information: Publication of results in a medical journal
Announcement: presentation of results at the 14thInternational Conference on Alzheimer's & Parkinson's Diseases (ADPD)
Company: Sangamo Therapeutics (USA - CA)
Product: zinc finger protein transcription factors (ZFP-TFs)
mechanism: gene editing/gene therapy.
Disease: Tau pathology, tauopathies
area: Neurodegenerative diseases
- • On March 29, 2019, Sangamo Therapeutics presented new preclinical data demonstrating significant (>80%) reduction of tau expression in the nonhuman primate brain following administration of zinc finger protein transcription factors (ZFP-TFs). Tau pathology is strongly linked to the progression of several neurodegenerative diseases. The data, reported in a podium presentation at the 14thInternational Conference on Alzheimer's & Parkinson's Diseases (ADPD) held in Lisbon, Portugal, described the effects of tau-targeted ZFP-TFs delivered with adeno-associated viruses (AAVs) in the mouse and nonhuman primate (NHP) brain.
- Sangamo's ZFP-TF technology acts at the DNA level to selectively repress or activate the expression of specific genes to achieve a desired therapeutic effect. Gene regulation differs from other genome editing approaches as it is designed to enable precise, robust, and long-term repression of a selected gene following a single administration of AAV and does not cut or modify the target DNA.The goal of the preclinical studies presented at ADPD was to assess the pharmacology of tau gene repression in the mouse and NHP brain. AAV vectors were used to deliver tau-targeted ZFP-TFs in vitro to neurons and in vivo to vulnerable brain regions that are impacted by tauopathies. The data demonstrate that ZFP-TFs selectively reduced mouse and human tau by up to 98% in vitro in both primary mouse and induced pluripotent stem cell-derived human neurons. Intrahippocampal ZFP-TF delivery to adult mice resulted in more than 80% tau reduction, and intravenous ZFP-TF administration reduced tau levels by 50-70% across the entire mouse brain. ZFP-TF expression and mouse tau reduction were sustained for at least six months following a single administration. Furthermore, in APP/PS1 mice, tau-targeted ZFP-TFs reduced dystrophic neurites by approximately 50% across the cerebral cortex.
- AAV ZFP-TFs targeting tau were administered to the adult NHP hippocampus using real-time MRI-guided stereotaxic infusion. ZFP-TF treatment resulted in more than 80% lowering of tau in the hippocampus and entorhinal cortex, and transgene expression levels were strongly correlated with tau reduction. The treatment was well tolerated for the duration of the study. Together these data from mice and NHPs highlight the potential for a single administration of ZFP-TF to lower tau as a treatment for tauopathies, including Alzheimer's disease.