel approaches ; novel strategy ; response to injury ; injury response ; pathogen ; Population ; Resistance ; resistant ; genetically modified cells ; genetically engineered cells ; transcriptomics ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; loss of function ; induced pluripotent stem cell ; iPS ; iPSC ; iPSCs ; precursor cell ; standard of care ; treatment strategy ; effective therapy ; effective treatment ; preclinical safety ; pre-clinical safety ; transcriptome ; global gene expression ; global transcription profile ; small molecule inhibitor ; experimental study ; experiment ; experimental research ; human pluripotent stem cell ; Injections ; preservation ;
