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Archive for September, 2013

Sep 13

Little Hercules Foundation contributes to its first research project

We are excited to announce our first financial contribution to promising research towards a cure for DMD.  We are thankful to the Duchenne Alliance for allowing us to interface directly with researchers conducting breakthrough therapies for DMD. Here is an excerpt of the project:

DMD Research in the Kunkel Lab

Our lab’s overarching goal is to develop “rational” therapies for DMD that target the underlying causes and mechanistic sequence of muscle degeneration. Our research is focused on determining why muscle breaks down and how we can interfere to slow or halt the disease’s progression.

We use a zebrafish model of DMD to test for drugs that have the potential to compensate for the loss of dystrophin in muscle. Zebrafish are excellent models of the human expression of the disease.  They are permeable to small molecules added to their water, and because of their optical transparency, they are the ideal vehicle to monitor positive outcomes in muscle, as well as positive or negative effects in other tissues, within the context of a living vertebrate animal. Zebrafish also grow at an extremely rapid rate, allowing large numbers of drug candidates to be screened quickly.

Promising drug candidates that are found in the zebrafish screens are moved into pre-clinical testing in mice to determine their efficacy in a mammalian model of DMD. These experiments involve biochemical analysis of the targeted pathways, studying the cell and tissue structure of the muscle, measuring the functional improvement in the muscle and improvement of exercise induced muscle damage.

We are currently targeting and testing libraries of drugs owned by Pfizer Inc., thanks to a first-of its-kind collaborative program that we launched in 2011. Among the compounds that our lab has identified with dystrophy-correcting potential are several that affect a target called PDE (phosphodiesterase enzymes). Pfizer has a successful track record of developing drugs that inhibit PDE, including sildenafil citrate (Viagra).

Because many of the Pfizer drugs are already approved for human use to treat other diseases, they can quickly be moved into the pre-clinical phase of testing in anticipation of ultimately launching human trials. This means that in contrast to other therapeutic approaches, which may ultimately prove to be a viable DMD treatment, our drug-based approach could generate benefits for most boys with DMD in the near term.

Promising results

We have already identified a lead compound that corrects nearly all zebrafish with muscular dystrophy and we have moved this drug into a blinded treatment trial in the mouse model of DMD. During the treatment period, mice are exercised using a treadmill for 15 minutes and then monitored for distance moved, rearing events (standing on hind legs) and resting time.

Preliminary data from these studies are very encouraging.  Mice treated with our lead compound performed as well in all three areas—they moved more, reared more, and rested less—as compared to the untreated mice and similar to mice treated with sildenafil (Viagra), a PDE inhibitor currently being tested in clinical trials. Our first test of this new PDE inhibitor failed to reach needed levels in the serum of the treated mice. We are now embarking on a second pre-clinical trial where more drug will be delivered to larger numbers of animals in a blinded study in parallel with sildenafil. We also are testing additional compounds in our zebrafish which give preliminary indications that they are as good as or better than our lead candidate being tested in mice.

We are optimistic that new DMD therapies are on the horizon.  With the positive results of our research to date, we expect that these studies will lead to human clinical trials in the very near future, giving fresh hope to people and families affected by the disease.


Louis M. Kunkel, PhD, Professor of Genetics and Pediatrics at Boston Children’s Hospital and Harvard Medical School, is internationally renowned for the discovery of the genes responsible for muscular dystrophy and other neuromuscular disorders. Since his discovery of dystrophin as the causative gene in DMD, he has been involved in the identification of genes altered to cause muscular dystrophy. From gene discovery his laboratory has turned to focus on developing therapies for the muscular dystrophies. A past Howard Hughes investigator and member of the National Academy of Sciences, Dr. Kunkel received the 2009 March of Dimes Prize in Developmental Biology for this pioneering work on muscular dystrophy.

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