The drug improved heart function and survival in mice with lamin A/C mutations, which cause lamin A/C-related Emery-Dreifuss MD and type 1B limb-girdle MD
|Update (June 1, 2012): This story was updated to include the availability of a podcast on this topic.|
An MDA-supported study has shown that an experimental drug called selumetinib, given to mice with heart disease mimicking that found in one form of Emery-Dreifuss muscular dystrophy (EDMD) and one form of limb-girdle muscular dystrophy (LGMD), increased cardiac contractility, prevented scar tissue formation in the heart, and prolonged survival, without apparent toxicity.
The mice in this study had a mutation in the lamin A/C gene. Mutations in this gene cause the lamin A/C-related form of EDMD and the type 1B form of LGMD (LGMD1B). The particular mutation these mice had is associated with EDMD.
The investigators say the results suggest that selumetinib or related drugs could potentially be used to treat the cardiac abnormalities associated with lamin A/C-related EDMD and LGMD1B. Selumetinib is now in clinical trials for cancer.
MDA supported Howard Worman at Columbia University in New York for this work. The investigators published their findings Feb. 1, 2012, in the journal Cardiovascular Research (a summary of the scientific paper is available at no cost).
Previous research by Worman and colleagues identified a biochemical cascade known as the MAP kinase pathway as overactive in the lamin A/C form of EDMD.
Last year, they identified a class of drugs known as MAP kinase inhibitors as potentially useful in treating the cardiac abnormalities found in lamin A/C-related EDMD and LGMD1B.
However, at the time, it wasn't clear whether the molecular abnormalities in human hearts with lamin A/C mutations were exactly the same as those in the mice. In addition, one MAP kinase inhibitor that was tested was judged unsuitable for human use.
In this most recent study, the researchers first established that the heart damage caused by lamin A/C mutations in humans is probably the same as that seen in the mice with lamin A/C mutations.
In both the human and mouse hearts, researchers found overactivation of a branch of the MAP kinase pathway known as ERK1/2. They discovered this by analyzing cardiac tissue samples from one person with EDMD and one with LGMD1B, each of whom had a lamin A/C mutation.
Researchers administered selumetinib to mice with a lamin A/C mutation corresponding to one that causes human EDMD. These mice develop cardiomyopathy (cardiac muscle deterioration) and have skeletal muscle abnormalities as well.
Researchers first evaluated the drug's effects on the heart and then, separately, evaluated its effects on survival, by comparing the selumetinib-treated mice to mice with the same lamin A/C mutation that did not receive selumetinib.
For the cardiac studies, the treated mice received daily injections of selumetinib starting at 16 weeks of age and continuing until they were 20 weeks old.
Compared to untreated mice with lamin A/C mutations, the mice that received the drug showed about 50 percent less activation in their hearts of the ERK1/2 branch of the MAP kinase pathway. Several measurements of heart function and structure also were significantly better in the treated mice.
For the survival studies, the treated mice received selumetinib in their drinking water starting at 16 weeks and continuing for the remainder of their lives.
Mice with lamin A/C mutations normally live from 4 to 9 months, with a median survival time of about 28 weeks (about 7 months). Mice treated with selumetinib in their drinking water had a median survival time of 30 weeks (about 7.5 months).
The survival increase was modest, the researchers admitted, but they noted that it was statistically significant. They also said that at least some of the deaths in the mice may have been related to problems other than heart disease, such as reduced respiratory capacity, that were not targeted by selumetinib.
Inhibition of the ERK1/2 branch of the MAP kinase pathway was similar whether selumetinib was given orally or by injection.
Although toxicity has been a concern with MAP kinase inhibitors, there were no observed adverse effects on the kidney, liver or pancreas in the treated mice.
"Our promising preclinical results suggest that selumetinib could potentially be used to treat [lamin A/C-related] cardiomyopathy," the researchers say in their paper. They caution, however, that proof of the safety or effectiveness of selumetinib or similar drugs for this type of cardiac abnormality will have to come from clinical trials.
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