Thursday, October 29, 2020

New Treatments for Narcolepsy

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Over the past 10 years, researchers have made great advances in understanding the underlying biology of narcolepsy, and these insights are now leading to new and possibly more effective treatments for narcolepsy. Some current research programs to develop innovative treatments are described below.

Increasing histamine signaling
Most current medications for narcolepsy improve alertness by increasing the amount of dopamine in the brain, but histamine is another brain chemical that is very effective for improving alertness. Normally, histamine levels are kept low by signaling through the histamine H3 receptor. Pharmaceutical companies are developing several compounds that block the H3 receptor, permitting histamine levels to rise. H3 receptors are also found on other types of neurons, and these new drugs may also increase levels of dopamine and other wake-promotingneurotransmitters. These compounds (pitolisant, for example) have been effective in people and mice with narcolepsy,1 and if approved for clinical use, they may become helpful approaches in the next several years.

Restoring hypocretin signaling
Narcolepsy with cataplexy is caused by a loss of the brain cells that produce hypocretin. Research in animal models of narcolepsy suggests that excellent improvements in all symptoms could be obtained by restoring hypocretin signaling. However, this is a challenge, as the hypocretins are relatively large molecules that cannot easily get into the brain. Some laboratories are working on methods to get hypocretins into the brain or designing drugs that can mimic the effects of hypocretins. As yet, the search has been challenging.

Another method would be to restore hypocretin production in the brain using gene therapy. For example, other cells in the brain could be coaxed to produce hypocretins to make up for the loss of the normal hypocretin-producing neurons. This approach has been very effective in reducing cataplexy and sleepiness in experiments using mice with narcolepsy.2, 3

A third approach would be to reintroduce new hypocretin-producing cells into the brain using stem cell techniques. This method would take an individual’s own cells and convert them into hypocretin-producing cells in the lab. In theory, those cells could then be placed into the brain to restore hypocretin signaling and improve the symptoms of narcolepsy.

Treatments for narcolepsy based on gene therapy or stem cells are exciting, as they could produce lasting improvements without the side effects of current medications. Much more research is needed before these can be developed into safe and effective treatments for people with narcolepsy.

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