Dying for sleep: Could there be a cure for Fatal Familial Insomnia?

On Rare Disease Day, we talk to a researcher who is in the middle of trialing a cure to deadly hereditary disease Fatal Familial Insomnia.

Globally, there are less than 200 sufferers of Fatal Familial Insomnia (FFI). Tremors, constipation, hallucinations, dementia and gait dysfunctions (all symptoms of FFI) pale in comparison to the insomnia that robs sufferers of all sleep for as long as a few months before they pass away.

However, there could be hope on the horizon for those carrying the FFI genotype: Gianluigi Forloni, the Head of the Neuroscience Department at the Mario Negri Institute in Milan, is currently testing a drug that he thinks could prevent the disease from manifesting. We talk to him to find out more.

ResearchGate: What drew you to study FFI?

Gianluigi Forloni: From the beginning of the nineties we were interested in learning more about the mechanism of prion diseases, considering them as possible models to clarify the development of other protein misfolding disorders that are much more complex (such as Alzheimer’s). The mad cow crisis in that time period also increased interest in these mysterious diseases. During our studies, we characterized new experimental models and tested possible therapeutic approaches to prion diseases. However, it was only ten years later that we had the chance to meet Dr Roiter from Treviso, who was the first person to come across some FFI cases. It was through him that we became interested in using the research we had already done to work on a cure for FFI, which is also a prion disease.

RG: Can you explain what happens in the final stage of the disease? How long does this stage generally last and do sufferers sleep at all in this stage?

Forloni: In the final stage of the disease, patients suffer a progressively greater loss of total sleep time, worsening ataxia (a lack of muscle control of voluntary movements such as walking and speech), and more profound confusion, leading ultimately to an awake but stuporous state as death approaches. It varies from sufferer to sufferer, but in general the final stage of the disease usually takes months or weeks.

RG: Has it been challenging to receive support to research a disease that only effects a very small cohort of people?

Forloni: The Italian charity Telethon, which is devoted to studying genetic disorders, provided funding for our research, as our proposal for a clinical trial was positively evaluated for its scientific content and for the extraordinary opportunity it offered to support these neglected patients.

RG: You are currently three years into a 10-year trial testing the drug Doxy hydrochloride on sufferers of FFI. Can you explain how you set up this trial?

Forloni: The trial we are conducting involves members of an Italian family that carries the FFI gene. Based on historical data, we defined the age that carriers of the gene are most at risk of developing FFI and identified ten subjects within this age bracket that we would give treatment to for the next ten years. Our statistical analysis indicates that the survival of at least one third of these subjects would demonstrate the efficacy of our drug, doxycycline, to interfere with the development of the disease.

RG: Do you have any results to report so far from this trial?

Forloni: The second follow-up of the trial is ongoing, but so far no clinical or instrumental evidence associated with FFI has appeared in any of the subjects.

RG: Running the trial on a family with FFI in their history involved significant ethical considerations, as many did not want to know if they carried the genetic mutation. How did you incorporate these considerations into your trial?

Forloni: When we proposed the trial to the family members they largely gave their consent, under the condition that they would not to be made aware of their genotype. For this reason, we recruited all members of the family who were around the same age, regardless of their genotype. We give the carriers doxycycline, while non-carriers receive a placebo, and all the medical operators treating the family are blind to the genotypes of the participants.

Additionally, the participants requested psychological support during the study and now have a specialized team following them throughout the whole study. This support is needed in case FFI symptoms begin to appear in any of the subjects, as this could result in other participants quitting the study. As the appearance of FFI in up to three of the subjects does not automatically mean that the treatment has not been effective, it is extremely important that they continue the study so that we can accurately judge the efficacy of doxycycline.

We have also established an independent "Data Safety Monitoring Board", which includes a neurologist, a psychiatrist, an expert in clinical trials, a statistician and an expert in ethical problems to help us ensure the correct development of the study.

Featured image courtesy of Martino Sabia.