AAV- GRN partially corrects motor deficits and ALS/FTLD-related pathology in Tmem106b-/-Grn-/- mice

Tuancheng Feng; Gregory Minevich; Pengan Liu; Henry Xin Qin; Glenn Wozniak; Jenny Pham; Khanh Pham; Akshata Korgaonkar; Michael Kurnellas; Nadine A Defranoux; Hua Long; Ananya Mitra; Fenghua Hu

doi:10.1016/j.isci.2023.107247

AAV- GRN partially corrects motor deficits and ALS/FTLD-related pathology in Tmem106b^-/-Grn^-/- mice

iScience. 2023 Jun 28;26(7):107247. doi: 10.1016/j.isci.2023.107247. eCollection 2023 Jul 21.

Authors

Affiliations

¹ Department of Molecular Biology and Genetics, Weill Institute for Cell and Molecular Biology, Cornell University, Ithaca, NY 14853, USA.
² Alector Inc, South San Francisco, CA 94080, USA.

Abstract

Loss of function of progranulin (PGRN), encoded by the granulin (GRN) gene, is implicated in several neurodegenerative diseases. Several therapeutics to boost PGRN levels are currently in clinical trials. However, it is difficult to test the efficacy of PGRN-enhancing drugs in mouse models due to the mild phenotypes of Grn^-/- mice. Recently, mice deficient in both PGRN and TMEM106B were shown to develop severe motor deficits and pathology. Here, we show that intracerebral ventricle injection of PGRN-expressing AAV1/9 viruses partially rescues motor deficits, neuronal loss, glial activation, and lysosomal abnormalities in Tmem106b^-/-Grn^-/- mice. Widespread expression of PGRN is detected in both the brain and spinal cord for both AAV subtypes. However, AAV9 but not AAV1-mediated expression of PGRN results in high levels of PGRN in the serum. Together, these data support using the Tmem106b^-/-Grn^-/- mouse strain as a robust mouse model to determine the efficacy of PGRN-elevating therapeutics.

Keywords: Cellular neuroscience; Human genetics; Molecular neuroscience.

Abstract

Grants and funding