Oligonucleotide-Based Therapy for Frontotemporal Degeneration
Abstract
Military personnel face a unique set of risk factors such as the use of improvised explosive devices and other explosives in recent military conflicts. In the recent wars in Iraq and Afghanistan, traumatic brain injury (TBI) has been one of the most common types of injury sustained by Soldiers and military personnel. Persistent and multiple blast-related TBI can lead to behavioral, neurodegeneration, and cognitive effects. One common form of this deleterious outcome is frontotemporal degeneration (FTD), which is a progressive neurodegenerative process marked by atrophy of the frontal and temporal lobes, a common form of dementia affecting behavior, cognition, and language. It is the most common cause of dementia for people under age 60, affecting more than 50,000 Americans. At present, there are no therapeutic interventions that prevent frontotemporal dementia or slow its progression. The available symptomatic treatments have limited efficacy and are often associated with significant side effects. Thus, there is a critical need to identify potential disease-modifying treatments that provide a higher quality of life for individuals affected with FTD. Frontotemporal dementia with parkinsonism-17 (FTDP-17), is one of the major degenerative dementias caused by mutations in the tau gene, which encodes a microtubule-binding protein. Tau promotes the stabilization of microtubules and provides structural support to the neurons. In pathological conditions, the mutation in the tau gene disrupts the normal structure and function of tau and facilitates tau aggregation to form intraneuronal neurofibrillary tangles within neurons and other brain cells. Given that accumulation of pathological tau directly correlates with cognitive impairment, tau-based therapy that suppresses pathological tau formation and aggregation is a potentially impactful approach to counter FTD. DNAzyme (DNZ) is a relatively novel type of gene therapy and offers a potentially superior method to reduce protein expression because it specifically cleaves targeted RNA, it is easier to control its dosing, and it does not show off-target effects. DNZs are an excellent choice to target FTD because they can be designed to selectively eliminate the mutant tau mRNA without any adverse effect, and they cross the blood-brain barrier, thus avoiding the need for direct central nervous system injection. We have designed a novel, brain penetrant, and specific anti-human tau DNAZyme (TDNZ) that selectively targets mutant forms of tau. The goal of this application is to determine the therapeutic potential of anti-Tau DNZ in reducing pathological tau burden, neurodegeneration, and behavioral deficits (cognitive and motor) in rTg4510 mice, a well-characterized mouse model linked with FTD. The rationale of this study is that a medical intervention that selectively reduces the amount of RNA (the messenger molecule used during gene expression) coming from the mutant pathologic allele is predicted to reduce the severity of symptoms. The objective of Aim 1 of this study is to determine the effective dose and length of DNAzyme treatment to obtain therapeutic benefits. The objective of Aim 2 is to investigate the therapeutic benefits of DNAzyme for the amelioration of cognitive function, and neurodegeneration in a mouse model of FTD. The proposed experiments will utilize genetically engineered mice that harbor mutations known to cause FTD in humans. Any observed benefits of TDNZ therapy in a mouse model of FTD will form the basis for translational testing in human cases.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310043
Entities
People
- Mohammad Moshahid Khan
Organizations
- United States Army
- University of Tennessee Health Science Center