2023 Tau Pipeline Enabling Program (T-PEP)
Late-Stage Development of a PIKFYVE Antisense Oligonucleotide Treatment for FTD
Can inhibiting the activity of a certain protein prevent brain cell damage and loss of brain function in frontotemporal dementia?
Peter Sazani, Ph.D.
AcuraStem Inc.
Monrovia, CA - United States
Background
Frontotemporal dementia (FTD) refers to a group of degenerative diseases characterized by progressive nerve cell loss in the brain’s frontal lobes (areas behind your forehead) or temporal lobes (regions behind your ears). Individuals with FTD can experience early onset of dementia (occurring by one's 40s or 50s), along with changes in personality, emotions, and difficulty in comprehending language. Developing FTD treatments has been challenging because different forms of FTDs involve different symptoms and different genetic changes. As a result, researchers are looking for common biological mechanisms that can be targeted in therapies for multiple FTD varieties.
Research indicates that two proteins, abnormal forms of tau and TAR DNA-binding protein 43 (TDP-43), each occur in about half of the individuals with FTD. Both proteins accumulate into clumps in the brain and may promote nerve cell damage in FTD. In initial studies, Dr. Peter Sazani and colleagues examined whether a protein called PIKFYVE, which is involved in autophagy (the clearing of unwanted molecules from the body), may also be linked to brain changes in frontotemporal dementia. They found that by reducing the activity of PIKFYVE, they could reduce tau- and TDP-43-related damage in (1) nerve cells engineered from the cells of people with FTD and (2) brain cells of mice genetically engineered to develop TDP-43. This treatment also restored the animals’ brain function.
Research Plan
Dr. Sazani and colleagues will now conduct a larger study to verify and expand on their earlier findings. They will examine a genetic treatment that inhibits PIKFYVE activity. Their approach uses small fragments of DNA which can target and reduce production of specific genes in cells. First, they will assess how well their technique reduces PIKFYVE activity, and whether the treatment impacts levels of other proteins involved in autophagy and FTD. If this is successful, the investigators will then develop and test an additional compound that can be used safely and effectively in future human clinical trials of PIKFYVE therapy.
Impact
The results of this project could refine our understanding of how changes in the body’s ability to clear unwanted proteins may lead to FTD and other brain diseases. They could also lead to a promising therapy for people who have FTD or are at risk for the disease.
The Tau Pipeline Enabling Program (T-PEP) is jointly funded by the Alzheimer's Association and Rainwater Charitable Foundation.