# Development of a novel gene therapy for the treatment of tauopathy

> **NIH NIH R03** · UNIVERSITY OF TENNESSEE HEALTH SCI CTR · 2022 · $308,000

## Abstract

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.

## Key facts

- **NIH application ID:** 10526133
- **Project number:** 1R03AG075597-01A1
- **Recipient organization:** UNIVERSITY OF TENNESSEE HEALTH SCI CTR
- **Principal Investigator:** Mohammad Moshahid Khan
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $308,000
- **Award type:** 1
- **Project period:** 2022-07-15 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10526133

## Citation

> US National Institutes of Health, RePORTER application 10526133, Development of a novel gene therapy for the treatment of tauopathy (1R03AG075597-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10526133. Licensed CC0.

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