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In the October 15, 2020 issue of the journal Cell, he published an article from the Motorpharmacology research group of the Institute of Biology at Eötvös Loránd University. In this, András Málnási-Csizmadia and his colleagues report in great detail on the preclinical (pre-trial) studies of the drug candidate MPH-220 developed by them.
The essence of the world-leading results is that the Hungarian-developed candidate drug effectively reduces spasmodic muscle contractions after nervous system injuries (eg, stroke), without causing side effects.
The efficacy of drugs currently on the market for this disease is low and causes significant neurological, psychiatric and circulatory side effects. MPH-220 acts directly on myosin, the protein responsible for muscle contraction, in all cases according to preclinical studies and does not cause the above adverse side effects.
My a stroke?
Stroke is a sudden stroke that, in the absence of prompt treatment, causes serious and permanent damage. In Hungary, a patient is hospitalized every 10 minutes for a stroke: according to the Hungarian Stroke Society, 30 to 32 thousand people in Hungary suffer strokes each year, of which 8 to 10 thousand die. Forty-two percent of the survivors suffer from unilateral paralysis and 22 percent cannot walk.
There are already serious drug candidates for myosin present in the myocardium, but no one has been able to target myosin in skeletal muscle in this way. This is also highlighted by one of the leading international experts in the field of research:
For me, the development of MPH-220, the next generation muscle relaxant drug candidate, is very exciting. MPH-220 is the world’s first skeletal muscle-specific drug to relieve muscle cramps in nervous system injuries or chronic low back pain that will affect nearly 10% of the population in the future. “ Says James A. Spudich, a Lasker Prize-winning professor at Stanford University. Spudich is a co-founder of three biotech pharmaceutical companies, Cytokinetics, MyoKardia and Kainomyx, which were the first in the world to develop drug candidates for myocardial myosin. This is a dynamic new direction of drug development, the importance of which is also indicated in the acquisition of MyoKardia, the area’s first acquisition last week, by multinational pharmaceutical company Bristol-Myers Squibb, which paid $ 13.1 billion for the company.
The great challenge
The mechanism of action of the highly targeted drug, MPH-220, was revealed by studies conducted by the Hungarian research group for the first time in the world: the atomic structure of myosin, which carries out contraction of skeletal muscle, was determined in collaboration with the Curie Institute in Paris.
It has been a major scientific challenge to develop an agent that effectively resolves skeletal muscle cramps without affecting myocardial function. The myosins in skeletal muscle and myocardium are very similar to each other, so it was necessary to find the small difference between them that the drug candidate acts only on one of them. We discovered that there is a very small and specific difference in the heart of myosin, in a single building block of a huge protein molecule, in a single amino acid ”, says the scientific director of the research group, Dr. Máté Gyimesi.
Build bridges and jambs
“In a simple analogy, the MPH-220 can be imagined building a toy castle from hundreds of building blocks and then building the same castle with the same set of building blocks, but at a very important point in the castle, let’s say a single building block on the castle drawbridge. Due to the change, those who besiege the castle will have the opportunity to use, say, a wedge to prevent the lifting bridge from being erected, while in the other version this is not possible “, – dr.
The same goes for the active ingredient from the Hungarian research group. In skeletal muscle, the active substance may be involved in the most important contractile part of myosin, but not in myocardial myosin. Due to entrapment, contraction of our skeletal muscles cannot take place, so muscle fibers remain relaxed and muscle cramps relax.
Why doesn’t all the skeletal muscle relax?
The question arises why, if MPH-220 acts on skeletal muscle, why doesn’t it loosen all skeletal muscle? An explanation of this can also be found in the above. Skeletal muscle myosins are approx. half consist of a type of myosin like that found in heart muscle. The active ingredient also does not inhibit this type of myosin in skeletal muscle, thus maintaining the muscle tone required for mobility. With the drugs currently in use, the entire muscle relaxes because they inhibit muscle innervation, so patients may experience a temporary but complete loss of muscle tone even in the case of a mild overdose.
Spectacular shots
The effect of MPH-220 in animal experimentation is very spectacular, as can be clearly seen in the videos published by the research team. As a result of the drug, the movement of the experimental rats improved significantly because their muscle cramps disappeared.
Experimental results show that the absorption of MPH-220 after oral treatment is highly effective, its effect on muscle cramps is maintained for 24 hours. A drug with this property would subsequently allow a gentle and effective treatment of patients.
The Hungarian research group also showed that the drug does not affect the pathways that regulate cell function and is not mutagenic, that is, it does not damage the gene pool.
Based on this, the treatment is also expected to be feasible safely in humans.
Printnet Kft., The project’s IT support provider, developed an artificial intelligence-based test system for animal experiments, in which the movement of animals could be tracked in 3D with sub-millimeter precision. The application of deep learning algorithms confirmed that treatment with MPH-220 improves muscle spasticity in animals due to nervous system injury to a healthy level.
Clinical trials will begin next year
The first phase of the clinical trials testing the safety of the active ingredient is carried out in Hungary, in an accredited phase 1 center. The study is also funded by the National Office for Research, Development and Innovation, an agreement signed by the parties in early May 2020. The study is currently being prepared and the active substance is being manufactured, from which they will be administered the first doses to healthy subjects who volunteer for the study early next year.
After a stroke and other diseases and injuries of the nervous system, nearly 40 percent of patients experience spasmodic muscle contractions. Lifetime condition, often continually deteriorating, is approx. It makes life difficult for 60 million people around the world, with an estimated cost of treatment of more than $ 500 billion.
In most patients, the antispasmodics used today are not effective enough and their use in the correct dose makes their side effects impossible. On behalf of stroke professionals, I can say that there is an urgent need for a new drug. We hope to enter medical practice in a few years. “ – says dr. László Szapáry, Associate Professor, President of the Hungarian Stroke Society.
(ELTE TTK, Motor Pharmacology Research Group)
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