Rescue of a lysosomal storage disorder caused by Grn loss of function with a brain penetrant progranulin biologic.
Cell
; 184(18): 4651-4668.e25, 2021 09 02.
Article
in En
| MEDLINE
| ID: mdl-34450028
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. PTVPGRN rescued various Grn-/- phenotypes in primary murine macrophages and human iPSC-derived microglia, including oxidative stress, lysosomal dysfunction, and endomembrane damage. Peripherally delivered PTVPGRN corrected levels of BMP, glucosylsphingosine, and disease pathology in Grn-/- CNS, including microgliosis, lipofuscinosis, and neuronal damage. PTVPGRN thus represents a potential biotherapeutic for GRN-FTD.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Biological Products
/
Brain
/
Lysosomal Storage Diseases
/
Progranulins
Type of study:
Prognostic_studies
Limits:
Animals
/
Female
/
Humans
/
Male
Language:
En
Journal:
Cell
Year:
2021
Document type:
Article
Affiliation country:
United States