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

AI Article Synopsis

  • Progranulin (PGRN) haploinsufficiency is linked to frontotemporal lobar degeneration (FTLD-) with TDP-43 pathology, prompting the development of gene therapy strategies to restore PGRN levels in the brain.
  • An innovative adeno-associated virus (AAV) was created to target the liver, allowing for the sustained release of a brain-penetrant PGRN variant, reducing FTLD- symptoms in mouse models.
  • The findings also showed that this method effectively improved conditions such as TDP-43 pathology and neurodegeneration in human induced pluripotent stem cell models, providing a promising avenue for FTLD- treatment and potentially other CNS disorders.

Article Abstract

Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43) pathology (FTLD-). 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-, namely, knockout and 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--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- 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- and potentially other CNS disorders.

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Source
http://dx.doi.org/10.1126/scitranslmed.adj7308DOI Listing

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