Ronni Cohn

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SUMMARY OF CURRENT RESEARCH ACTIVITIES

Three years ago, I received a phone call from Doron, who called me to discuss the diagnosis of Duchenne Muscular Dystrophy (DMD) in his son, who had a previously not described duplication mutation of the dystrophin gene. The fascinating aspect of Gavriel was, that despite a complete loss of the dystrophin protein, his phenotype was not as severe as one would have expected, given the extensive clinical experience of other boys with DMD. During the first few minutes of our conversation, I realized that this case seemed somewhat familiar to me. I had just returned from a World Muscle Society Meeting in Bruges, where, over a glass of wine, I discussed an unusual case of DMD with Prof. Dubowitz, who asked me whether I have ever seen a patient with this kind of duplication without being severely affected. It did not take me much longer to realize that Gavriel and the patient I discussed with Prof. Dubowitz were the same person. This remarkable coincidence then lead to an hour-long conversation with Doron and the development of a strong interpersonal connection, which I felt was yet another unusual aspect of this entire phone call. When Doron asked me whether he could support my laboratory efforts in muscular dystrophy research with money from the GM Trust fund, I simply felt that this was not what I wanted him to do. Rather, I offered him help to evaluate scientific proposals for the Trust. Today, I can say, that I am honoured to not only advise the board of trustees with evaluation of scientific proposals and their merit (I have established a rigorous peer- review process for these proposals), but at the same time to call Doron and Kerry, one of the most remarkable couples I have ever met, my friends. As outlined by Prof. Dubowitz, Gavriel is a clinical and scientific enigma, whose currently mild phenotype provides physicians and scientists with an intellectual and scientific treasure.

What are the underlying mechanisms that allow Gavriel, who has no dystrophin, to still to jump, run around and ride his bike? The search for an answer to this question is the main goal and motivation of the GM Trust fund. The overall goal of the GM Trust is to support scientific projects which carry the potential to elucidate mechanisms underlying the disease pathogenesis of Gavriel and at the same time provide insights into novel treatment strategies to combat disease progression in Gavriel and other patients with Duchenne Muscular Dystrophy.

The following are a list and brief synopsis of the various Research Projects which the GM Trust has been or are currently funding:

PROJECT 1 (UK & Australia)
Exon Skipping for duplication mutations of the dystrophin gene (UK & Australia)
Under the leadership of Drs. Nic Wells, Steve Wilton, and Francesco Muntoni this team of world experts in exon skipping is working on establishing whether large duplications of the dystrophin gene (similar to the one of Gavriel) can be skipped similarly to what has been shown and is currently in clinical trials for deletion mutations. If indeed possible, exon skipping would create a situation where muscle cells would produce some level of dystrophin protein, which would be able to ameliorate the severity of the disease.

PROJECT 2 (UK)
Identifying a small molecule to upregulate utrophin expression in skeletal muscle
Previous evidence suggest that upregulation of utrophin can compensate for the loss of dystrophin, which makes this protein an excellent candidate for therapy. This project is headed by Vastox/Summit and has revealed two promising candidates, which have been tested in animal models of muscular dystrophy. These compounds are being tested for toxicity and efficacy in mice clinical trials are suspected to start soon.

PROJECT 3 (USA)
CombinatoRx: Identifying drug combinations for the treatment of muscular dystrophy
The general goal of this project is to perform high-throughput screening of already existing and FDA-approved drugs, which in combination may lead to modifications of various targets, which have been shown to be promising in the treatment of muscular dystrophy. Specifically, this project is analyzing compounds that decrease an inflammatory parameter called NFkappaB; that causes an upregulation of alpha7 integrin (a membrane stabilizing protein) and is trying to identify a combination of drugs to antagonize myostatin, which has been shown to increase muscle size.

PROJECT 4 (Brazil)
Ringo: A golden retriever with dystrophin-negative muscular dystrophy and an exceptionally mild phenotype
Under the leadership of Dr. Mayana Zatz, a team of researchers has recently identified a dog within their colony of golden retrievers, muscular dystrophy that has a phenotype much milder than all of the other dogs in the colony. This is somewhat similar to the clinical situation of Gavriel. This project is currently trying to characterize the underlying molecular mechanisms responsible for this rather mild case of muscular dystrophy. The overall aim of this study is to potentially identify molecular pathways, which can be targeted to ameliorate disease progression in patients with Duchenne muscular dystrophy.