Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic

• Published in: Cell Vol. 184; no. 18; pp. 4651 - 4668.e25
• Main Authors: 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 E.K., 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., Di Paolo, Gilbert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02-09-2021
• Subjects: Animals; Biological Products - therapeutic use; Bone Morphogenetic Proteins - metabolism; Brain - metabolism; Endosomes - metabolism; Female; Frontotemporal Dementia - blood; Frontotemporal Dementia - cerebrospinal fluid; galectin-3; GBA; Gliosis - complications; Gliosis - pathology; Humans; Induced Pluripotent Stem Cells - metabolism; Inflammation - pathology; LBPA; Lipid Metabolism; lipidomics; lipids; lipofuscin; Lipofuscin - metabolism; lysobisphosphatidic acid; Lysosomal Storage Diseases - therapy; lysosome; Lysosomes - metabolism; Macrophages - metabolism; Male; Membrane Glycoproteins - metabolism; metabolomics; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microglia - metabolism; Nerve Degeneration - pathology; neurodegenerative disease; Phenotype; Progranulins - deficiency; Progranulins - metabolism; Progranulins - therapeutic use; Receptors, Immunologic - metabolism; Receptors, Transferrin - metabolism; Tissue Distribution; lipids; neurodegenerative disease; LBPA; metabolomics; lysobisphosphatidic acid; GBA; lipofuscin; lysosome; galectin-3; lipidomics
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2021.08.002

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.
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•Grn–/– mice exhibit robust BMP lipid deficiency with concurrent GlcSph accumulation•BMP stimulates glucocerebrosidase activity and lysosome function in Grn–/– models•PGRN was fused to a human transferrin receptor binding Fc to increase CNS exposure•PTV:PGRN biologic rescues Grn–/– CNS lysosomal, microglial, and neuronal dysfunction
Peripherally delivered progranulin biologic with enhanced CNS biodistribution corrects CNS disease pathology of the GRN mouse model of frontotemporal dementia.