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)
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 Citing these two individuals and two other unpublished, fruitless case studies, Benito-León comfortably concluded that quinacrine and chlorpromazine are not suitable for treating human prion diseases.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)
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.
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.
For the full list of references please see: