An Interview With Dr. Emmanuel Mignot

Germantown, TN - August 29, 2000

The results of a new narcolepsy study from the Stanford Center for Narcolepsy Research will be published in the September 1 issue of Nature Medicine. This study proves that the lack of a brain protein - a peptide called hypocretin - is the cause of narcolepsy in most humans. Dr. Emmanuel Mignot, MD, PhD, a world-renowned researcher in the field of narcolepsy research, heads the Stanford team.

Talk About Sleep contacted Dr. Mignot to discuss the results of the study.

TalkAboutSleep: Dr. Mignot, for persons who have narcolepsy, these study results seem very exciting. Can you explain a bit more about your findings?

Dr. Mignot: This work extends on our CSF (cerebrospinal fluid) finding published in Lancet last January. It is also the direct consequence of finding the canine narcolepsy gene last year. In the Lancet study we had found that patients with narcolepsy lacked the hypocretin-1 peptide in their cerebrospinal fluid; in the Nature Medicine report, we are now showing that both the hypocretin-1 and hypocretin-2 peptides are missing in the brain of narcoleptic patients.

In the Nature Medicine report, we also show that most patients do not have abnormal hypocretin gene mutations causing narcolepsy. This explains why narcolepsy in people is not genetic to the same extent it is in dogs or mice. In fact, we found that only one patient had a mutation destroying the hypocretin gene. This patient is a very unusual case and started severe narcolepsy-cataplexy at 6 months of age. This person clearly has a different and very rare form of narcolepsy.

TalkAboutSleep: Does this new research point to better treatments for narcolepsy?

Dr. Mignot: The CSF and brain findings suggest that replacing the hypocretin peptide will be the most logical and effective treatment for narcolepsy, the same way insulin is for patients with diabetes mellitus. Unfortunately however, the hypocretin peptide is largely broken down before reaching the brain if taken orally or administered intravenously.

Drug companies thus need to develop a drug that can mimic the effect of the hypocretin but have a different chemical structure. The eventual hypocretin drugs should be far superior to the current older treatments (antidepressants, stimulants) because they would treat (or act at ) the cause of the disease and not just treat the symptoms. Giving these drugs would really replace what is missing! It may, however, take several years until drug companies actually develop these drugs.

TalkAboutSleep: What are the long-term implications for narcolepsy research?

Dr. Mignot: The Nature Medicine and Neuron reports are important because they suggest the cells that normally secrete the hypocretin peptide have been destroyed. We may thus be able to treat patients by replacing the hypocretin molecule with a drug, but probably this will not cure narcolepsy. You would still need to take the drug.

Longer term, we need to figure out what is killing these cells and try to prevent this from happening. Also, in the more distant future, we may want to transplant hypocretin-secreting cells in the brain to replace the missing hypocretin cells. If the graft holds, this could be a cure. Similar work is now ongoing for Parkinson disease (to replace dopamine-producing cells) or for insulin dependent diabetes mellitus (to replace insulin-producing cells).

TalkAboutSleep: Are there other research issues that need to be looked at?

Dr. Mignot: These findings raise a lot of other important questions. For example:

What is destroying the brain hypocretin cells? Based on the fact narcolepsy is associated with HLA, we feel the immune system might be involved. We have to find out how it works, and if confirmed, we have to find a way to stop the autoimmune process before it is too late. Prevention and finding a way to catch narcolepsy early may thus be key, for example by measuring hypocretin levels early in subjects at risk or finding a way to measure the autoimmune process.

We also need to use the finding of low hypocretins to improve diagnosis. Now we have to measure hypocretins in the cerebrospinal fluid; hopefully one day we will be able to use brain imaging, or to measure hypocretins in blood levels.

What is the role of hypocretins in patients without cataplexy? All our results are in patients with cataplexy.

What is the cause of narcolepsy in subjects with normal hypocretin levels or with strong tendency to have narcolepsy running in their family? We look at the hypocretin genes of many cases who had a strong family history and found no mutations. Other genes and systems must be involved.

What is the role of hypocretins in regulating normal sleep?

Some results suggest a role of hypocretins in regulating appetite and general body energy. We need to better understand the connection between sleep, energy metabolism, feeding and hypocretins in narcolepsy.

TalkAboutSleep: Thank you, Dr. Mignot, for your comments. We look forward to more breakthroughs from your team in the future.