Potential Possibilities of Fronto-temporal Dementia Treatment
Background
Frontotemporal dementia (FTD), is a common form of dementia that affects a person’s behavior, activity, and cognition. It typically happens when nerve cells are lost in the frontal and temporal lobes of the brain. Currently people still use treatments for AD(alziemers) patients for FTD because of limited research, with the outcome of mixed results. The FDA (US Food and Drug Association) has no approved therapies for FTD, and there are currently no treatments to change or stop the course of FTD progression.
Objective
This study’s objective is to provide more options for people to look into to help treat FTD. This is because there are no current FTD treatments, all being used for FTD are made for psychiatric disorders and AD (alzeimers) due to the two diseases having overlapping symptoms. The testing has been limited so they have to use AD treatments despite FTD patients being more vulnerable to side effects concerning motor activity, and having a higher mortality rate. Finding a treatment specific for those with FTD would benefit the patients greatly.
Study/methods
One of the first methods they tried had to do with tau. Tau is a protein, and reducing tau levels in the brain seems to help AD and FTD. Salsalate, a non-steroidal anti-inflammatory drug, seems to lower tau levels (in the mouse models this study experimented with), preserve what is needed, and improve memory deficits so it is currently being tested on human patients.
However when tau binds to microtubules, it leads to microtubule instability and may harm the tau’s function. To make up for their loss of function, the testers needed to find out how to stabilize the microtubules. The scientists tried Davunetide, a peptide suspected to improve microtubule stability. It did not give results, but the tests proved that international clinical trials in FTD are possible! They tried Paclitaxel, a chemotherapy agent, which fixes disassembly of microtubules, but it cannot go through the blood-brain barrier. They are now currently doing clinical trials for TPI-287, a synthetic compound which easily passes through the blood brain barrier.
Haploinsufficiency is what happens when one copy of a gene is deleted and the remaining copy is not good enough to preserve normal gene function , which ends up in readily measurable decreased levels of progranulin (PGRN) protein in serum and CSF (cerebrospinal fluid). Haploinsufficiency results from GRN mutation .Mutations in the GRN (Gene regulatory network) account for a good amount of FTD cases! Even though scientists are not sure yet of PGRN’s exact purpose, a readily measurable CSF and PGRN level can be used as a useful biomarker in diagnosis and to see how patients respond to treatment. Because haploinsufficiency happens to the GRN mutation patients, raising PGRN levels could be an effective therapy. Other drugs were also attempted, and some did increase PGRN expression, but could not make it past the blood brain barrier.
Results
The recent davunetide trial for PSP, (Progressive supranuclear palsy, a disease under the FTD umbrella) although unsuccessful, has proven that vast international trials for rare neurodegenerative diseases are possible.
As most of FTD cases are similar to AD, many treatment initiatives have been launched for AD recently, and can be used as models, examples for data collection, clinical trial design, and lead the way to more possibilities for FTD.
Adding to this, a number of anti-inflammatory drugs are already approved for systemic autoimmune disease, clinical trials of such agents could potentially be pursued in FTD. Biomarkers, using haploinsufficiency to our advantage, and using tau are all promising possibilities to help progress the advancement of FTD treatment.
Thanks to the Longitudinal Evaluation of Familial Frontotemporal Dementia project and Genetic FTD Initiative, more efforts to get progress in research and biomarkers for FTD are happening, which is great news for the patients.
Conclusion
New cellular and animal models are helping scientists advance towards reaching disease-modifying effects. Biomarker development is a big part of this, it would help accurately diagnose those with FTD and not similar diseases such as AD. Biomarkers would also give us more information on target engagement, and provide more experience for future clinical trials. All of the trials in this study, even if they may not have been successful, have brought more valuable experience to the table on FTD, more possibilities, and are leading towards a promising decade for therapy development for FTD and its related disorders.