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

Cell
Todd LoganGilbert Di Paolo

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.

References

Aug 4, 2009·Acta Neuropathologica·Alice S Chen-PlotkinVirginia M-Y Lee
Dec 23, 2009·The Journal of Experimental Medicine·Fangfang YinAihao Ding
Oct 7, 2011·Journal of Neuroinflammation·Kimberly R ByrnesAlan I Faden
May 23, 2012·American Journal of Human Genetics·Katherine R SmithSamuel F Berkovic
Oct 9, 2012·The Journal of Clinical Investigation·Lauren Herl MartensRobert V Farese
Jan 19, 2016·Nature Biotechnology·John G DoenchDavid E Root
Sep 9, 2016·Annals of Clinical and Translational Neurology·Lieke H MeeterJohn C van Swieten
Jan 28, 2017·Journal of Lipid Research·Misbaudeen Abdul-HammedKonrad Sandhoff
Apr 14, 2017·Science Translational Medicine·Michael E WardAri J Green
Apr 25, 2017·Nature Reviews. Neuroscience·Aimee W KaoEric J Huang
Apr 26, 2017·Proceedings of the National Academy of Sciences of the United States of America·Grietje KrabbeLi Gan
Apr 30, 2017·Human Molecular Genetics·Sander BeelPhilip Van Damme
May 12, 2017·Acta Neuropathologica·Xiaolai ZhouFenghua Hu
Jul 25, 2017·Autophagy·Owen A BradyRosa Puertollano
Jul 27, 2017·Molecular Neurodegeneration·Chris W LeeLeonard Petrucelli
Aug 25, 2017·Molecular Neurodegeneration·Xiaolai ZhouFenghua Hu
Aug 30, 2017·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Yumiko V TaguchiSreeganga S Chandra
Sep 12, 2017·Trends in Molecular Medicine·Eline WautersChristine Van Broeckhoven
Mar 8, 2018·Proceedings of the National Academy of Sciences of the United States of America·Andrew D NguyenRobert V Farese
May 11, 2018·Acta Neuropathologica·Daniel H PaushterFenghua Hu
Jul 11, 2019·PloS One·Xiaolai ZhouFenghua Hu
Aug 27, 2019·Journal of Molecular Biology·Chrisovalantis PapadopoulosHemmo Meyer
Nov 9, 2019·Lancet Neurology·Mike A NallsUNKNOWN International Parkinson's Disease Genomics Consortium
Dec 20, 2019·Traffic·Jean Gruenberg
Dec 25, 2019·Acta Neuropathologica Communications·Andrew E ArrantErik D Roberson

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