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

Cell. 2021 Sep 2;184(18):4651-4668.e25. doi: 10.1016/j.cell.2021.08.002. Epub 2021 Aug 26.


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.

Keywords: GBA; LBPA; galectin-3; lipidomics; lipids; lipofuscin; lysobisphosphatidic acid; lysosome; metabolomics; neurodegenerative disease.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Biological Products / therapeutic use*
  • Bone Morphogenetic Proteins / metabolism
  • Brain / metabolism*
  • Endosomes / metabolism
  • Female
  • Frontotemporal Dementia / blood
  • Frontotemporal Dementia / cerebrospinal fluid
  • Gliosis / complications
  • Gliosis / pathology
  • Humans
  • Induced Pluripotent Stem Cells / metabolism
  • Inflammation / pathology
  • Lipid Metabolism
  • Lipofuscin / metabolism
  • Lysosomal Storage Diseases / therapy*
  • Lysosomes / metabolism
  • Macrophages / metabolism
  • Male
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microglia / metabolism
  • Nerve Degeneration / pathology
  • Phenotype
  • Progranulins / deficiency
  • Progranulins / metabolism
  • Progranulins / therapeutic use*
  • Receptors, Immunologic / metabolism
  • Receptors, Transferrin / metabolism
  • Tissue Distribution


  • Biological Products
  • Bone Morphogenetic Proteins
  • GRN protein, human
  • Grn protein, mouse
  • Lipofuscin
  • Membrane Glycoproteins
  • Progranulins
  • Receptors, Immunologic
  • Receptors, Transferrin
  • Trem2 protein, mouse