Stories about: Duchenne muscular dystrophy

Two resilient dogs point to new targets for Duchenne muscular dystrophy

Duchenne muscular dystrophy protective genes
Suflair, at right, is alive and well at 11 years despite having the DMD mutation (courtesy Natássia Vieira)

Two golden retrievers that had the genetic mutation for Duchenne muscular dystrophy (DMD), yet remained healthy, have offered up yet another lead for treating this muscle-wasting disorder.

For several years, Natássia Vieira, PhD, of the University of São Paolo, also a fellow in the Boston Children’s Hospital lab of Louis Kunkel, PhD, has been studying a Brazilian colony of golden retrievers. All have the classic DMD mutation and, as expected, most of these dogs are very weak and typically die by 2 years of age. That’s analogous to children with DMD, who typically lose the ability to walk by adolescence and die from cardiorespiratory failure by young adulthood.

But two dogs appeared unaffected. Both ran around normally. The elder dog, Ringo, lived a full lifespan, and his son Suflair is still alive and well at age 11.

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Muscular dystrophy study suggests new therapeutic approaches to autism

muscular dystrophy autism social interaction
In addition to weakening muscle cells, loss of dystrophin also impairs Purkinje cells in the cerebellum.

Robin Kleiman, PhD, is Director of Preclinical Research at Boston Children’s Hospital’s Translational Neuroscience Center.

One of the hardest parts of developing new treatments for autism spectrum disorder (ASD) is that almost every patient has a different combination of environmental and genetic risk factors. This suggests that every patient could take a unique path to their diagnosis. It is hard to come up with a single treatment that will help patients with fundamentally different root causes of ASD.

One way to approach this problem is to look for ways to cluster sub-types of autism for clinical trials, based on genetic risk factors or the types of neural circuits that are affected. If circuit dysfunction could be monitored and diagnosed easily in patients, it might be possible to develop treatments to reverse the dysfunction that cut across genetic and environmental causes of ASD. That is the hope of research on well-defined “syndromic” causes of autism such as tuberous sclerosis complex, Fragile X syndrome and Rett syndrome.

Accelerating research collaborations to design clinical trials for children with brain disorders, including ASD, is a major mission of Boston Children’s Hospital’s Translational Neuroscience Center (TNC). A recent study in Translational Psychiatry, led by Mathew Alexander, PhD, in the Boston Children’s lab of Lou Kunkel, PhD, in collaboration with the TNC and Pfizer, is a prime example. It suggests that patients with Duchenne muscular dystrophy (DMD) may constitute another subset of ASD patients — one that could benefit from phosphodiesterase (PDE) inhibitors, a family of drugs including Viagra.

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An unusual dog, a new approach to muscular dystrophy: Stimulating a protective gene

muscular dystrophy
Vieira with Ringo

Ringo was a golden retriever that defied the odds. Despite having the gene mutation for Duchenne muscular dystrophy (DMD), he remained healthy. And he’s provided a new lead for boosting muscle strength in DMD, one of the most common forms of muscular dystrophy. Unlike other dogs with the dystrophin mutation, who are weak and typically die by 2 years of age, Ringo was able to walk and run normally and lived to the age of 11, within the normal range for golden retrievers.

What made Ringo so resilient?

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Duchenne muscular dystrophy: The decade of therapy

A cocktail of approaches is most likely to successfully preserve muscle.
A 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.”

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Zebrafish plus iPS cells make a drug discovery platform with muscle

Cell cover about using zebrafish and iPS cells to find muscle-building drugs.
In a one-two-three punch, a rapid screen in zebrafish can quickly identify a short list of drug candidates to test in mice and in patient-derived cells.

Scientists have had little success in growing skeletal muscle for patients with muscular dystrophy and other disorders that degrade and weaken muscle. Undertaking experiments in zebrafish, mouse and human cells, researchers have identified a way to do that, creating cells that Leonard Zon, MD, hopes to see tested in patients in the next several years.

But what really excites Zon, director of the Stem Cell research program at Boston Children’s Hospital, is the power of the chemical screening platform he and his colleagues used. Described last week in the journal Cell, it found a cocktail of three compounds that induced human muscle cells to grow—in just a matter of weeks. Zon believes it could fast-track drug discovery for multiple disorders.

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The fish are biting

The zebrafish (above, in a microtiter well) packs a lot of research punch in a small package.
They’re small, they’re transparent, and they breed at an amazing rate. They may hold the key to understanding the genetics of many human diseases. And they may help scientists discover new drugs – quicker and cheaper. Oh, and they’re fish.

The zebrafish (Danio rerio to the taxonomists) is a striped tropical fish, no longer than your pinky finger, that looks like it would be more at home in someone’s aquarium than in a laboratory. But for several reasons, zebrafish are powerful organisms for stem cell, developmental, and genetic research:

  • Despite our distance from zebrafish on the evolutionary tree, they’re surprisingly similar to us from a genetic standpoint.
  • Because of their small size, they can be housed at high densities.
  • Compared to other model organisms like mice, they’re relatively inexpensive to care for.
  • An adult female zebrafish can lay 300 eggs each week. By comparison, a mouse might have a single 12-pup litter each month.
  • Their skin is permeable, so they can absorb drugs directly from the water of their tank.
  • Zebrafish embryos are transparent, offering a window into their bodies; some lines, like Casper, remain transparent through adulthood.
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The Gene Hunter: 30 years and still seeking a cure

Kunkel (right) with DNA sequencing technologist Hal Schneider look on as a robot prepares sequencing reactions.

In the March/April Harvard Magazine, an in-depth profile recaps Louis Kunkel‘s long career as a gene hunter. In 1986, Kunkel’s identification of the gene responsible for Duchenne muscular dystrophy (DMD) was widely considered a milestone in genetics, and helped crystallize the idea of a Human Genome Project.

Today, nearly 30 years later, as director of the Genomics Program at Children’s Hospital Boston, Kunkel is still in touch with patients and families he met long ago.

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