A gene therapy for Progressive Supranuclear Palsy : slowing tau spread and symptom progression by enhancing TFEB-mediated autophagy in a macaque model – TFEB-for-PSP

Progressive supranuclear palsy (PSP) is a rare neurodegenerative tauopathy, with no treatment available. We have recently shown that brain injections in the supra-nigral area of tau aggregates derived from patients with PSP induce typical neuronal and glial PSP lesions that can trigger parkinsonism and behavior impairments in macaques. In addition to the pathophysiological information about the prion-like nature of the disease, these findings support using PSP-tau-inoculated macaques as relevant animal models to accelerate drug development targeting tau pathology in PSP. Because the autophagy-lysosomal pathway is the main cellular mechanism for clearing intracellular aggregates, we propose in this project to enhance the activity of TFEB, the master regulator of this pathway, in the brain of PSP macaques to alleviate tau aggregation, tau spreading, neurodegeneration and the appearance/progression of symptoms.
We have previously shown in macaques that intrathecal injections of adeno-associated virus (AAV)-PHP.eB were particularly efficient in transducing both neurons and glial cells in many brain regions, including the ones usually affected in PSP (substantia nigra, putamen, caudate,…). We thus propose in this project to generate 14 PSP macaques: 7 will receive intrathecal injections of AAV-PHP.eB expressing TFEB every 6 months as a therapeutic strategy, and 7 will receive AAV-PHP.eB expressing EGFP as a control procedure. We will also follow 4 "control" macaques injected with tau protein from healthy aged brains to compare the effectiveness of our therapeutic strategy to the "normal" performance of macaques. We will assess at baseline and every 6 months fine-grained anthropomorphic cognitive and motor skills known to be impaired in PSP macaques, using quantitative analysis of kinematic features in a corridor gait platform and the object retrieval task. We will also collect blood and CSF at baseline and every 6 months for biomarker analyses. We will finally terminate the macaques after 18 months to perform the neuropathological evaluation.
If effective and safe in macaques, this study will pave the way to a clinical trial in PSP patients.