Could clomipramine work against progressive forms of MS?
In a paper published in Nature Communications, they describe how they came to this conclusion after selecting 1,040 generic drugs, screening the most promising candidates in cell cultures to yield clomipramine, and testing it in mice.
Many experts believe that multiple sclerosis (MS) is a type of autoimmune disease that develops because the immune system mistakes tissue in the central nervous system — which consists of the brain and spinal cord — as a threat and attacks it.
In those with MS, the immune system attacks myelin, or the fatty layer that surrounds and protects axons. Axons are fibers that link nerve cells to one another and carry messages to and from the brain and spinal cord to other parts of the body, such as the muscles, eyes, ears, and mouth.
As myelin degrades, it exposes the axons and weakens the signals that they carry.
The symptoms of MS vary widely, with some experiencing just a few and others experiencing many, and severity can also vary. Symptoms include, but are not limited to, muscle weakness, visual disturbance, difficulty with balance and coordination, pain, numbness and prickling sensations, speech impediments, dizziness, tremors, and hearing loss.
MS can also cause depression and problems with memory, attention, concentration, thinking, and decision-making.
Official estimates suggest that around 2.5 million people worldwide have MS, including 300,000–400,000 in the United States. But new research, which is to be reviewed in 2018, claims that the number of people with MS in the U.S. is closer to 1 million.
Relapsing-remitting and progressive MS
There are two main MS types: relapsing-remitting MS (RRMS) and primary progressive MS (PPMS). People with RRMS experience unpredictable flare-ups of symptoms — such as visual impairment, numbness, or paralysis — that then subside.
Around 85 percent of people with MS have RRMS. However, in the majority of cases, after around 15–20 years, most people with RRMS develop secondary progression, in which the symptoms gradually get worse.
In PPMS, which affects around 10 percent of people with MS, the disease is progressive from the start, without any relapses.
Scientists are now discovering some key differences between RRMS and PPMS that could be important when making decisions about treatment.
"The mechanisms causing damage in progressive MS," says first study author Dr. Simon Faissner, "are not always the same as in relapsing-remitting MS. This is why the latter requires different therapeutic approaches."
For example, in PPMS, there is much less inflammation of myelin, and people with this form of MS have fewer brain lesions or plaques than people with RRMS. These differences make it difficult to diagnose and treat PPMS.
Another difference is that in RRMS, two to three times more women are affected than men, while in PPMS, the number of men and women affected is about the same. There are also other differences, including differences in age of onset and severity of symptoms.
Screening already approved drugs
There are currently many more approved treatments for the relapsing forms than the progressive forms of MS.
In their search for new drugs for progressive types of MS, the team behind the new study decided to look in the vast pool of already approved drugs, becase although they have been approved for use with other illnesses, their potential side effects are already well-documented.
A vital requirement of a drug for treating progressive MS is that it should be well-tolerated and able to cross the blood-brain barrier to enter the central nervous system safely.
Using this rationale, the team pared down the starting list of 1,040 generic candidates that they had gleaned from clinical studies to just 249.
"An advantage of generic drugs is the fact that there is ample clinical experience regarding their potential side effects. Accordingly, there is no need to perform phase I trials to study the tolerance of the drug in healthy volunteers."
Dr. Simon Faissner
In the study paper, the scientists explain that for a drug to be effective against progressive MS, it must target three drivers of the disease: damage to nerve cells caused by iron that is released; damage to mitochondria, or powerhouses of cells, caused by oxidative stress; and, finally, the activity of lymphocytes, the white blood cells that attack the myelin.
Using nerve cells grown in the laboratory, the researchers then tested the 249 candidate drugs to see how well they met the three requirements. This screening found clomipramine to be the most promising candidate.
The team then tested clomipramine in a mouse model of RMSS and found that it minimized damage to nerve cells and inflammation.
Further tests against a placebo in a mouse model of progressive MS also showed that the drug could reduce symptoms such as paralysis — as long as it was given as soon as they appeared.
Dr. Faissner, who contributed to the study while working as a visiting scholar in Calgary, is now back at Ruhr-Universität Bochum in Germany, where he intends to continue to search for new drugs for MS and to improve understanding of the progressive forms.