Development of a novel gene therapy for the treatment of tauopathy

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Tauopathies, including frontotemporal dementia and Alzheimer's disease (AD), are neurodegenerative diseases characterized by abnormal deposition of tau protein in the brains of affected individual. Currently, there is no therapeutic interventions that prevent tauopathies or slow its progression. The intensity of tau burden strongly correlates with cognitive impairment and progressive neuropathological symptoms, thus supporting the development of therapies targeting pathological tau. We have been examining an alternative approach for tauopathy gene therapy that involves the use of DNAzymes (DNZs), which cross the blood-brain barrier and have been shown to be effective in treating multiple sclerosis, cancer and atherosclerosis. DNAzymes – RNA- cleaving single-stranded DNA oligonucleotides– are a relatively novel and underutilized therapeutic molecule that can be designed to cleave mRNA transcripts to regulate the expression of protein it codes for. The advantages of DNZs over other gene therapies are their catalytic activity, leading to a better dose-response efficacy; stability and systemic delivery to all organs including brain thus, avoiding the need for direct CNS injection. DNAzymes thus represent a novel gene therapy approach that can be used to reduce levels of mRNA for disease-causing proteins. Based on above observation, we propose that DNAzymes can be designed to regulate the expression of human tau proteins by selectively targeting their mRNAs transcripts and ameliorate neurodegeneration and cognitive deficits in a mouse model of tauopathy. In our preliminary studies, we have designed a novel and specific anti-human tau DNZ (TDNZ) targeting the 1N4R transgene of human tau expressing the P301S mutation and showed that TDNZ effectively cleave human tau mRNA in vitro and in vivo. The objective of this application is to determine whether TDNZ targeting mutant human tau can prevent cognitive deficits and neuropathology characteristics of tauopathies in a preclinical mouse model of tauopathy. In Aim 1, we will determine distribution, stability and safety of TDNZ delivery as well as efficacy needed to maintain therapeutic knockdown. In Aim 2, we will assess benefit by extent of human Tau mRNA and protein knockdown in the brain, cognitive function and brain neurochemistry and pathology in PS19Tg mice. Based on the expected outcomes, these studies will help advance the development of DNZs as a disease modifying treatment for tauopathy, as well as provide foundational studies for the clinical use of DNZs in other primary tauopathies and, potentially, other neurological diseases.