A newly developed adeno-associated virus vector can treat the progressive neurodegenerative disorder chronic traumatic encephalopathy (CTE)


A new study shows the feasibility of using gene therapy to treat the progressive neurodegenerative disorder chronic traumatic encephalopathy (CTE).

The study, which demonstrated the effectiveness of direct delivery of gene therapy into the brain of a mouse model of CTE, is published in Human Gene Therapy.

Ronald Crystal and colleagues from Weill Cornell Medical College, New York, NY, coauthored the article entitled “Anti-Phospho-Tau Gene Therapy for Chronic Traumatic Encephalopathy.”

There is currently no treatment for CTE, which is caused by repeated trauma to the central nervous system (CNS), such as that suffered by soldiers, athletes in contact sports, and in accident-related trauma.

Inflammation results in the accumulation of hyperphosphorylated forms of Tau protein (pTau). Crystal et al. developed an adeno-associated virus (AAV) vector to deliver an anti-pTau antibody to the (CNS).

They showed that direct delivery of the AAVrh.10anti-pTau directly into the hippocampus of brain-injured mice was associated with a significant reduction in pTau levels across the CNS. They propose that doses could be scaled up and this strategy could be effective in humans as well.

They showed that direct delivery of the AAVrh.10anti-pTau directly into the hippocampus of brain-injured mice was associated with a significant reduction in pTau levels across the CNS.

“CTE is much more prevalent than was initially realized, and there is currently no therapy available,” says Editor-in-Chief Terence R. Flotte, MD, Celia and Isaac Haidak Professor of Medical Education and Dean, Provost, and Executive Deputy Chancellor, University of Massachusetts Medical School, Worcester, MA. “This new work from the Crystal laboratory is potentially ground-breaking as a means to remove the offending Tau phoshoprotein.”

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disease caused by repetitive trauma to the central nervous system (CNS).1–4 Clinically, CTE is associated with behavioral and mood changes, including impulsivity, violence, depression, and irritability, with eventual cognitive and memory impairment.1,2,5 

Originally identified in boxers exhibiting “punch drunk syndrome,”6 CTE occurs in military personnel following traumatic brain injury (TBI), in civilians following accident-related CNS trauma, and a range of contact sport athletes, including football, hockey, soccer, boxing, and rugby players.7–12 TBI is a significant, underrecognized public health threat.13

While professional football players and military personnel have received the most attention,14–16 2.5 million people in the United States sustain TBI every year, with related health care costs estimated to be $80 billion annually.17–19 

There are no accurate estimates of the proportion of TBI cases who develop CTE, but as more attention is focused on the risk, the numbers of identified cases are increasing.4 

CTE is common in military personnel exposed to blast injury.20–22 Up to 2 million soldiers (20% of returning service members) deployed to Iraq and Afghanistan have experienced some TBI and are at risk for CTE.22,23

Biologically, CTE is a CNS tauopathy characterized by pathologic hyperphosphorylation of the microtubule-associated Tau, coded by a single gene on chromosome 17.1,24 The pathogenesis of CTE starts with repetitive CNS trauma initiating chronic inflammation that, in turn, mediates the development of hyperphosphorylation of protein Tau (pTau), resulting in the generation of neurofibrillary Tau tangles, causing progressive loss of neurons and the clinical symptoms of CTE.1,5,24–26 

Whereas Aβ pathology is upstream and appears to initiate Tau pathology in the Alzheimer’s mouse model, in CTE, Tau pathology appears to be independent of CTE and thus a distinct mechanism from that of age-related neurodegenerative disease.27–29

 In humans, CTE Tau pathology also has a distinctly different distribution in the brain than that found in Alzheimer’s disease.30

At present, there is no therapy for CTE.31,32 Systemic anti-pTau antibody therapy has been successful in treating a murine model of CTE,33,34 but this strategy is unlikely to be successful in humans, as has been found with systemic administration of anti-pTau in clinical studies of Alzheimer’s disease35–37; the blood/brain barrier limits the amount of systemically administered antibodies reaching the brain to <0.5% of the administered dose.38 

To circumvent the blood/brain barrier, we hypothesized that direct CNS administration of an adeno-associated virus (AAV) gene transfer vector coding for an anti-pTau antibody would mediate expression of the anti-pTau antibody within the brain, leading to suppression of the accumulation of pTau following TBI.

To test this hypothesis, we used an AAVrh.10 serotype gene transfer vector because there is low anti-AAVrh.10 seroprevalence in humans,39 AAVrh.10 mediates high expression of transgenes in neurons in experimental animal models,40–43 and AAVrh.10 vectors have been used safely in clinical trials to deliver the therapeutic genes to the CNS of children with mucopolysaccharidosis IIIB and metachromatic leukodystrophy.44,45 

To evaluate an AAVrh.10 anti-Tau-based therapy, we developed a murine repetitive TBI model that is mechanistically unlike the age-related degenerative disease models. The data with this model demonstrate that direct CNS administration of AAVrh.10 vectors coding for anti-pTau antibodies can be used to genetically modify the CNS to persistently secrete an anti-phospho-tau antibody to suppress the progression and spread of pTau, suggesting a novel strategy to treat CTE.

Mary Ann Liebert Inc
Media Contacts:
Kathryn Ryan – Mary Ann Liebert Inc

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.


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