Anti-Phospho-Tau Gene Therapy for Chronic Traumatic Encephalopathy

Abstract

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative disorder caused by repetitive trauma to the central nervous system (CNS) suffered by soldiers, contact sport athletes, and civilians following accident-related trauma. CTE is a CNS tauopathy, with trauma-induced inflammation leading to accumulation of hyperphosphorylated forms of the microtubule-binding protein Tau (pTau), resulting in neurofibrillary tangles and progressive loss of neurons. At present, there are no therapies to treat CTE. We hypothesized that direct CNS administration of an adeno-associated virus (AAV) vector coding for an anti-pTau antibody would generate sufficient levels of anti-pTau in the CNS to suppress pTau accumulation thus interrupting the pathogenic process. Using a serotype AAVrh.10 gene transfer vector coding for a monoclonal antibody directed against pTau, we demonstrate the feasibility of this strategy in a murine CTE model in which pTau accumulation was elicited by repeated traumatic brain injury (TBI) using a closed cortical impact procedure over 5 days. Direct delivery of AAVrh.10 expression vectors coding for either of the two different anti-pTau antibodies to the hippocampus of these TBI mice significantly reduced pTau levels across the CNS. Using doses that can be safely scaled to humans, the data demonstrate that CNS administration of AAVrh.10anti-pTau is effective, providing a new strategy to interrupt the CTE consequences of TBI.

Effects of antifibrinolytics on systemic and cerebral inflammation after traumatic brain injury

“…Some of the cerebral inflammatory mediators shown to be important in modulating neuroinflammation after TBI include TNF-α, INF-γ, IL-1β, IL-6, and IL-10 28 . Our study provides evidence that TXA administration may blunt the post-TBI cerebral cytokine release of IL-6, TNF-α and MCP-1 with a notable reduction in 30-day p-tau accumulation, which is a known marker of chronic traumatic encephalopathy 30 . Hiramoto et al 31 provided evidence that TXA and aprotonin administration ameliorated the aging-induced decline in memory and learning ability with notable reductions in cerebral IL-1β and TNF-α in TXA administered mice.…”

“…28 Our study provides evidence that TXA administration may blunt the post-TBI cerebral cytokine release of IL-6, TNF-α and MCP-1 with a notable reduction in 30-day p-tau accumulation, which is a known marker of chronic traumatic encephalopathy. 30 Hiramoto et al 31 provided evidence that TXA and aprotonin administration ameliorated the aginginduced decline in memory and learning ability with notable reductions in cerebral IL-1β and TNF-α in TXA administered mice. Although this study was not performed on TBI subjects, it did demonstrate that administration of antifibrinolytic medications may alter cerebral cytokine profiles.…”

Chronic Traumatic Encephalopathy: Update on Current Clinical Diagnosis and Management

“…Immunotherapy by the use of monoclonal antibodies has also been studied in preclinical studies investigating tauopathies. Notably, a recent study demonstrated that the delivery of an adeno-associated virus (AAV) vector coding for an anti-pTau antibody reduced CNS pTau levels in rodent models of repeated traumatic brain injury [84]. An in-vitro study demonstrated that several tau antibodies successfully prevented neuronal tau uptake.…”

Chronic traumatic encephalopathy – current state of knowledge

“…Expression of the gene should provide a sufficient level of antibodies that would prevent its accumulation. A research conducted on mice showed that delivery of AAVrh.10 expression vectors that encoded an antibody against tau protein to the hippocampus resulted in a significant decrease of the tau protein in central nervous system [38]. It is considered that inflammatory process plays an important role in the pathogenesis of CTE.…”