In MS, the immune system damages the insulating coating on nerve cells, known as myelin. The human body has a limited and often insufficient ability to repair myelin, in a process known as remyelination. While there are many MS treatments available that target the immune system, there are no treatments available that target remyelination. Repairing myelin is thought to be important as it may reverse some symptoms of MS and could provide protection against further damage to the nerves. This is believed to be important in treating progressive MS, however, identifying new drugs to treat progressive MS is difficult because it is still poorly understood and there aren’t any models that represent the entirety of the disease.
More recently, drug repurposing has garnered attention for the treatment of currently untreatable clinical processes, such as myelin damage in MS. This involves finding new uses for approved drugs or drugs that are already being investigated for other diseases. It is becoming quite popular because these drugs have already been clinically tested for safety, making the whole clinical trial process substantially quicker compared to completely new treatment options. Therefore, drug repurposing is an attractive avenue for discovering new progressive MS therapies.
As part of the BRAVEinMS platform of the International Progressive MS Research Alliance researchers from Germany, Canada and Australia aimed to identify approved drugs or drugs that are currently being investigated for other conditions that could boost remyelination and potentially treat progressive MS. Published in EBioMedicine, they performed a drug screen using the changing location of a protein called p57kip2 in myelin-producing cells as a marker of whether the drug can increase myelination. When this protein is in the nucleus (where genetic material such as chromosomes are located), it blocks myelin-producing cells forming myelin. When the protein p57kip2 is out of the nucleus, myelin-producing cells can then form myelin. This occurs very early in the myelin production process and is a unique way of performing a drug screen – most initial screens for progressive MS look at the level of myelin protein, which focuses on a much later process of myelin production.
Those drugs that moved the protein p57kip2 out of the nucleus were then shortlisted. Following this, the researchers narrowed down the list of drugs further by looking at the level of myelin protein and the ability of cells to myelinate and remyelinate after treatment with these drugs.
The researchers initially screened 1,280 drugs – most of these drugs were predicted to penetrate the blood brain barrier (BBB), a border that prevents many substances from reaching the brain, such as toxins. By penetrating the BBB, these drugs could potentially act directly on the brain and spinal cord to prevent further damage to the myelin. Of the 1,280 drugs screened, 21 drugs were capable of moving the protein p57kip2 out of the nucleus, suggesting that they may promote myelin production.
Next, the researchers tried to confirm the findings by looking at the amount of a protein called myelin basic protein (MBP) in the cells after treatment with each drug. This protein is part of the myelin sheath and is believed to be important in myelination. They found four drugs that increased the level of this protein, suggesting that these drugs may promote myelin production. In fact, the researchers confirmed that three of these drugs did significantly promote myelin-producing cells to mature without much toxic effect – these drugs were danazole, parbendazole and methiazole, which have been linked to anti-viral, anti-microbial and anti-cancer activities.
The researchers found that all three drugs had the ability to promote myelination in a model of brain development. For the remyelination study, the researchers decided to focus on parbendazole and danazole, which haven’t been characterised as well. They found that both drugs had the ability to promote remyelination in a laboratory model of MS.
This exciting study shows that focusing on early cellular processes involved in myelin production, such as the movement of the protein p57kip2 in the cells, is a powerful way to identify drugs that promote the production of myelin. The study reveals that parbendazole and danazole may be potential therapeutic candidates for treatment of progressive MS, although further research will be required to confirm this.
As a managing member of the International Progressive MS Alliance, MS Australia is invested in international research into myelin repair for progressive MS. It is hoped that this research will pave the way for effective therapies promoting myelin repair in progressive MS.