Treatment & Management

If FFI was completely treatable it would not be called FATAL familial insomnia. There is no ‘cure’ for FFI, but there are some avenues for management. Korth & associates (2001) set out to find an effective treatment for prion diseases by treating scrapie prion protein (PrPSc) infected neuroblastoma cells (ScN2a) with various drugs and recording the inhibition and/or clearance of PrPSc formation. The authors screened tricyclic acridine and phenothiazine derivatives that were known to cross the blood brain barrier (BBB) and interact with the central nervous system (CNS). Specifically, chlorpromazine and quinacrine were used and found to inhibit PrPSc formation and possibly enhance clearance from cells. Chlorpromazine has been used as an anti-psychotic for about 50 years and quinacrine has been used for over 60 years as an antimalarial agent. These two molecules were suggested for immediate treatment because their chronic use is well tolerated by the human body. In this same study, the authors stated that statins inhibit PrPSc formation due to their propensity to develop in cholesterol rich environments. Unfortunately, the level of cholesterol inhibition required is not feasible in animals. (Korth et. al. 2001)

Figure 1. Chemical structure of chlorpromazine. (Generated via ChemDraw)
Figure 1. Chemical structure of chlorpromazine. (Generated via ChemDraw)
Figure 2. Chemical structure of quinacrine. (Generated via ChemDraw)
Figure 2. Chemical structure of quinacrine. (Generated via ChemDraw)

To follow up with Korth’s work, a case study of two individuals, inflicted with FFI, reported on a combination therapy of quinacrine and chlorpromazine. (Benito-León 2004) Combination therapy was used on both patients, and quinacrine and chlorpromazine were administered orally and daily at dosages of 100-1000 mg and 100-600 mg, respectively. Side effects were observed with both drugs: psoriasis vulgaris and psychosis were associated with quinacrine, while chlorpromazine was primarily responsible for orthostatic hypotension. Citing these two individuals and two other unpublished, fruitless case studies, Benito-León comfortably concluded that quinacrine and chlorpromazine are not suitable for treating human prion diseases. (2004)

After striking out with quinacrine and chlorpromazine, physicians needed to look elsewhere for treating FFI. Similarly, individuals inflicted with major depressive disorder (MDD) also have difficulty sleeping. Agomelatine is an antidepressant that acts as an agonist to melatonergic MT1&2 receptors, as well as an antagonist at serotonergic 5-HT2C receptors. Agomelatine was found to be effective advancing sleep onset, redistributing SWS and increasing slow-wave activity without suppressing REM sleep. Agomelatine is preferable to other sleep-promoting agents because it actually improves daytime alertness, as opposed to promoting daytime sleepiness. (Salva et. al. 2007)

Agomelatine was found to be effective in a case study. (Fröbose et. al. 2012)

Figure 3. Chemical structure of agomelatine. (Generated via ChemDraw)
Figure 3. Chemical structure of agomelatine. (Generated via ChemDraw)

A middle-aged woman received 25 mg of agomelatine per day, which improved her overall quality of sleep by increasing SWS capabilities and decreasing awakening during sleep periods. This was clinically stated to mean that she was less restless during nighttime and more active during daytime, which nicely reinforces the discussion of agomelatine by Salva & associates (2007). The results herein were significant to a degree, but have only been shown in this patient, who was also taking valproate for hypertension. Valproate is not typically considered a sleep-promoting agent, but it has been found to increase stage 3 and stage 4 of non-rapid-eye-movement (NREM) sleep in patients with restless legs syndrome. To this extent, the combination of medication may have altered the pure effects of agomelatine. Although an increase in sleep by agomelatine may have contributed to lessening her symptoms, the patient still died within 10 months after onset of the disease.

Figure 3. (a) Five months after onset of FFI. (b) After the second night of agomelatine treatment. (c) after three months of agomelatine treatment. Note increased sleep efficiency. (Fröbose et. al. 2012)
Figure 4. (a) Five months after onset of FFI. (b) After the second night of agomelatine treatment. (c) after three months of agomelatine treatment. Note increased sleep efficiency. (Fröbose et. al. 2012)

In the past, mice models of prion diseases have only been able to mimic the acquired kind. Acquired disease is created by injecting the infectious protein into the mouse and allowing its dissemination to lead to the disease state. Unfortunately, the acquired disease model is not indicative of the sporadic onset and incomplete penetrance inheritance pattern. Jackson & acquaintances (2013) were able to create a knock-in mouse with the single significant amino acid substitution (D178N) of the PRNP gene and breed the line for multiple generations. The onset of the disease was similar to humans in that it occurred around middle age and was spontaneous. Furthermore, the findings were confirmed by observing that the thalamus was most disturbed in their FFI models, while the hippocampus was the target site of infection in the Creutzfeldt-Jakob Disease models. Often times mouse models will overexpress proteins causing a disease state, which complicates analysis due to uncertainty in associating disease characteristics with the malady or the overexpression of protein. The establishment of a reliable model is significant because FFI is such a rare infliction and the window between onset and death is very short in humans (18 months on average). A model organism not only allows for observations of the disease state, but can also help us hone in on viable drug treatments that can be utilized when an individual is found with FFI.

To continue:

What’s Up Next with FFI

Return to:

General Overview

The History and Metabolic Context of FFI

The Genetic and Biomolecular Basis for FFI

For the full list of references please see:

Annotated Bibliography

2 Replies to “Treatment & Management”

  1. Hi Ryan,

    Good job with this disease! I have a few questions, but I was firstly interested in the treatment with quinacrine and chlorpromazine, which both inhibit PrPSc formation. If PrPSc really is the root cause of this disease, then removing these misfolded aggregate proteins seems like a really promising treatment that should reduce symptoms. Is it known/do you have any hypothesis as to why this treatment method was not as effective as expected?

    This case study of quinacrine and chlorpromazine only explored this treatment in a few patients, so do you think it is possible that this sample size was simply too small to observe the real effects? It could be possible that the treatment did not improve the condition of these particular patients, but still could potentially improve the lives of other patients. Also, you noted that the prevalence of many side effects helped the researchers decide that this combination treatment was not effective. However, if the disease is ultimately fatal, wouldn’t some side-effects be a fair trade-off for living a longer life, especially if these side effects could be controlled using other medications?

    I was also interested in the other combination treatment method, agomelatine and valproate, which promoted SWS sleep. You mentioned on a different page that SWS is the most important and restorative phase of the sleep cycle, so it seems that this medication should be highly effective. While the patient did experience increased SWS sleep, the lifespan of the patient did not increase. If many of the problems with FFI are related to the loss of NREM (and SWS) sleep, why do you think this medication does not increase lifespan, if only by a little bit? You mentioned that a lack of NREM sleep is related to aging, and is similar to “hyper-aging,” so wouldn’t increasing the amount of NREM sleep via agomelatine slow down this aging process?

    Finally, I also noticed that you did not mention anything about medicines that are commonly used to treat sleep disturbances, such as Ambien or Lunesta. These medications are known to increase the ability to fall asleep and stay asleep, so do you think they could also be useful for FFI patients? Have there been any clinical trials to show the potential effectiveness of this treatment?

    1. Hey Mike, these are some really great questions! I’ll start from the top. All I can say for the ineffectiveness of quinacrine & chlorpromazine treatment is that we went from in vitro to in vivo. You know as well as I that that transition is unpredictable. Mice to humans doesn’t correlate well and sometimes even monkeys to human isn’t translatable. While the treatment was backed up by strong bench top work, FFI is a mysterious and unpredictable disease.

      Many speculate that the loss of SWS promotes some of the most distressing symptoms. This is not to say that loss of SWS kills you. While restoration of SWS may function to regulate metabolism and psychoses, scrapie prion proteins are still neurotoxic to the thalamus and related regions of the brain. The prion is more deadly than the loss of SWS, so even if a treatment could induce SWS, the patient is still able to die as quickly.

      Lots of what I have discussed are case studies, which seems to be our best glimpse into the disease state because until recently there has not been a suitable model organism and FFI is so rare. I think that the efficacy of agomelatine can be called into question as strongly as the failures of quinacrine and chlorpromazine. These are one or two individuals at a time and we must account for variability in any form of treatment, in that it will work on some people and not on others. However, because the disease is so deadly we shouldn’t be afraid to try them out again and see if they work at least a portion of the time. Saving one life is better than saving none.

      In my research I did not come across Ambien or Lunesta treatments. Most of what I found was failed trials and I sort of ignored those because misery isn’t fun to talk about. Often times with publications, we hear about successes over failures. If I wasn’t able to find anything on other sleep promoting agents I’m going to have to say that they were duds.

      Thanks again for your comment, I appreciate the effort you put into this discussion!

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