Israeli researchers were successful in slowing the progression of a patient with severe muscular dystrophy, and the drug may also provide pain relief for statin users worldwide.
A previously unidentified form of muscular dystrophy was discovered by Israeli researchers, and the medication they created to treat it may be able to help thousands of people with other muscular conditions.
The hereditary condition was recently uncovered by researchers from Soroka Medical Center and Ben-Gurion University of the Negev. The study’s findings have just been released in the United States. journal The study, which was published in Proceedings of the National Academy of Sciences, started with research on the disease’s genetic and biochemical causes and ended with the creation and use of a medication to treat it. This medication has significantly reduced patients’ muscular damage.
That medication may be useful in treating patients who take statins, a class of drugs that lowers cholesterol. Muscle pain is a typical statin side effect. Some people experience this pain, which in some cases is potentially fatal, even after stopping their medication use. For these patients, there is currently no proven effective treatment.
Prof. Yuval Yogev (left) and Dr. Ohad Birk, who led the study.Credit: Ben-Gurion University of the Negev
“The story began with a Bedouin family in the Negev, where marriage between relatives is common,” says Professor Ohad Birk is the director of the Genetics Institute at the Soroka Medical Center in Be’er Sheva and the head of the Morris Kahn Laboratory of Human Genetics at Ben-Gurion University of the Negev.
“In that one family, an unknown hereditary disease was discovered that is characterized by muscle pain starting at around age 30,” says Birk. “By the time the patient reaches the age of 50, the condition has gotten so bad that they are unable to move their limbs and have breathing difficulty due to paralysis of the respiratory muscles. It’s an unnamed illness, one of many uncommon hereditary conditions we’ve uncovered in the lab over the years but which have gone unrecognized worldwide.”
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As a component of Dr.’s doctoral thesis, the study was completed. At the Safra Children’s Hospital in Tel Hashomer, Yuval Yogev is currently a pediatrics resident. Additional laboratory students and medical professionals from Tel Hashomer’s Soroka and Sheba Medical Center participated in the research, which was directed by Birk.
The cause of hereditary muscular dystrophy was identified by the researchers as a faulty gene. An enzyme called HMG CoA Reductase, which is necessary for healthy muscle function, is produced when a gene that encodes genetic information is mutated, leading to the development of the disease.
The researchers created a medication that contains methyl mevalonolactone, a substance that is the biochemical byproduct of the defective enzyme’s activity, in an effort to treat patients with the rare disease. After a long process, which included synthesizing the drug and meticulous experimentation to prove its safety, the researchers received emergency approval for “compassionate use” – to administer the drug to a 52-year-old woman in terminal condition, who was unable to use her muscles and was under constant respiration.
“This is the oldest patient to suffer from the disease, and she was in critical condition, which is why we received emergency approval,” says Birk. “She and her family were informed of the high level of risk, and given the severity of her condition, they chose to accept the risk and take the medication.”
Following four months of treatment with the medication, the woman can be seen in a video that is included with the journal article lying in bed and lifting her arm by herself, something she was unable to do for a number of years prior to taking the medication.
After the study was over, according to Birk, the patient’s condition kept getting better. “For the past year and a half, the woman has been taking the medication orally three times a day, and her condition has improved immeasurably,” he says. “She can move her hands and feet fluidly, and she even feeds her grandson. She can also be disconnected from an oxygen concentrator for hours – something we couldn’t imagine before.”
Statin pains
The drug’s success in treating the rare disease prompted the researchers to investigate whether it might also be helpful for another condition with a similar mechanism that also results in muscle damage.
Tens of millions of people worldwide take statins to prevent cardiac diseases and heart attacks, making them one of the most widely used medications in the world. These drugs function by slowing the activity of the HMG-CoA Reductase enzyme, which regulates the rate of cholesterol synthesis in the liver and is the same enzyme that the researchers looked at.
Approximately 20% of patients who take statins experience noticeable muscular side effects, and 1% of patients experience extremely serious side effects that do not go away and may be fatal.
“The HMG-CoA Reductase enzyme is active in almost all our body’s tissues,” says Yogev. “It produces a wide range of chemical compounds, each of which has a different function, as well as cholesterol, which performs a number of important roles in each of our cells. The steroid hormones and coenzyme Q10 are the two most well-known of these substances.
“Despite decades of research on the subject and an endless number of theories, the mechanism by which statins cause muscle damage is unknown, despite the fact that we are aware of the importance of this enzyme for the operation of all cells. Our research provides some insight into the causes by demonstrating that blocking the enzyme results in muscle disease in people even without statins.”
Birk says because the new drug “is effective against muscular dystrophy, we wondered whether it would relieve the side effects people taking statins have, since statins affect the same enzyme and mechanism.” In a lab experiment, the researchers gave mice high doses of statins. “This is a customary model for studying statin-induced muscular problems,” he says.
The mice were then tested on their capacity to balance on a tightrope using only their front legs, as demonstrated in a study-related video. The mice’s muscles deteriorated and fell off as a result of the high doses of statins they had been given. The mice’s ability to hang onto the string for an extended period of time after receiving the research team’s drug in their water, which attested to a significant improvement in muscle function, belonged to the group of mice that received the drug.
The study on mice is just the beginning of a protracted process of research and development for the drug, just like any preclinical trial. On statin-using humans, it has not yet been tested. According to the researchers, even a small improvement in quality of life for a small percentage of statin users would benefit thousands of Israelis and a much larger number of people worldwide. Yogev claims that they anticipate using the medication for purposes other than treating hereditary muscular dystrophy and the severe side effects of statin therapy.
A life’s work
A multi-year program led by Birk resulted in both the identification of the rare disease and the subsequent development of a medication to treat it. This is the focus of his life’s work, which aims to recognize and describe hereditary genetic diseases in Israel’s various populations.
Pediatrician Birk has been in charge of the Soroka Medical Center’s Genetics Institute for the past 22 years. He also serves as the director of the National Knowledge Center for Rare/Orphan Diseases, which was established at Ben-Gurion University in 2018. “The goal was to detect diseases among the population,” he says. “To fully understand the biochemical mechanisms underlying rare diseases, we established a research facility that is capable of identifying the defective genes that cause these conditions and producing mouse models with these gene mutations.”
Over the last two decades, Birk’s lab has discovered more than 50 rare diseases which had not been previously recognized in medical literature. “Common diseases among the Bedouin population, as well as among Jews from Morocco and Iraq, were found in our lab,” says Birk.
Preventative measures
Academic and medical ties established between Soroka Medical Center and Ben-Gurion University are crucial to the process of genetically identifying and diagnosing rare diseases. In order to gather samples from various populations, this involves using public health nurses in local communities.
“When the genetics institute I work in at Soroka identifies a new disease that has no recognized diagnosis, this goes to my lab across the road [at the university], where it is studied for a year or two before being returned to Soroka,” Birk explains. Local nurses from the Clalit health maintenance organization, which operates the hospital, “go to villages in the area in order to conduct population surveys. There was only one nurse when we first started, but there are now 10.”
There are also community information sessions, such as gatherings with religious leaders, seminars for future teachers, and talks in elementary and high schools. Birk claims that half of the 100 rare diseases that Soroka currently tests for are ones that he and his team have discovered. “We invite them in for testing before or during a pregnancy when we discover that two spouses share a gene that increases their risk of contracting one of these illnesses. In vitro fertilization is a possibility if both partners are carriers and the woman is not yet pregnant. During this procedure, embryos without the defective gene can be chosen, preventing the disease from passing to the unborn child.
“The Bedouin population’s infant mortality decreased over the past ten years from 17 deaths per 1,000 births (up to one year after birth) to 10 as a result of these developments. These diseases are gradually disappearing,” adds Birk.
According to Birk, genetic analysis of specific cases reveals that severe hereditary diseases are very common. “For instance, we discovered a disease that originated in Egypt and affected Jews, Ethiopians, and Bedouins. The mutation causing this disease is found to be linked to 500,000 of the three billion “letters” in the genome. This indicates that all of these groups have some ancestry that dates back several hundred years, most likely as a result of trade connections between the regions they lived in.”
