Summary: Researchers have developed an adeno-associated virus (AAV) vector that delivers an antibody targeting phosphorylated Tau (pTau) directly into the hippocampus, producing a substantial reduction in pTau accumulation associated with chronic traumatic encephalopathy (CTE) in a mouse model.
Source: Mary Ann Liebert Inc
A new study demonstrates the feasibility of using gene therapy to address chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disorder triggered by repeated trauma to the central nervous system (CNS). The work, showing effective direct delivery of gene therapy to the brain in a mouse model, appears in the journal Human Gene Therapy.
The study was coauthored by Ronald G. Crystal and colleagues at Weill Cornell Medical College, New York, NY, under the article title “Anti-Phospho-Tau Gene Therapy for Chronic Traumatic Encephalopathy.” Their work explores a novel gene therapy approach to reduce disease-driving phosphorylated Tau protein (pTau) in the CNS after repeated traumatic brain injury (TBI).
CTE develops following repeated CNS trauma—commonly seen in military personnel, contact-sport athletes, and people who have sustained repeated head injuries in accidents—and currently lacks approved therapies. The condition is characterized as a CNS tauopathy: trauma-induced inflammation promotes the accumulation of hyperphosphorylated Tau (pTau), which forms neurofibrillary tangles and contributes to progressive neuronal loss.
To interrupt this pathogenic cascade, Crystal and colleagues designed an adeno-associated virus vector (AAVrh.10) encoding a monoclonal antibody that specifically targets pTau. They hypothesized that local CNS expression of this anti-pTau antibody, produced after vector administration, would reduce pTau accumulation and thereby slow or halt downstream neurodegenerative effects. The team tested this concept in a mouse model of CTE created by repeated closed cortical impact over five days to induce TBI and subsequent pTau accumulation.
In their experiments, the investigators administered AAVrh.10 vectors encoding one of two distinct anti-pTau monoclonal antibodies directly into the hippocampus of TBI mice. They report that this localized gene transfer produced sufficient antibody expression within the CNS to significantly lower pTau levels across multiple brain regions. Importantly, the doses used in the study were selected to reflect levels that could be scaled safely toward human use, supporting the potential translational relevance of the approach for future clinical development.
Terence R. Flotte, MD, Editor-in-Chief of Human Gene Therapy and Celia and Isaac Haidak Professor of Medical Education at the University of Massachusetts Medical School, commented on the significance of the findings: “CTE is much more prevalent than was initially realized, and there is currently no therapy available. This new work from the Crystal laboratory is potentially ground-breaking as a means to remove the offending Tau phosphoprotein.”
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Mary Ann Liebert Inc
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Original Research: Open access
“Anti-Phospho-Tau Gene Therapy for Chronic Traumatic Encephalopathy”. Chester Bittencourt Sacramento, Dolan Sondhi, Jonathan B. Rosenberg, Alvin Chen, Stephanie Giordano, Eduard Pey, Vladlena Lee, Katie M. Stiles, David F. Havlicek, Philip L. Leopold, Stephen M. Kaminsky, and Ronald G. Crystal.
Human Gene Therapy doi: 10.1089/hum.2019.174.
Abstract
Anti-Phospho-Tau Gene Therapy for Chronic Traumatic Encephalopathy
Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder caused by repetitive trauma to the central nervous system (CNS) in soldiers, contact sport athletes, and civilians following accident-related injuries. CTE is characterized by inflammatory responses that promote accumulation of hyperphosphorylated forms of the microtubule-binding protein Tau (pTau), producing neurofibrillary tangles and progressive neuronal loss. There are currently no therapies for CTE.
The authors hypothesized that direct CNS administration of an adeno-associated virus vector encoding an anti-pTau antibody could generate therapeutic antibody concentrations within the brain sufficient to suppress pTau accumulation and disrupt the disease process. Using an AAVrh.10 serotype vector coding for a monoclonal antibody against pTau, the team evaluated this approach in a mouse CTE model in which repeated traumatic brain injury induced pTau accumulation. Direct hippocampal delivery of AAVrh.10 vectors encoding either of two anti-pTau antibodies significantly reduced pTau across the CNS. The study used vector doses that could be feasibly scaled to humans and concludes that CNS administration of AAVrh.10 anti-pTau is effective in this preclinical model, offering a potential new strategy to counteract the consequences of TBI leading to CTE.