The News Hub at Washington State University recently carried an article describing initial success by researchers towards developing a drug for a rare form of muscular dystrophy.
Several thousand people are affected with limb girdle muscular dystrophy (LGMD) nationwide. As with many other rare disorders, funding and development of drugs for it is not a priority with pharmaceutical companies. This form of muscular dystrophy affects hips and muscles, eventually causing the inability of patients to walk or to lift their arms over time.
As published in Neurology Genetics, the university team that discovered a subtype of this rare form of muscular dystrophy in 2012 has now found that lithium expands the strength and size of muscles in mice with the disease. This gives the researchers at the university’s Neuromuscular Disease Center an excellent therapeutic target and brings them a step closer to developing a therapy.
The journey began with the diagnosis of a muscular dystrophy patient whose subtype was listed as “unknown cause”. With the help of genetic sequencing, the team was able to pinpoint a new subtype.
Another piece of the puzzle surfaced a few years ago when the researchers discovered two families with several members who had symptoms of muscular dystrophy but did not exhibit any of the variants known to the researchers.
The researchers, using a panel that analyzes up to 34 genes associated with LGMD, studied the DNA of both families and discovered that a deviation in a gene known as DNAJB6 was the cause.
One Door Closes
Since a mutation in one gene out of 12 different genes can cause LGMD, the next challenge for the researchers was to find why muscle atrophy results specifically from a variation in DNAJB6.
A decision was made to “cut out” the DNAJB6 gene. The results were unexpected. The researchers were fairly certain that they would see an even greater loss of muscle. On the contrary, muscle fibers expanded to almost 3 times normal size.
Now they believed that they should change course to find out what is causing the muscle growth.
Genetically Modified Mice
The mice that the researchers decided to use had been genetically modified in 2015 and carried a genetic variant similar to that of the patients. The lab mice exhibited the same muscle weakness as the patients once they reached adulthood.
Upon analyzing the muscle from the mice, they discovered that variants of the disease stimulate a protein that limits muscle growth. By using lithium chloride and inhibiting the GSK3beta protein, improvements were made in both the muscle mass and the strength of the mice.
About Lithium Chloride
In 1949 lithium chloride, which had been sold as common table salt, was removed from the market because doctors found that using it in quantity on food can be fatal. However, several other forms of lithium are used to treat various types of psychiatric illnesses,
Prior to being treated with lithium chloride, the mutant mice exhibited the strength of about one-fifth of that of normal mice. A 75% improvement was seen after only one month of treatment.
The researchers theorized that if other forms of lithium can be used safely for psychiatric disorders, perhaps they could identify a form that can be used to treat LGMD. For the time being though, the team is advising people not to take lithium chloride until it has been proven to be safe.
The Future of LGMD Therapy
Before advancing to LGMD therapy, doctors agree that there are several areas, such as the natural history of LGMD, that must be defined.
The range of progression of the disease has not yet been determined and the pathways of LGMD have not yet been identified. This requires a diagnosis of as many LGMD people as possible. The doctors want to be confident that when they start clinical trials of investigational drugs they can make a significant impact on the disease.
The Washington University team will be joined by other U.S. and U.K. teams to study LGMD patients with variations of the disease caused any gene. In preparation for future clinical trials, the study will record disease progression.
Each year the study participants will visit the neuromuscular clinic for functional assessments. These assessments will include timed stair climbs and completion of questionnaires that will assign ratings for their performance of normal daily tasks.