Israeli researchers were able to reverse the deterioration of a patient with severe muscular dystrophy, and the medication may also relieve pain for statin users worldwide.
Israeli researchers discovered a previously unknown muscular dystrophy disease, and the medication they developed to treat it could help thousands of people suffering from other muscular issues.
The hereditary disease was recently discovered by researchers from Ben-Gurion University of the Negev and Soroka Medical Center. The study’s findings were recently published in the journal Proceedings of the National Academy of Sciences in the United States; the study began with genetic and biochemical research on the disease and concluded with the development and use of the medication to treat it, which has resulted in a dramatic improvement in patients’ muscular damage.
That drug may be effective in treating people who take statins, a class of cholesterol-lowering medications. Muscle pain is a common side effect of statins. Some people’s pain does not go away after they stop taking their medications, and it can be life threatening. So far, no effective treatment for these patients has been discovered.
“The story began with a Bedouin family in the Negev, where marriage between relatives is common,” says Prof. Ohad Birk, director of the Genetics Institute at Soroka Medical Center in Be’er Sheva and head of the Morris Kahn Laboratory of Human Genetics at Ben-Gurion University of the Negev.
“An unknown hereditary disease characterized by muscle pain beginning around the age of 30 was discovered in that one family.” “Birk explains. “By the age of 50, it has progressed to the point where [patients] are unable to move their limbs and have respiratory muscle paralysis, necessitating respiration. It’s a disease with no name, one of dozens of rare hereditary diseases discovered in the lab over the years but unknown to the rest of the world.”
The research was carried out as part of Dr. Yuval Yogev’s doctoral thesis, and he is now a pediatric resident at Tel Hashomer’s Safra Children’s Hospital. Birk oversaw the research, which included students from the laboratory as well as doctors from Tel Hashomer’s Soroka and Sheba Medical Centers.
The researchers discovered that hereditary muscular dystrophy is caused by a faulty gene. A mutation in a gene that encodes genetic information during the production of an enzyme called HMG CoA Reductase causes the enzyme to stop working, which is critical for proper muscle function.
In an attempt to cure patients with the rare disease, the researchers created a medication that contains methyl mevalonolactone, a biochemical product of the defective enzyme’s activity. 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 on constant respiration – after a lengthy process that included synthesizing the drug and meticulous experimentation to prove its safety.
“This is the disease’s oldest patient, and she was in critical condition, which is why we got emergency approval,” Birk says. “We explained the high level of risk to her and her family, and they decided to take the risk and take the medication because of her condition.”
A video accompanying the journal article shows the woman lying in bed and independently lifting her arm in the air after four months of treatment with the medicine – something she had not been able to do for several years prior to taking the drug.
According to Birk, the patient’s condition improved after the study ended. “The woman has been taking the medication orally three times a day for the past year and a half, and her condition has improved immeasurably,” he says. “She has good hand and foot movement and even feeds her grandson.” She can also be disconnected from an oxygen concentrator for hours at a time, which was unthinkable before.”
Pains from statins
The success of the drug in treating the rare disease prompted the researchers to investigate whether it could be used to treat another condition with a similar mechanism, one that also causes muscle damage.
Statins are among the most widely used medications in the world, with tens of millions of people taking them to prevent cardiac diseases and heart attacks. These medications work by delaying the enzyme HMG-CoA Reductase, which is responsible for the rate of cholesterol production in the liver – the same enzyme studied by the researchers.
About 20% of patients who take statins experience significant muscular side effects, with about 1% experiencing very serious side effects that do not go away and can be life-threatening.
“The HMG-CoA Reductase enzyme is present in almost all of our body’s tissues,” Yogev says. “It’s in charge of producing cholesterol, which plays several important roles in each of our cells, as well as an array of chemical compounds, each of which serves a different purpose.” The steroid hormones and coenzyme Q10 are the most well-known of these compounds.
“Despite the fact that we know this enzyme is essential for the proper functioning of all cells, and despite decades of research and endless theories, the mechanism by which statins block the enzyme causes muscle damage is unknown. Our findings point to the causes, demonstrating that inhibiting the enzyme, even in the absence of statins, causes muscle disease in humans.”
Because the new drug “is effective against muscular dystrophy,” Birk says, “we wondered whether it would relieve the side effects that people taking statins have, because statins affect the same enzyme and mechanism.” The researchers carried out a laboratory study in which mice were given high doses of statins. “This is a standard model for researching statin-induced muscular problems,” he explains.
The mice’s ability to walk a tightrope using their front legs was then tested, as shown in a video accompanying the study. The mice’s muscles were damaged and fell off as a result of the high doses of statins they had received. When half of the mice were given the researchers’ drug in their drinking water, they were able to hang onto the string for an extended period of time, indicating a significant improvement in muscle function.
The mouse experiment, like any other preclinical trial, is only the first stage of the drug’s lengthy research and development process. It has yet to be tested on humans who are taking statins. The researchers believe that even if the drug only improves the lives of a small percentage of patients taking statins, it will benefit thousands of people in Israel and many more around the world. Yogev anticipates that the drug will be used for purposes other than treating hereditary muscular dystrophy and the harsh side effects of statin therapy.
A lifetime’s work
Birk led a multi-year program that resulted in the discovery of the rare disease and the subsequent development of a drug to treat it. This is his life’s work, identifying and characterizing hereditary genetic diseases in Israeli populations.
Birk, a pediatrician who specializes in genetics, has led the Soroka Medical Center’s Genetics Institute for the past 22 years, as well as the National Knowledge Center for Rare/Orphan Diseases, which was established at Ben-Gurion University in 2018. “The goal was to detect diseases in the general population.” “he claims. “We established a research lab that understands how to detect faulty genes that cause rare diseases, as well as creating mice models with these genes’ mutations to fully understand their biochemical mechanisms.”
Birk’s lab has discovered more than 50 previously unknown diseases in the medical literature over the last two decades. “Common diseases among Bedouins, as well as Jews from Morocco and Iraq, were discovered in our lab,” says Birk.
Preventative actions
Academic and medical links established between Soroka Medical Center and Ben-Gurion University are critical in the process of genetically identifying and diagnosing rare diseases. This includes using public health nurses in communities to collect samples from various populations.
“When the genetics institute where I work at Soroka discovers a new disease with no known cause, it is sent to my lab across the street [at the university], where it is studied for a year or two before being returned to Soroka.” “Birk elaborates. Local nurses from the hospital’s operating organization, the Clalit health maintenance organization, “Visit villages in the area to conduct population surveys. We started with one nurse and now have ten.”
There are also community information sessions, such as meetings with religious figures, seminars for teaching students, and lectures in elementary and secondary schools. According to Birk, Soroka now tests for 100 rare diseases, half of which he and his team discovered. “When we discover that two spouses have a gene that puts them at risk for one of these diseases, we invite them in for testing before or during a pregnancy.” If both are carriers and the woman is not yet pregnant, in vitro fertilization can be used to select embryos lacking the faulty gene, preventing newborns from carrying the disease.
“As a result of these developments, infant mortality among the Bedouin population has decreased over the last decade from 17 to 10 deaths per 1,000 births (up to one year after birth).” “These diseases are gradually fading,” Birk adds.
Birk claims that genetic research into individual cases reveals a high prevalence of severe hereditary diseases. “For example, we discovered a disease that was shared by Jews, Ethiopians, and Bedouin and originated in Egypt. It turns out that half a million of the three billion ‘letters’ in the genome are linked to the disease-causing mutation. This means that there is some blood relation between all of these groups that dates back a few hundred years, most likely as a result of commercial ties between the areas they lived in.”
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