BGU and Soroka Researchers Develop Drug Effective in Rare Hereditary Muscle Disease

Dr. Yuval Yogev (BGU)

A research team from Ben Gurion University (BGU) in Be’er Sheva and Soroka University Medical Center discovered a severe hereditary muscle disease that develops around the age of 40 years, progressing by the early 50s to complete immobility of the limbs and the chest muscles, necessitating full-time artificial ventilation and eventually culminating in death. They went on to demonstrate that the disease is caused by a mutation in the gene encoding HMG CoA reductase, inhibiting the enzyme’s activity.

The Mayo Clinic explains statins are drugs that can lower your cholesterol. They work by blocking a substance your body needs to make cholesterol. Lowering cholesterol isn’t the only benefit associated with statins. These medications have also been linked to a lower risk of heart disease and stroke. These drugs may help stabilize the plaques on blood vessel walls and reduce the risk of certain blood clots.

Statins are the most commonly used medication in lowering blood cholesterol, prescribed to tens of millions in the Western world. Statins act through inhibition of the enzyme HMG CoA reductase. Nearly 20% of statin users develop muscle symptoms (“statin myopathy”) including weakness and pain. In about 1%, this myopathy is severe and does not subside months after cessation of statin treatment.

Attempting to cure the severe hereditary disease, the research group synthesized and purified Methylmevalonolactone, the normal product of HMG CoA reductase, which is lacking in those patients. Following testing for safety in mice, the team got an exceptional “compassionate use” permit to give the novel medication, never given to humans before, to the most severely affected patient, who was near death – completely immobile and fully dependent on artificial ventilation. The patient has now been treated with the medication (orally, 3 times a week) for more than a year, with no side effects.

Not only did she stop deteriorating, but she has also improved dramatically: she can breathe without support for hours at a time, move her arms and legs extensively, and even feed her grandchild. Other patients, some of whom are already in the late stages of the disease, are awaiting treatment. The researchers estimate that there are dozens to hundreds of people affected by this hereditary disease – that could benefit from this effective life-saving treatment.

Based on the successful treatment of the hereditary disease, the research group went on to test whether the medication can be effective in the treatment of the non-remitting muscle problems occurring in ~1% of statin users. Indeed, they showed that the medication was extremely effective in a mouse model system mimicking human statin myopathy. This is the first study to link muscle pain and weakness to statin use.

The entire research – from the human genetics and biochemistry studies to the generation and purification of the medication, to the human and mouse trials – was carried out as part of the Ph.D. thesis of Dr. Yuval Yogev, guided by Prof. Ohad Birk, head of the Morris Kahn Laboratory of Human Genetics at Ben-Gurion University and director of the clinical genetics institute at Soroka University Medical Center. Prof. Birk is also a member of the National Institute for Biotechnology in the Negev (NIBN).

The study, published recently in the Proceedings of the National Academy of Sciences (PNAS), was supported by the Israel Science Foundation.

Based on the findings, the research team is now seeking financial support/collaboration with the pharmaceutical industry to push forward standardized production and licensing of the medication, to save the lives of many individuals worldwide suffering from this hereditary disorder, as well as enable treatment of tens of thousands of statin-myopathy patients. It should be noted that the FDA procedures are more lenient in licensing medications for rare diseases, thus rapid progress is expected in this regard.