Sunday, October 30, 2016

Center for Duchenne Muscular Dystrophy

When Valerie Pappas Llauro’s 5-year-old son Alexander was diagnosed with Duchenne muscular dystrophy – a rare and fatal form of the genetic illness that primarily affects boys – doctors said her son’s only treatment options were “steroids and hope.”

The steroids would help to slow down the muscle damage caused by his progressive disease, while the family held onto the hope that scientific research would lead to new treatments.

After countless doctors told Pappas and her husband, Jorge Llauro, that nothing more could be done, the Los Angeles, California, couple found Stan Nelson, a brilliant researcher who has dedicated his life to understanding and treating the rare disease. 

“Meeting Stan was the first moment where we felt there could actually be some hope,” Pappas Llauro tells PEOPLE.

Stan Nelson knows exactly what to say to parents of boys with Duchenne, because his own son has the diease. Nelson and wife M. Carrie Miceli’s son Dylan was diagnosed with Duchenne in 2004 at 3 years old.

Both professors and researchers at the University of California, Los Angeles, Nelson and Miceli were shocked by Dylan’s doctor’s assertion that nothing could be done to save their son from losing the ability to walk by adolescence and eventually dying from heart or lung failure in his twenties…

So, the couple refocused their already prolific careers and dedicated their lives to fighting the disease that affects one in 5,000 boys worldwide.

Their efforts led to the founding of the Center for Duchenne Muscular Dystrophy (CDMD) at UCLA – one of a few centers in the nation that conduct cutting edge research and give boys with Duchenne access to state-of-the-art care and clinical trials.

Dylan, now 15, is one of more than 100 boys currently enrolled in various treatment programs at the CDMD. These programs, involving coordinated efforts of care specialists, research labs (there are 13 at UCLA alone) and clinicians, are likely to add 10-plus years to many patients’ lives.

“As both scientists and parents of a boy with Duchenne, Carrie and Stan’s unique perspective on the research and their value to the DMD community is unparalleled,” says Dr. Barry Byrne, a professor at the University of Florida School of Medicine and a researcher who studies muscle diseases…
When Dylan found out that his parents’ biggest challenge was Duchenne’s relative obscurity, he reached out to his favorite YouTubers asking for help.

The resulting videos – in which Dylan pranks Smosh with Jennifer Lawrence and throws trick shots with ease from his wheelchair with Dude Perfect – have earned more than 17 million views and brought awareness of Duchenne to a whole new community.

“Raising awareness was my primary goal,” he explains. “I think that’s anybody’s goal if you’re living with a disease.”…

Now, Dylan serves as a role model for boys with disabilities – through his own YouTube channel and his continued advocacy for the CDMD.

“Dylan has handled everything with the most amazing grace,” says Pappas Llauro. “When Alexander sees him and he sees his super cool motorized wheelchair and his videos on YouTube, he looks up to him. He’s an incredible source of inspiration for a lot of kids.”

Dylan’s remarkable optimism will continue to be a necessity, as he and his family know things wont get easier any time soon. Developing successful treatments can take decades and while the FDA is currently reviewing what could be the first drug ever approved to treat Duchenne, only 13 percent of patients will benefit – and Dylan is not among them.

Even so, the whole family takes pride – and comfort – in knowing that strides towards new treatments that can improve quality of life and extend lifespans are happening every day at the CDMD.

Videos at link

Courtesy of my daughter


  1. Wang RT, Nelson SF. What can Duchenne Connect teach us about treating Duchenne muscular dystrophy? Curr Opin Neurol. 2015 Oct;28(5):535-41.

    This review aims to describe the benefits and limitations of using the Duchenne Connect patient registry to provide information particularly in regard to active treatment choices in Duchenne muscular dystrophy and their impact on disease progression.
    Clinical trials and natural history studies are difficult for rare diseases like Duchenne muscular dystrophy. Using an online patient self-report survey model, Duchenne Connect provides relevant data that are difficult to gather in other ways. Validation of the overall dataset is supported by comparable mutational spectrum relative to other cohorts and demonstrated beneficial effect of corticosteroid use in prolonging ambulation. These types of analyses are provocative and allow multivariate analyses across the breadth of patient and physician medication and supplement practices. Because the data are self-reported and online, the barrier to participation is low and great potential exists for novel directions of further research in a highly participatory forum.
    Patient registries for Duchenne and Becker muscular dystrophy (DBMD) are powerful tools for monitoring patient outcomes, comparing treatment options, and relating information between patients, researchers, and clinicians. Duchenne Connect is an online patient self-report registry for individuals with DBMD that facilitates aggregation of treatment modalities, outcomes, and genotype data and has played a vital role in furthering DBMD research, particularly in the USA, in a highly participatory and low-cost manner.

  2. Young CS, Hicks MR, Ermolova NV, Nakano H, Jan M, Younesi S, Karumbayaram S, Kumagai-Cresse C, Wang D, Zack JA, Kohn DB, Nakano A, Nelson SF, Miceli MC,Spencer MJ, Pyle AD. A Single CRISPR-Cas9 Deletion Strategy that Targets the Majority of DMD Patients Restores Dystrophin Function in hiPSC-Derived Muscle Cells. Cell Stem Cell. 2016 Apr 7;18(4):533-40.

    Mutations in DMD disrupt the reading frame, prevent dystrophin translation, and cause Duchenne muscular dystrophy (DMD). Here we describe a CRISPR/Cas9 platform applicable to 60% of DMD patient mutations. We applied the platform to DMD-derived hiPSCs where successful deletion and non-homologous end joining of up to 725 kb reframed the DMD gene. This is the largest CRISPR/Cas9-mediated deletion shown to date in DMD. Use of hiPSCs allowed evaluation of dystrophin in disease-relevant cell types. Cardiomyocytes and skeletal muscle myotubes derived from reframed hiPSC clonal lines had restored dystrophin protein. The internally deleted dystrophin was functional as demonstrated by improved membrane integrity and restoration of the dystrophin glycoprotein complex in vitro and in vivo. Furthermore, miR31 was reduced upon reframing, similar to observations in Becker muscular dystrophy. This work demonstrates the feasibility of using a single CRISPR pair to correct the reading frame for the majority of DMD patients.

  3. Miceli MC, Nelson SF. The case for eteplirsen: Paving the way for precision medicine. Mol Genet Metab. 2016 Jun;118(2):70-1.

    Eteplirsen (Sarepta Therapeutics), a phosphoramidite morpholino sequence complementary to a portion of exon 51, is designed to force the exclusion of exon 51 from the mature DMD mRNA. This drug is relevant for approximately 13% of the DMD population harboring specific DMD mutations. Similar drugs targeting other DMD exons are under development and could theoretically restore reading frame in up to 80% of patients. The fact that these drugs rely on specific sequence information and target the proximate cause of the disease make this one of the first examples of precision genetic medicine.

    The promise of personalized medicines is enormous, particularly for rare disease. However, their approval relies on the application of regulatory tools designed to specifically empower the FDA to use flexibility in approvals for severely debilitating rare disease with unmet need, like Duchenne. Thus, DMD exon skipping trials are drawing considerable attention from the drug industry, rare disease advocates, patients, physicians and scientists...

    The three year, and the now four year, data make a compelling case that there is substantive evidence of effectiveness, which seems in stark contrast to conclusions reached in the FDA Briefing Document. This has prompted a group of 36 leading Duchenne experts to provide written commentary to clarify several issues while the FDA deliberates on the approval of eteplirsen. This expert commentary, in the form of a letter, was sent to the Director of the Division of Neurology Products, CDER. The signatories include leaders in DMD biology, therapy development, patient care and natural history.

    In considering whether disease progression in the eteplirsen treated boys is substantially deviating from the expected disease course, the group of Duchenne experts comments “The collective signatories note that the group of 12 eteplirsen treated boys, even accounting for daily deflazacort usage or twice-weekly prednisone, is clearly performing better than our collective clinical experience and the published literature would predict. Collectively, a portion of us represent a group of physicians who have observed over 5,000 DMD patients in our practices over an average of more than 15 years. Published external natural history data and our clinical experience strongly support that the 12 boys treated for over 4 years show a milder clinical progression, likely due to a positive treatment effect of eteplirsen.”

    The group of Duchenne experts also considered whether the drug showed any convincing evidence of dystrophin protein induction. The letter states “In considering that eteplirsen promotes on average 0.93% of normal control levels of dystrophin (range 0%-2.47%), concentrated within an average of 16% “dystrophin positive” fibers (range 1.4%–33.5%), it is reasonable to expect that levels of dystrophin expressed in some positive fibers could be as high as 5–12% of normal; levels clearly predicted to impart some, albeit incomplete, protection of myofibers from contraction induced damage. We conclude that the findings of this trial are sufficiently robust to support the proposed mechanism of action of eteplirsen, to provide a plausible explanation for the relative gain in function observed within the treatment group, and serve to bolster confidence that there is a positive treatment effect.”