Update (Sept. 10, 2012): Information about the potential for serious side effects with temsirolimus and rapamycin was added to this article.
Mutations in the lamin A/C gene, which codes for the lamin A and lamin C proteins, underlie one form of Emery-Dreifuss muscular dystrophy (EDMD) and the type 1B form of limb-girdle muscular dystrophy (LGMD1B). In both these disorders, cardiomyopathy (cardiac muscle deterioration) can develop along with skeletal muscle weakness. The cardiac problems are the most serious aspect of these disorders and can shorten life, making treatment development a priority.
In February 2012, MDA grantee Howard J. Worman at Columbia University in New York and colleagues reported that an experimental medication called selumetinib improved heart function and prolonged survival in mice with a lamin A/C mutation found in human EDMD. Selumetinib is being investigated as a possible treatment for cancer.
Now, Worman and colleagues report that the drug temsirolimus also treats lamin A/C-associated cardiomyopathy in this same lamin A/C mutant mouse, via a different pathway from that of selumetinib. Temsirolimus is on the market as Torisel, a treatment for kidney cancer.
At the same time, Fresnida Ramos at the University of Washington, Seattle, and colleagues, report that the drug rapamycin had similar effects in mice with a different lamin A/C mutation, improving heart function and prolonging survival, as well as showing some benefit for skeletal muscle function. Rapamycin is marketed as Rapamune, a treatment to prevent rejection of transplanted kidneys.
While selumetinib inhibits the ERK1/2 branch of the MAP kinase biochemical pathway, temsirolimus and rapamycin interfere with a pathway known as AKT-mTOR.
These two biochemical pathways converge, and both of them inhibit a process called autophagy ("self-digestion") by which cells regularly degrade and recycle their component parts.
When either the ERK1/2 or the AKT-mTOR pathways are overactivated — as they appear to be when there's a lamin A/C mutation — autophagy is inhibited, keeping cells from performing the recycling that's crucial to their maintenance.
Selumetinib, temsirolimus and rapamycin all appear to enhance autophagy, thereby allowing cells to recycle components in a more effective way.
In their paper, Worman and colleagues suggest that combining medications might be optimal for treating lamin A/C-related cardiomyopathy, but note that further studies are needed to confirm this.
"While it can sometimes be a big jump from mice to men," Worman said, "the preclinical results from our group and those published by Ramos et al. provide a strong rationale for designing pilot studies in humans. However, establishing the best short-term endpoints to obtain evidence of efficacy in humans is not so simple and will take considerable thought and input from cardiologists experienced in clinical trials for heart failure."
That both temsirolimus and rapamycin are approved to treat other conditions and that selumetinib and similar drugs in the same class are being studied as possible cancer treatments simplifies the regulatory approval process to some extent. However, both drugs can have serious side effects and must be used with extreme caution.
Human trials of any of these drugs for cardiomyopathy associated with EDMD or LGMD1B will be necessary, but the extensive safety studies of these drugs that normally precede efficacy studies may not be needed.