Author:
Reich Marvin,Simon Matthew J.,Polke Beate,Werner Georg,Schrader Christian,Paris Iñaki,Robinson Sophie,Davis Sonnet S.,de Melo Gabrielly Lunkes,Schlaphoff Lennart,Spieth Lena,Berghoff Stefan,Logan Todd,Nuscher Brigitte,Buschmann Katrin,Edbauer Dieter,Simons Mikael,Suh Jung H.,Sandmann Thomas,Kariolis Mihalis S.,DeVos Sarah L.,Lewcock Joseph W.,Paquet Dominik,Capell Anja,Paolo Gilbert Di,Haass Christian
Abstract
AbstractProgranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TDP-43 pathology (FTLD-GRN). Multiple therapeutic strategies are in clinical development to restore PGRN levels in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD-associated pathologies may be their inefficient brain exposure and biodistribution. We therefore developed an adeno-associated virus (AAV) targeting the liver (L) to achieve sustained peripheral expression of a transferrin receptor (TfR) binding, brain-penetrant (b) PGRN variant (AAV(L):bPGRN) in two mouse models of FTLD-GRN, namelyGrnknockout andGrnxTmem106bdouble knockout mice. This therapeutic strategy avoids potential safety and biodistribution issues of CNS-administered AAVs while maintaining sustained levels of PGRN in the brain following a single dose. AAV(L):bPGRN treatment reduced several FTLD-GRNassociated disease pathologies including severe motor function deficits, aberrant TDP-43 solubility and phosphorylation, dysfunctional protein degradation, lipid metabolism, gliosis and neurodegeneration in the brain. Translatability of our findings was confirmed in a novel humanin vitromodel using co-cultured human induced pluripotent stem cell (hiPSC)-derived microglia lacking PGRN and TMEM106B and wild-type hiPSC-derived neurons. As in mice, aberrant TDP-43, lysosomal dysfunction and neuronal loss were ameliorated after treatment with exogenous TfR-binding protein transport vehicle fused to PGRN (PTV:PGRN). Together, our studies suggest that peripherally administered brain-penetrant PGRN replacement strategies can ameliorate FTLD-GRNrelevant phenotypes including TDP-43 pathology, neurodegeneration and behavioral deficits. Our data provide preclinical proof of concept for the use of this AAV platform for treatment of FTLD-GRNand potentially other CNS disorders.One sentence summaryPeripheral AAV-mediated delivery of brain-penetrant PGRN rescues TDP-43 pathology, neurodegeneration and motor phenotypes in FTLD-GRNmodels.
Publisher
Cold Spring Harbor Laboratory
Cited by
1 articles.
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