In bid to cure rare disease, scientists discover treatment for statin side effect
Ben Gurion University and Soroka Medical Center genetic researchers focus on commonalities between a type of limb-girdle muscular dystrophy and the cholesterol synthesis pathway
Renee Ghert-Zand is the health reporter and a feature writer for The Times of Israel.
Researchers at Ben-Gurion University of the Negev and Soroka Medical Center, both in the southern city of Beersheba, have developed a drug to reverse the symptoms of a rare type of muscular dystrophy, and potentially also help the thousands of people who suffer from debilitating muscle pain caused by statin use.
Statins are a group of drugs that lower the level of low-density lipoprotein (LDL) cholesterol (often referred to as “bad cholesterol”) in the blood. Some 200 million people worldwide take statins, and 20 percent complain of muscle pain as a side effect. For most of these people, the pain resolves when they stop taking the medication or switch to a different one. However, 1-2% of those who stop the medication (4,000 new cases per year) still suffer, and in some cases, the myopathy leads to death.
The BGU-Soroka study’s results were published earlier this year in the peer-reviewed Proceedings of the National Academy of Sciences (PNAS) journal.
The discovery of the drug took place in Prof. Ohad Birk’s research lab focusing on genetic diseases of the Negev population, specifically the Sephardic-Mizrahi Jewish and Bedouin communities. Birk has discovered 50 genetic diseases among the Bedouin, who have a 50% rate of first-cousin marriage.
“This case started with a Bedouin family where there are quite a few members who are fine until the age of 20 or 30, but then they show symptoms of limb-girdle muscular dystrophy (LGMD),” Birk said.
There are a variety of types of LGMD, each caused by a different hereditary mutation. However, all of them cause atrophy of the limb-girdle muscles, or the muscles in the shoulder, hip, and upper leg area. Some subcategories of the disease also cause atrophy of other types of muscles, including ones involved with breathing, as was the case with the type of LGMD the Bedouin family had.
“We saw that the oldest family members with the disease had so deteriorated by about age 50 that they could no longer move their arms or legs and had to be put on ventilators to breathe,” Birk said.
The research was led by MD-PhD student Dr. Yuval Yogev, who is now doing a medical residency in pediatrics. Yogev determined that the HMGCR gene mutation is behind this type of LGMD. The mutation interferes with the production of the HMG CoA reductase enzyme and inhibits its activity.
“The mutation doesn’t completely eliminate the production of the enzyme. It just reduces the production to about 30% of normal,” Birk noted.
The reduction in HMG CoA reductase in turn leads to a lack of its normal product, a substance called methylmevalonolactone (mevalonate). Having understood this, the researchers spent more than a year synthesizing methylmevalonolactone in their lab and testing it on mice for safety.
After receiving an exceptional “compassionate use” permit from the Health Ministry, the team administered the substance to the sickest member of the Bedouin family, a woman in her early 50s who was completely immobilized and on a ventilator.
“She started taking the methylmevalonolactone in syrup form three times a week. We started at a low dose and went up gradually and she has had no side effects,” Birk said.
Birk reported that after four months the patient could move her arms and began breathing without support. Now, more than a year and a half later, she can breathe without a ventilator and feed her grandchild.
Having demonstrated the success of methylmevalonolactone in this LGMD single case, the researchers turned their attention to the fact that HMG CoA reductase is the enzyme in the cholesterol synthesis pathway that is inhibited by statins. The brand name of some of the most common statins are Lipitor, Zocor, and Pravachol.
According to Birk, there are hundreds of studies on possible explanations for muscle problems among statin users, but none have led to a solution desperately needed by those who do not recover from the myopathy after going off the cholesterol-lowering medication.
Gordon Haber, a 54-year-old writer in New York, and Anne Picker, a 63-year-old attorney in New Jersey, fortunately recovered from their statin-related myopathy. But the pain was intense.
“I was on a low dose of a statin and my cholesterol wasn’t coming down enough, so my doctor doubled the dosage. Then I got COVID, and then when that cleared I was in so much muscle pain I thought I would never be able to take a walk with my son again. My upper legs were super-painful,” Haber said.
“I couldn’t exercise. It was hard getting out of bed… It was constant and made movement quite painful. I wouldn’t say it was agony, but it was bad and it came out of nowhere,” he said.
Picker had been on one statin for six years and then switched to another. During the COVID pandemic, she was diagnosed with Parkinson’s disease. When her muscles started hurting, she thought it might be related to her Parkinson’s medication.
“Seriously, everything hurt. My legs, my arms, my back, my neck. If you could find a muscle, it hurt. It was miserable. And at the same time, I was trying to up my exercise level because of the Parkinson’s. Trying to do a boxing class when everything hurt was awful,” she said.
After reading online that muscle pain can be a side effect of statin use, Haber saw his doctor, who switched him to a different statin, which eliminated the problem. Picker’s doctor took her off her statin and within two weeks she was feeling back to normal. She is now on a non-statin drug to control her cholesterol.
“So we said, wait a minute, if we have something that’s given to a human being with no side effects and resolves the problem where the HMG CoA reductase does not work, then it might be effective for statin myopathy,” Birk said.
Subsequently, the researchers tested this possibility on mice. When they fed mice high doses of statins, they could not hold on to and hang on a string. They dropped off within seconds — the equivalent of myopathy in humans.
But when these mice statin-affected mice drank the lab’s methylmevalonolactone, they could hang from the string for 10 minutes without a problem, according to Birk.
“So it seems that in mice at least the statin myopathy is indeed resolved by methylmevalonolactone,” he said.
Birk said he hopes that within a year his lab will be partnered with a major pharmaceutical company for manufacture and clinical testing of the drug. He also hopes it can be fast-tracked for the treatment of LGMD patients through the FDA approval process for rare-disease drugs.
“After that, we can think about getting it approved for severe statin myopathy, which would help even more people,” Birk said.
