We have developed a platform technology that uses induced human pluripotent stem cells (iPSCs) to generategenetically corrected microglia at scale and with high purity for transplantation. In this study, we will demonstratethe safety and therapeutic efficacy of our microglia transplantation technology using a mouse genetic model ofadult-onset leukoencephalopathy with axonal spheroids & pigmented glia (ALSP), a fatal disease with noeffective treatments. The three overlapping aims to be investigated in this Phase I project are: Aim 1: Optimize microglial transplantation delivery parameters in a mouse genetic model of microglialinsufficiency. We have preliminary data showing that our iPSC-derived microglia can repopulate the brains ofmicroglia-deficient mice. We will test three different microglia injection locations, and after determining theoptimal injection location using whole brain clearing and quantification, we will then evaluate different numbersof cells at this optimized location. Aim 2: Determine the safety of microglial transplantation in the mouse model of microglial insufficiency. Toassess the safety of our microglial repopulation, we will determine the percentage of cells that express non-microglial markers, examine brain tissue using immunohistochemistry for markers of undifferentiated iPSCs andproliferative cell markers, and determine the presence of any non-native human cells in relevant peripheraltissues. Aim 3: Demonstrate the efficacy of microglial transplantation on reduction of pathological ALSP hallmarks inthe mouse model brain. Brain calcification, axonal spheroids, and astrogliosis are hallmarks of ALSP in humancases, as well as the mouse model. We have preliminary data demonstrating that microglial transplantationreduces these hallmark pathologies. Our delivery parameters from Aim 1 will be used for microglialtransplantation. We will assess pathology reduction in the Aim 1 optimized delivery paradigm mice using confocalimaging and quantification of: osteopontin and Alazarin Red staining to identify calcified tissue, neurofilamentlight chain staining to identify axonal spheroids, and GFAP staining to identify astrogliosis. We expect a > 30%reduction in all of these pathologies with microglial transplantation.Our Phase I results will provide proof-of-concept data to support the development of iPSC-derived microglial celltherapy for ALSP and related neurodegenerative microgliopathies.
Public Health Relevance Statement: Project Narrative
Our project seeks to develop our platform technology to produce microglia from human induced pluripotent stem
cells for the treatment of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. This fatal
neurodegenerative disease is caused by mutations in the microglia gene CSF1R. In this work we will use a
mouse model of this disease to demonstrate the safety and efficacy of our microglia transplantation therapy, with
our future goals focused on developing a much needed treatment for human patients.
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 ; Axon ; Biotechnology ; Biotech ; Bone Marrow ; Bone Marrow Reticuloendothelial System ; Brain ; Brain Nervous System ; Encephalon ; Brain Pathology ; Cell Count ; Cell Number ; Cells ; Cell Body ; Clinical Trials ; Disease ; Disorder ; Flow Cytometry ; Flow Cytofluorometries ; Flow Cytofluorometry ; Flow Microfluorimetry ; Flow Microfluorometry ; flow cytophotometry ; Future ; Genes ; Glial Fibrillary Acidic Protein ; Astroprotein ; GFA-Protein ; GFAP ; Glial Fibrillary Acid Protein ; Glial Intermediate Filament Protein ; Goals ; Human ; Modern Man ; Immunohistochemistry ; Immunohistochemistry Cell/Tissue ; Immunohistochemistry Staining Method ; Industry ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; leukodystrophy ; Light ; Photoradiation ; Liver ; hepatic body system ; hepatic organ system ; Genetic Models ; Mus ; Mice ; Mice Mammals ; Murine ; Mutation ; Genetic Alteration ; Genetic Change ; Genetic defect ; genome mutation ; Neoplasms ; neoplasia ; neoplastic growth ; Nerve Degeneration ; Neuron Degeneration ; neural degeneration ; neurodegeneration ; neurodegenerative ; neurological degeneration ; neuronal degeneration ; nervous system disorder ; Nervous System Diseases ; Neurologic Disorders ; Neurological Disorders ; neurological disease ; neurofilament ; Neuroglia ; Glia ; Glial Cells ; Kolliker's reticulum ; Neuroglial Cells ; Non-neuronal cell ; Nonneuronal cell ; nerve cement ; Pathology ; Patients ; Pigments ; Research ; Research Personnel ; Investigators ; Researchers ; Risk ; Safety ; Spleen ; Spleen Reticuloendothelial System ; Stains ; Staining method ; stem cells ; Progenitor Cells ; Technology ; Testing ; Tissues ; Body Tissues ; Transplantation ; transplant ; Work ; osteopontin ; 2aR phosphoprotein I ; 2ar peptide ; Eta-1 protein ; Eta-1-Op protein ; bone sialoprotein 1 ; bone sialoprotein I ; early T-lympocyte activation-1 protein ; secreted phosphoprotein 1 ; sialoprotein 1 ; Enhancers ; calcification ; Calcified ; Organ ; Peripheral ; Phase ; Undifferentiated ; Microglia ; Hortega cell ; gitter cell ; mesoglia ; microglial cell ; microgliocyte ; perivascular glial cell ; insight ; Licensing ; Leukoencephalopathy ; cell mediated therapies ; cell-based therapeutic ; cell-based therapy ; cellular therapy ; Cell Therapy ; Therapeutic ; 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 ; Hereditary ; Inherited ; Immunes ; Immune ; Location ; Deep Cervical Lymph Node ; 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 ; Cell Growth in Number ; Cell Multiplication ; Cellular Proliferation ; Cell Proliferation ; Pharmacology and Toxicology ; disorder model ; Disease model ; motor deficit ; Single Base Polymorphism ; single nucleotide variant ; Single Nucleotide Polymorphism ; Modeling ; stem cell based therapy ; stem cell mediated therapy ; stem cell therapeutics ; stem cell treatment ; stem cell-based treatment ; stem cell therapy ; neuropathology ; CD115 ; CD115 Gene ; CSF1R ; Colony Stimulating Factor 1 Receptor Gene ; c-FMS ; c-fms Genes ; c-fms Proto-Oncogenes ; CSFMR ; CSF1R gene ; drug discovery ; Therapeutic Uses ; therapeutic testing ; therapeutic evaluation ; Address ; Symptoms ; Progenitor Cell Transplantation ; Stem Cell Transplantation ; Stem cell transplant ; Data ; Regulatory Element ; Stem Cell Development ; progenitor cell development ; Cognitive ; Pathologic ; Process ; Development ; developmental ; Behavioral ; astrogliosis ; genome wide association study ; GWA study ; GWAS ; genome wide association ; genome wide association scan ; genome wide association studies ; genomewide association scan ; genomewide association studies ; genomewide association study ; whole genome association analysis ; whole genome association studies ; whole genome association study ; PGRN gene ; PC cell-derived growth factor ; PCDGF ; PGRN protein ; Progranulin ; granulin precursor ; progranulin gene ; progranulin protein ; Treatment Efficacy ; intervention efficacy ; therapeutic efficacy ; therapy efficacy ; loss of function mutation ; clinically relevant ; clinical relevance ; mouse model ; murine model ; induced pluripotent stem cell ; iPS ; iPSC ; iPSCs ; commercialization ; effective therapy ; effective treatment ; phase 2 study ; phase II study ; non-Native ; nonnative ; experimental study ; experiment ; experimental research ; human pluripotent stem cell ; Injections ; confocal imaging ; post-transplant ; post-transplantation ; posttransplant ; posttransplantation ; mouse genetics ; stem cell proliferation ; progenitor cell proliferation ; transplantation therapy ; transplant therapy ; transplant treatment ; transplantation treatment ; stem cell biomarkers ; stem cell markers ;
