1. Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic
- Author
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Logan, Todd, Simon, Matthew J, Rana, Anil, Cherf, Gerald M, Srivastava, Ankita, Davis, Sonnet S, Low, Ray Lieh Yoon, Chiu, Chi-Lu, Fang, Meng, Huang, Fen, Bhalla, Akhil, Llapashtica, Ceyda, Prorok, Rachel, Pizzo, Michelle E, Calvert, Meredith EK, Sun, Elizabeth W, Hsiao-Nakamoto, Jennifer, Rajendra, Yashas, Lexa, Katrina W, Srivastava, Devendra B, van Lengerich, Bettina, Wang, Junhua, Robles-Colmenares, Yaneth, Kim, Do Jin, Duque, Joseph, Lenser, Melina, Earr, Timothy K, Nguyen, Hoang, Chau, Roni, Tsogtbaatar, Buyankhishig, Ravi, Ritesh, Skuja, Lukas L, Solanoy, Hilda, Rosen, Howard J, Boeve, Bradley F, Boxer, Adam L, Heuer, Hilary W, Dennis, Mark S, Kariolis, Mihalis S, Monroe, Kathryn M, Przybyla, Laralynne, Sanchez, Pascal E, Meisner, Rene, Diaz, Dolores, Henne, Kirk R, Watts, Ryan J, Henry, Anastasia G, Gunasekaran, Kannan, Astarita, Giuseppe, Suh, Jung H, Lewcock, Joseph W, DeVos, Sarah L, and Di Paolo, Gilbert
- Subjects
Biochemistry and Cell Biology ,Biomedical and Clinical Sciences ,Biological Sciences ,Rare Diseases ,Alzheimer's Disease Related Dementias (ADRD) ,Frontotemporal Dementia (FTD) ,Neurodegenerative ,Dementia ,Acquired Cognitive Impairment ,Brain Disorders ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurosciences ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Animals ,Biological Products ,Bone Morphogenetic Proteins ,Brain ,Endosomes ,Female ,Frontotemporal Dementia ,Gliosis ,Humans ,Induced Pluripotent Stem Cells ,Inflammation ,Lipid Metabolism ,Lipofuscin ,Lysosomal Storage Diseases ,Lysosomes ,Macrophages ,Male ,Membrane Glycoproteins ,Mice ,Mice ,Inbred C57BL ,Mice ,Transgenic ,Microglia ,Nerve Degeneration ,Phenotype ,Progranulins ,Receptors ,Immunologic ,Receptors ,Transferrin ,Tissue Distribution ,GBA ,LBPA ,galectin-3 ,lipidomics ,lipids ,lipofuscin ,lysobisphosphatidic acid ,lysosome ,metabolomics ,neurodegenerative disease ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - Abstract
GRN mutations cause frontotemporal dementia (GRN-FTD) due to deficiency in progranulin (PGRN), a lysosomal and secreted protein with unclear function. Here, we found that Grn-/- mice exhibit a global deficiency in bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid we identified as a pH-dependent PGRN interactor as well as a redox-sensitive enhancer of lysosomal proteolysis and lipolysis. Grn-/- brains also showed an age-dependent, secondary storage of glucocerebrosidase substrate glucosylsphingosine. We investigated a protein replacement strategy by engineering protein transport vehicle (PTV):PGRN-a recombinant protein linking PGRN to a modified Fc domain that binds human transferrin receptor for enhanced CNS biodistribution. PTV:PGRN rescued various Grn-/- phenotypes in primary murine macrophages and human iPSC-derived microglia, including oxidative stress, lysosomal dysfunction, and endomembrane damage. Peripherally delivered PTV:PGRN corrected levels of BMP, glucosylsphingosine, and disease pathology in Grn-/- CNS, including microgliosis, lipofuscinosis, and neuronal damage. PTV:PGRN thus represents a potential biotherapeutic for GRN-FTD.
- Published
- 2021