Emmie Mendes was lucky enough to be diagnosed before age 3, but many families face a much longer journey.
At first, Corrie and Adam Mendes thought their daughter Emmie had an inner ear problem. She was late with several early milestones, including walking, and when she did walk, she often lost her balance. The family pediatrician sent them to a neurologist, who ordered a brain MRI and diagnosed her with pachygyria, a rare condition in which the brain is smoother than normal, lacking its usual number of folds.
Additionally, Emmie’s ventricles, the fluid-filled cushions around the brain, looked enlarged, so the neurologist recommended brain surgery to install a shunt to drain off fluid. He advised Corrie and Adam that Emmie’s life expectancy would be greatly reduced.
As Corrie recounts on her blog, Emmie’s Story, she went online and came across the research laboratory of Christopher Walsh, MD, PhD, at Boston Children’s Hospital. The lab does research on brain malformations and has an affiliated Brain Development and Genetics Clinic that can provide medical care.
After Walsh’s team reviewed Emmie’s MRI scan, genetic counselor Brenda Barry invited the family up from Florida. Full story »
Giving patients the right kind of immune cells could curb their IBD, research suggests.
Inflammatory bowel disease (IBD) is miserable for anyone, but when it strikes a child under age 5, it’s much more severe, usually causing bloody diarrhea, wrenching abdominal pain and stunted growth. Early-onset IBD is rare, but on the rise: For reasons unknown, its incidence is increasing by about 5 percent per year in some parts of the world.
A recently identified form of early-onset IBD shows up within months of birth, causing severe inflammation in the large intestine and abscesses around the anus. Recently linked to genetic mutations in the cellular receptor for a signaling protein, interleukin-10 (IL-10), it can also lead to lymphoma later in life.
As with all early-onset IBD, IL-10-receptor deficiency has no good treatment. A bone marrow transplant is actually curative, but carries many risks, especially in infants.
“We’ve been trying to understand why IBD in these children is so severe and presents so early,” says Dror Shouval, MD, a pediatric gastroenterologist at Boston Children’s Hospital and a fellow in the lab of Scott Snapper, MD, PhD. The beginnings of such an understanding—detailed recently in the journal Immunity—could lead to a new treatment approach for this and perhaps other kinds of early-onset IBD. Full story »
Emir Seyrek was the first patient with Wiskott-Aldrich syndrome to be treated in the U.S. in an international gene therapy trial.
Seeing that his mother, Kadriye, wasn’t looking, Emir Seyrek got an impish grin on his face, the kind only a two-year-old can have. He quietly dumped his bowl of dry cereal out on his bed and, with another quick look towards his mother, proceeded to pulverize the flakes to dust with his toy truck. The rest of the room burst out laughing while his mother scolded him. Despite the scolding, though, the impish grin remained.
It was hard to believe that he arrived from Turkey six months earlier fighting a host of bacterial and viral infections. Emir was born with Wiskott-Aldrich syndrome (WAS), a genetic immunodeficiency that left him with a defective immune system. He was here because he was the first patient—of two so far—to take part in an international trial of a new gene therapy treatment for WAS at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center. And that day he was having his final checkup at Boston Children’s Hospital’s Clinical and Translational Study Unit before going home. Full story »
Rather than a single drug, cocktail of approaches is most likely to successfully preserve muscle.
It’s been 28 years since a missing dystrophin protein was found to be the cause of Duchenne muscular dystrophy (DMD), a disease affecting mostly boys in which muscle progressively deteriorates. Dystrophin helps maintain the structure of muscle cells; without it, muscles weaken and suffer progressive damage, forcing boys into wheelchairs and onto respirators.
Today, a variety of approaches that attempt to either restore dystrophin or compensate for its loss are in the therapeutic pipeline.
“We’re at the point where lots of things are going into clinical trials,” says Louis Kunkel, PhD, who is credited with identifying dystrophin in 1987. “I call it the decade of therapy.” Full story »
It was the variability that intrigued pediatric cardiologist William Pu, MD, about his patient with heart failure. The boy suffered from a rare genetic mitochondrial disorder called Barth syndrome. While he ultimately needed a heart transplant, his heart function seemed to vary day-to-day, consistent with reports in the medical literature.
“Often patients present in infancy with severe heart failure, then in childhood it gets much better, and in the teen years, much worse,” says Pu, of the Cardiology Research Center at Boston Children’s Hospital. “This reversibility suggests that this is a disease we should really be able to fix.”
Though it needs much more testing, a potential fix may now be in sight for Barth syndrome, which has no specific treatment and also causes skeletal muscle weakness and low white-blood-cell counts. It’s taken the work of multiple labs collaborating across institutional lines. Full story »
Perhaps counter-intuitively, rare diseases can present attractive business opportunities for pharmaceutical companies. As discussed previously on Vector, they generally offer:
1) a population of patients with a high, unmet need, greatly lowering the bar to FDA approval
2) a closely networked disease community, greatly lowering the bar to creating disease registries and mounting clinical trials
3) well-studied disease pathways.
Recoiling from expensive failures of would-be blockbuster drugs, companies like Pfizer, Novartis, GlaxoSmithKline, Sanofi, Shire and Roche are embracing rare diseases, despite their small market sizes, because of their much clearer path to clinic. But in the current risk-averse industry environment, some projects are stalling. Industry may need more incentive to jump in—and Cydan Development is basing its business model on providing it. Full story »
In this screen grab from a Nature video, a siRNA, cradled by an argonaute protein, binds to a messenger RNA. (More at www.youtube.com/watch?v=cK-OGB1_ELE)
RNA interference (RNAi) is a therapeutic technology that blocks gene expression with either small interfering RNAs (siRNA) or microRNAs (miRNA). RNAi’s discovery was considered transformative enough to earn the 2006 Nobel Prize for Physiology or Medicine
, but from the start the challenge of delivering RNA-silencing therapeutics to the right tissues has hobbled efforts to use RNAi to treat patients.
Citing this challenge, the pharmaceutical giant Novartis is the latest major company to withdraw from RNAi research, following Merck and Roche. Forbes was prompted to write:
…for certain diseases where an RNAi therapeutant can be more readily introduced, such as the eye, or ‘privileged compartments’ such as the liver, RNAi still has potential. But given that these therapies would be expensive due to the high cost-of-goods involved in synthesizing these agents, they would have to be targeted to diseases where the cost of therapy would be justified by the beneficial medical effects. … to say that RNAi therapy will rival monoclonal antibodies in terms of revenue potential—well, that’s a bit of a stretch.
Barry Greene, COO of Alnylam Pharmaceuticals, a biotech that’s championed RNAi, countered in Fierce Drug Delivery: “Novartis pulling out is an exemplar of Big Pharma not being able to innovate, and historically they have never been able to innovate.” Full story »
The butterfly effect is defined as “the sensitive dependence on initial conditions, where a small change at one place in a deterministic nonlinear system can result in large differences to a later state.” In medicine, the identification of a rare disease or a genetic mutation may provide insights that spread well beyond the initial discovery.
And in genetics, scientists are learning just how widespread the effects are for mutations in one gene: filaminA (FLNA).
FLNA is a common cause of periventricular nodular heterotopia (PVNH), a disorder of neuronal migration during brain development. The syndrome was first described by the late Peter Huttenlocher, MD, and the gene was identified by Christopher Walsh, MD, PhD, of Boston Children’s Hospital.
In normal brain development, neurons form in the periventricular region, located around fluid-filled ventricles near the brain’s center, then migrate outward to form six onion-like layers. In PVNH, some neurons fail to migrate to their proper position and instead form clumps of gray matter around the ventricles. Full story »
This post is the first in a two-part series on clinical trials in autism spectrum disorders. Read part 2.
In the world of neurodevelopmental disorders, an exciting trend is the emergence of specific molecular targets and treatments through genetic research. A case in point is IGF-1 therapy for Rett syndrome, a devastating disorder in girls that affects their ability to speak, walk, eat and breathe. It causes autism-like behaviors, intellectual disability and repetitive hand-wringing movements—a hallmark of the disorder.
A Phase I trial, published this week in the Proceedings of the National Academy of Sciences Early Edition, has modest but consistent results suggesting improvements in some salient features of the disorder.
Current treatments for Rett syndrome address only the symptoms and comorbidities, such as seizures, anxiety and scoliosis, but not the disease itself. But in 2007, findings in a mouse model (which even replicated the hand-wringing) changed how scientists think about Rett and other neurodevelopmental disorders, previously thought to be untreatable. Full story »
Alison Frase with Nibs, a carrier of MTM whose descendants provided the basis for the gene therapy study.
Babies born with X-linked myotubular myopathy (MTM), which affects about one in 50,000 male births, are commonly referred to as “floppy.” They have very weak skeletal muscles, making it difficult to walk or breathe; survival requires intensive support, often including tube feeding and mechanical ventilation. Most children with MTM never reach adulthood.
One of these children, Joshua Frase, succumbed to MTM on Christmas Eve, 2010. The son of former NFL player Paul Frase, he lived to age 15. But his parents, who continue to actively support MTM research, now see a glimmer of hope for children born with the disease today.
A preclinical study on the cover of last week’s Science Translational Medicine, funded in part by the Joshua Frase Foundation, showed dramatic improvements in muscle strength using gene replacement therapy in mouse and dog models of MTM—paving the way for a potential clinical trial. Full story »