Late-Stage Development of a PIKFYVE Antisense Oligonucleotide Treatment for FTD
Abstract
Frontotemporal dementia (FTD) is a complex disease that results from many diverse causes. While there are currently no drugs that slow the progression of FTD, most of the new promising therapeutic strategies are focused narrowly on modifying the specific genetic mutations known to cause disease, however, these treatments won t work for the vast majority (>70%) of patients for whom the genetic cause of their FTD has no known genetic cause. Therefore, AcuraStem s focus has been to develop treatments that can work for all FTD patients, including those for whom the genetic factors driving their disease have yet to be discovered -- a large population with urgent unmet need. AcuraStem s technology platform utilizes cellular reprogramming technology to create living neurons from FTD patients with both sporadic and known genetic causes of disease. We used this platform to scan in an unbiased fashion for therapeutic approaches that could help the diseased patient neurons function more like healthier neurons from healthy donors. We have tested many FTD patients with different familial and sporadic forms of FTD, and there are a lot of differences between patients in what works. We found that reducing the functionality of a protein called PIKFYVE is the most effective way to help neurons from most of the FTD patients. One of the most common features of neurodegenerative diseases is that the neurons in the brain have trouble clearing aggregated and misfolded proteins, and this ultimately results in the death of the neurons (neurodegeneration). It turns out that by reducing the function of PIKFYVE, you trigger the cells to engage an alternative method to clear these clogged proteins. This alternative method is highly innovative and has yet to be tested in the clinic for neurodegenerative diseases. A small molecule that reduces the function of PIKFYVE has been tested safely in the clinic for autoimmune disorders, but it is not a good drug for FTD because it does not do a good job getting past the blood brain barrier and into the central nervous system (CNS) where it needs to do its job. Furthermore, studies suggest that it may cause toxicity if you reduce levels of PIKFYVE too much outside the CNS. Antisense oligonucleotides (ASOs) are a type of gene targeted therapy that can be used to reduce the function of PIKFYVE by suppressing the PIKFYVE gene. ASOs are injected into the spine (and CNS) similar to an epidural block given during childbirth and therefore they don t have to be engineered to cross the blood brain barrier, and they are relatively restricted to the CNS, which may cause less toxicity than a small molecule that distributes throughout the body. The half-life of ASOs is typically long and patients do not need to have an injection more than once a month (sometimes once every 3 months). In our internal studies, we have benchmarked the efficacy of our own best PIKFYVE small molecule inhibitor and ASO and found that the ASOs are much more effective in mouse models. We believe this is because the ASO achieves a steady reduction in PIKFYVE levels over 1 month, as compared to the small molecule, which reduces PIKFYVE transiently on a daily basis. Thus we are advancing an ASO drug candidate AS-202 in late stage development as a treatment for FTD. The objective of this proposal is to advance AS-202 through late stage development activities including toxicity studies in nonhuman primates (NHP), drug manufacturing and characterization, and U.S. Food and Drug Administration (FDA) approval for the investigational new drug (IND) application. All studies will be done in accordance with FDA regulations for Good Laboratory and Manufacturing Practice (GLP and GMP). At the conclusion of this project AS-202 will be ready for first-in-human studies.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311018
Entities
People
- Peter Sazani
Organizations
- United States Army