Ludwig-Maximilians-Universität, Chair of Metabolic Biochemistry

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Peripheral expression of brain-penetrant progranulin rescues pathologies in mouse models of frontotemporal lobar degeneration

Sci Transl Med. 2024 Jun 5;16(750):eadj7308.

Authors/Editors: Marvin Reich
Matthew J Simon
Beate Polke
Iñaki Paris
Georg Werner
Christian Schrader
Lena Spieth
Sonnet S Davis
Sophie Robinson
Gabrielly Lunkes de Melo
Lennart Schlaphoff
Katrin Buschmann
Stefan Berghoff
Todd Logan
Brigitte Nuscher
Lis de Weerd
Dieter Edbauer
Mikael Simons
Jung H Suh
Thomas Sandmann
Mihalis S Kariolis
Sarah L DeVos
Joseph W Lewcock
Dominik Paquet
Anja Capell
Gilbert Di Paolo
Christian Haass
Publication Date: 2024
Type of Publication: Journal Article



Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43) pathology (FTLD-GRN). Multiple therapeutic strategies are in clinical development to restore PGRN 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, namely, Grn knockout and GrnxTmem106b double knockout mice. This therapeutic strategy avoids potential safety and biodistribution issues of CNS-administered AAVs and maintains sustained concentrations of PGRN in the brain after a single dose. AAV(L):bPGRN treatment reduced several FTLD-GRN–associated pathologies including severe motor function deficits, aberrant TDP-43 phosphorylation, dysfunctional protein degradation, lipid metabolism, gliosis, and neurodegeneration in the brain. The potential translatability of our findings was tested in an in vitro model using cocultured 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 ameliorate FTLD-GRN relevant 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-GRN and potentially other CNS disorders.

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