Three small molecules that normalize muscle structure and function and improve survival in dystrophin-deficient zebrafish have been identified by scientists at Children's Hospital Boston, Harvard Medical School, and Alaska Fisheries Science Center in Juneau.
The three chemicals, which already are approved for other medical uses, were found to increase survival and normalize muscle structure and function in the dystrophin-deficient fish without increasing production of the muscle protein dystrophin.
The chemicals have potential for development into drugs to treat Duchenne muscular dystrophy (DMD) or Becker muscular dystrophy (BMD), which result from mutations in the dystrophin gene, causing a complete or partial absence of dystrophin protein in skeletal and heart muscles.
About the zebrafish chemical screening study
MDA research grantee Louis Kunkel at Children's Hospital Boston and Harvard Medical School led the study team, which published its results online March 14, 2011, in Proceedings of the National Academy of Sciences USA.
Zebrafish are a good animal model for screening chemicals because they have transparent bodies in which internal structures can easily be seen; they soak up chemicals from their water environment easily; they multiply rapidly; and they're relatively inexpensive to maintain compared to larger, more complex animals.
The researchers started with a commercial library of 1,120 chemicals, 90 percent of which of which are on the market as medications, then narrowed the number of potentially beneficial chemicals to three. One is an anti-inflammatory agent called epirizole; another is pentetic acid, a chelating (chemical binding) agent; and the third is aminophylline, which is used to treat asthma.
The three lead chemicals all conferred survival advantages on the dystrophin-deficient fish, with aminophylline resulting in the largest survival effect. All surviving fish treated with the three front-running chemicals appeared to move normally, and all showed normal muscle structure.
None of three chemicals restored dystrophin production, indicating that the treatments allowed the zebrafish muscles to develop normal structure and function despite their lack of dystrophin. This could be an advantage for drug development.
Aminophylline is in a class of drugs known as phosphodiesterase (PDE) inhibitors. Currently, two other PDE inhibitors, sildenafil and tadalafil, are in clinical trials to test their effect on skeletal or cardiac muscle function in DMD patients. Sildenafil (on the market as Viagra and Revatio), is used to treat erectile dysfunction and pulmonary arterial hypertension, respectively. Tadalafil (Cialis) is marketed for erectile dysfunction treatment.
Meaning for people with DMD or BMD
The study shows the value of screening large numbers of potentially useful chemicals for treating DMD or BMD very rapidly and relatively inexpensively using dystrophin-deficient zebrafish.
That the chemicals were able to cause improvements without also causing dystrophin production in the fish suggests that they might do the same in larger animals, including perhaps in humans.
Since increasing dystrophin production is challenging and has the potential to elicit an unwanted immune response in patients who are not making this protein, the ability to improve the DMD or BMD disease course without increasing dystrophin production may have some advantages.
The fact that aminophylline has been used for many years as a treatment for asthma and that the other candidate chemicals have been used in human diseases will make it easier to move them through the regulatory process, should that prove desirable.
However, testing the chemicals in a mouse model of DMD will probably be required by regulatory agencies prior to undertaking human trials in DMD.