Kennedy Krieger Institute – December 17, 2009

It is probably safe to say, you have heard of Kathryn Wagner, M.D., PhD. She is one of us, one of those doctors who wraps a protective arm around her patients and families, always thinking about what could or should be done to protect and preserve function and to ensure quality of life. You may know her from John Hopkins where she is an Associate Professor of Neurology. At Hopkins, she concentrated her energy on neuromuscular and neurogenetic diseases with a special emphasis on hereditary muscle diseases – Duchenne muscular dystrophy. You may know Kathryn as a co-director of an NIH-funded, Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center with Lee Sweeney. Their Wellstone Center is focused on modulation of muscle growth for muscular dystrophies, inhibition of Myostatin (negative regulator), and IGF-1 (positive regulator) She is also interested in mechanisms to promote muscle regeneration for a variety of neuromuscular disorders. Kathryn was also the principal investigator of a multicenter trial of an inhibitorof myostatin in adult muscular dystrophy sponsored by Wyeth pharmaceuticals. I have known her as a friend for many years.

Kathryn has recently accepted a position at Kennedy Krieger Institute. Why Kennedy Krieger? Kennedy Krieger Institute is dedicated to helping children and adolescents with disorders of the brain, spinal cord, and musculoskeletal system achieve their potential and participate as fully as possible in family, school, and community life. A perfect fit. Before Kathryn, they had no program for Duchenne muscular dystrophy, but it is safe to say, that when Kennedy Krieger Institute makes a decision to concentrate on a specific disorder, they waste no time getting started and they do whatever it takes to hit the ground running.

Kathryn invited me to tour. She met me in the train station and smiling, said “It feels like I’m meeting a family member”. And that is exactly how it felt to see Kathryn and spend the day with her colleagues at Kennedy Krieger.

The schedule was packed full – Mike, the ‘muscle nurse’ is wonderful and it is obvious he relates well to the boys. You already know I think nurses make all the difference in the world. And he does. The facility is bright, loads of windows with smiling staff who are incredibly helpful. First impressions!

Kathryn and I spent some time talking, discussing interdisciplinary care, what this means, what concerns families may have, and the need for teamwork. We talked about details – small things really, but things that make a substantial difference: accessibility, scheduling, wait times, teamwork, communication, etc. And we talked about the big things: care, treatment, research, clinical trials. Kathryn had organized the agenda. I was scheduled to meet several of the subspecialists who are part of Kennedy Krieger’s Duchenne team.

Emily Germain-Lee, MD. Emily is an endocrinologist who is both smart and tender about her patients and about endocrine issues in Duchenne. She is Kennedy Krieger’s new Associate Director of the Bone Center and Director of the Bone Research Center, as well as, an Associate Professor in the Division of Pediatric Endocrinology in the Department of Pediatrics at the Johns Hopkins University School of Medicine. She is the Director of the Johns Hopkins Pediatric Bone and Mineral Clinic and runs a General Endocrine clinic as well. She is Vice President and on the Board of Directors of the Human Growth Foundation. And she has a teenage son. Lucky for us, Emily will be seeing our boys.

Our next stop was with Gary Goldstein, MD. Dr. Goldstein is the President and Chief Executive Officer of Kennedy Krieger Institute. He is also a Professor of Neurology and Pediatrics at Johns Hopkins University, School of Medicine and a Professor of Environmental Health Sciences at Johns Hopkins University, School of Hygiene and Public Health. He was just about to be interviewed for a TIME magazine article on autism. New statistics were to be released that day. 1:110 children will have autism. Frightening actually. The facts: Autism is 4 times more likely to occur in boys. Autism Spectrum Disorders (ASD), which includes Pervasive Developmental Disorders (PDDs), cause severe and pervasive impairment in thinking, feeling, language, and the ability to relate to others. It is a spectrum disorder varying in severity and impact from individual to individual, ranging from those with no speech and severe learning disabilities to people (approximately 60%) with IQs in the average range who are able to hold down a job or start a family. I asked Dr. Goldstein if there was one symptom, one sign that stood out and he simply said “children with autism have no friends, it is the child on the playground who is always alone”. OK, so this is not to suggest that all children who enjoy playing alone have autism, but his words hit home. We talked about Duchenne, about the fact that approximately 30% of the boys are on the autism spectrum. He was aware of the papers published by numerous groups about dystrophin deficiency in Duchenne, suggesting that the absence of dystrophin in the mdx mouse model appears to impair intracellular calcium homeostasis and to disrupt multiple protein–protein interactions that normally promote information transfer and signal integration from the extracellular environment to the nucleus within regulated microdomains. We discussed recent publications related to Dystrophin in the brain describing the dystrophin protein as part of the highly conserved dystrophin-associated glycoprotein complex (DGC) which accumulates at the neuromuscular junction (NMJ) and at a variety of synapses in the peripheral and central nervous system and the many years of research into the roles of the DGC in muscle that have revealed its structural function in stabilizing the sarcolemma and that the DGC also acts as a scaffold for various signaling pathways. We agreed, Duchenne may be one key to autism and adds one more reason to the long list of reasons why collaboration is essential.

Kathryn and I headed over to Johns Hopkins to meet Drs. Dan Judge and David Kass, both Cardiologists. They talked nonstop about Duchenne, about the need to treat the dilated cardiomyopathy and about prevention. We talked about their recent NIH Wellstone grant submission and their focus on the Duchenne heart. And we talked about the clinical trial they are planning – Sildenafil (Viagra) belongs to a class of drugs called PDE inhibitors. PPMD has been funding this area of research for many years in the laboratories of Andrew Hoey (U. Southern Queensland) and Stan Froehner (U. Washington). Research suggests that at least part of the muscle degeneration observed in DMD patients may result from the reduced production of muscle membrane-associated neuronal nitric oxide synthase. This reduction is thought to lead to impaired regulation of the vasoconstrictor response and eventual muscle damage. Sildenafil and other phosphodiesterase-5 (PDE) inhibitors may delay or even reverse cardiac damage associated with Duchenne muscular dystrophy. We already know that the absence of dystrophin causes the weakness and muscle wasting of Duchenne muscular dystrophy, as well as cardiomyopathy and cardiac failure. Previous research showed that nitric oxide (NO) signaling is defective in the hearts of mdx mice and downstream of NO signaling, cyclic guanine monophosphate (cGMP) acts a secondary messenger. Enhancing cGMP signaling prevents and reverses pressure-overload hypertrophy. Sildenafil has been used in the pediatric population (pulmonary hypertension) and is safe and well-tolerated by adults. The study they are planning will involve older boys (13+), adolescents to young adults. At the Atlanta PPMD meeting, I looked out to the audience and said “We need trials for our young men.” Apparently, Kathryn was listening.The Sildenafil trial is the clinical piece of the Wellstone application but Drs. Kass and Judge said the clinical trial does not depend on the success of the Wellstone application. They are moving forward.

Kathryn drove me back to the train. My brain was racing, but I was smiling. Kennedy Krieger is an amazing place. The capacity for care is remarkable. The facilities are better than accessible. They are welcoming. They are focused on Duchenne: Making every day count and ensuring tomorrow.

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Comment by Ofelia Marin on January 14, 2010 at 10:42am
Several clinicians confirmed now that the PRO051 Phase III trial, planned to start “EARLY” 2010, will start “LATE” 2010. I thought that the entire point of having GSK partner with Prosensa was to bring this medication to the patients SOONER. I am not able to understand how this will be accomplished by WAITING almost one year. This is very disappointing!

Comment by Pat Furlong on January 13, 2010 at 1:24pm
There is progress...
Comment by Ofelia Marin on January 13, 2010 at 1:15pm
No FDA approval for start of exon skipping trials in the US yet... Things are moving in the EU though. PRO044 trial started recruiting the the EU; they corrected the announcement and the US site is no longer there... so great we have the FDA to protect our boys from possible harm. :-)

Comment by Pat Furlong on January 13, 2010 at 12:36pm
No reason to move to Europe. Trials are planned for the US.

Melissa - Thanks for your kind words. I love to talk and honestly, this is the only subject I have! :-)
Comment by Wyatt's Mommy, Melissa on January 12, 2010 at 11:28pm
That is so much great information. It's funny when I read your blog, I feel like I'm listening to you talk. So full of energy through your word, that's amazing! Take care.

Melissa Staffenhagen, Washington State
Comment by Ofelia Marin on January 11, 2010 at 3:22am
Thanks Pat.

Unrelated note. PRO044 trial ( is delayed in the US and moves ahead in Europe. Do you have an idea on why this is happening? The fact that exon skipping trials are again delayed in the US is very unfortunate. Does the FDA really get it? Should we do something or forget about it an just move to Europe to be able to treat our sons anytime soon?
Comment by Ian Anthony Griffiths on January 10, 2010 at 7:56pm
Thanks Pat, I thought that was the case, thanks for the update. I always seem to be a bit 'old' lately but it is definitely worth figuring out cut off points etc.

Comment by Pat Furlong on January 10, 2010 at 6:57pm
There are no reference about DMD and prevention of dilated cardiomyopathy. Some physicians are taking a proactive approach, recommending ace inhibitors early (age 9-11 range). This is where a great deal more work is needed. The comments about 'prevention or practive approach" are based on other conditions where DCM is present.

Ian -Like you, I have heard the concern about Sildenafil at a certain age. Beth McNally (chicago) does not recommend Sildenafil in adults with DMD. As it stands the Kennedy Kreiger trial will involve boys 13+ and there are other trials planned with younger boys. We just don't know at this moment IF Sildenafil will have benefit and where the cut off point will be in terms of risk.

Comment by Pat Furlong on January 10, 2010 at 6:51pm
Contact information for Kennedy Kreiger
Michael Munchel, RN
Center for Genetic Muscle Disorders
Comment by Julie Garcia on January 9, 2010 at 2:34am
Thank you for the update and your constant never ending commitment to change the course of duchennes. My family and I are grateful for you, Parent Project Muscular Dystrophy and all the doctors, nurses, researchers and those who also are dedicated to help change duchennes.

A friend told me the viagra trial would be for those who are showing signs of heart problems already. Is this true?

Again, thank you,


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