Robotic Exoskeleton Could Be Right Step Forward for Kids with Cerebral Palsy

More than 17 million people around the world are living with cerebral palsy, a movement disorder that occurs when motor areas of a child’s brain do not develop correctly or are damaged early in life. Many of those affected were born extremely prematurely and suffered brain hemorrhages shortly after birth. One of the condition’s most common symptoms is crouch gait, which is an excessive bending of the knees that can make it difficult or even impossible to walk. Now, a new robotic device developed by an NIH research team has the potential to help kids with cerebral palsy walk better.

What’s really cool about the robotic brace, or exoskeleton, which you see demonstrated above, is that it’s equipped with computerized sensors and motors that can detect exactly where a child is in the walking cycle—delivering bursts of support to the knees at just the right time. In fact, in a small study of seven young people with crouch gait, the device enabled six to stand and walk taller in their very first practice session!

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Huntington’s Disease: Gene Editing Shows Promise in Mouse Studies

Cas9 clipping the Huntington's repeatsMy father was a folk song collector, and I grew up listening to the music of Woody Guthrie. On July 14th, folk music enthusiasts will be celebrating the 105th anniversary of Guthrie’s birth in his hometown of Okemah, OK. Besides being renowned for writing “This Land is Your Land” and other folk classics, Guthrie has another more tragic claim to fame: he provided the world with a glimpse at the devastation caused by a rare, inherited neurological disorder called Huntington’s disease.

When Guthrie died from complications of Huntington’s a half-century ago, the disease was untreatable. Sadly, it still is. But years of basic science advances, combined with the promise of innovative gene editing systems such as CRISPR/Cas9, are providing renewed hope that we will someday be able to treat or even cure Huntington’s disease, along with many other inherited disorders.

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Creative Minds: Can Diseased Cells Help to Make Their Own Drugs?

Matthew Disney

Matthew Disney

Matthew Disney grew up in a large family in Baltimore in the 1980s. While his mother worked nights, Disney and his younger brother often tagged along with their father in these pre-Internet days on calls to fix the microfilm machines used to view important records at hospitals, banks, and other places of business. Watching his father take apart the machines made Disney want to work with his hands one day. Seeing his father work tirelessly for the sake of his family also made him want to help others.

Disney found a profession that satisfied both requirements when he fell in love with chemistry as an undergraduate at the University of Maryland, College Park. Now a chemistry professor at The Scripps Research Institute, Jupiter, FL, Disney is applying his hands and brains to develop a treatment strategy that aims to control the progression of a long list of devastating disorders that includes Huntington’s disease, amyotrophic lateral sclerosis (ALS), and various forms of muscular dystrophy.

The 30 or so health conditions on Disney’s list have something in common. They are caused by genetic glitches in which repetitive DNA letters (CAGCAGCAG, for example) in transcribed regions of the genome cause some of the body’s cells and tissues to produce unwieldy messenger RNA molecules that interfere with normal cellular activities, either by binding other intracellular components or serving as templates for the production of toxic proteins.

The diseases on Disney’s list also have often been considered “undruggable,” in part because the compounds capable of disabling the lengthy, disease-causing RNA molecules are generally too large to cross cell membranes. Disney has found an ingenious way around that problem [1]. Instead of delivering the finished drug, he delivers smaller building blocks. He then uses the cell and its own machinery, including the very aberrant RNA molecules he aims to target, as his drug factory to produce those larger compounds.

Disney has received an NIH Director’s 2015 Pioneer Award to develop this innovative drug-delivery strategy further. He will apply his investigational approach initially to treat a common form of muscular dystrophy, first using human cells in culture and then in animal models. Once he gets that working well, he’ll move on to other conditions including ALS.

What’s appealing about Disney’s approach is that it makes it possible to treat disease-affected cells without affecting healthy cells. That’s because his drugs can only be assembled into their active forms in cells after they are templated by those aberrant RNA molecules.

Interestingly, Disney never intended to study human diseases. His lab was set up to study the structure and function of RNA molecules and their interactions with other small molecules. In the process, he stumbled across a small molecule that targets an RNA implicated in a rare form of muscular dystrophy. His niece also has a rare incurable disease, and Disney saw a chance to make a difference for others like her. It’s a healthy reminder that the pursuit of basic scientific questions often can lead to new and unexpectedly important medical discoveries that have the potential to touch the lives of many.

Reference:

[1] A toxic RNA catalyzes the in cellulo synthesis of its own inhibitor. Rzuczek SG, Park H, Disney MD. Angew Chem Int Ed Engl. 2014 Oct 6;53(41):10956-10959.

Links:

Disney Lab (The Scripps Research Institute, Jupiter, FL)

Disney NIH Project Information (NIH RePORTER)

NIH Director’s Pioneer Award Program

NIH Support: Common Fund; National Institute of Neurological Disorders and Stroke

Cool Videos: Patching and Sealing the Cell Membrane

Cell Repair Video

Bill Bement describes himself as a guy who “passionately, obsessively, and almost feverishly” loves to study cells. His excitement comes through in our final installment of the American Society for Cell Biology’s Celldance 2014. Bement, an NIH grantee at the University of Wisconsin, Madison, shares his scanning confocal microscope with us for this fascinating glimpse into the rapid response of cells to repair holes, tears, and other structural damage in their protective outer membranes.

For most people, this damage response runs on biochemical autopilot, sealing any membrane break within seconds to keep the cell viable and healthy. But some people inherit gene mutations that make sealing and patching difficult, particularly in cells that operate under repetitive mechanical stress. For example, some forms of muscular dystrophy stem specifically from an inherited inability to repair breaks in the cell membrane of skeletal muscle cells. In one type of disease that affects both skeletal and cardiac muscle, a gene mutation alters the shape of a protein called dysferlin, which normally binds annexin proteins that, as noted in the video, play a vital role in patching holes. In the presence of a glitch in dysferlin, the rapid chain of biochemical events needed to enable such repair breaks down.

There’s still an enormous amount to learn about cell membrane repair, so it will be interesting to see what Bement’s microscope and camera will show us next.

Links:

Bement Lab, University of Wisconsin-Madison

Celldance 2014, American Society for Cell Biology

NIH Support: National Institute of General Medical Sciences

Snapshots of Life: Lost Connections in Pompe Disease

Junctions between motor neurons (green) and muscle fibers (red)

Caption: Abnormal connections between leg muscle fibers (red) and nerves (green) in Pompe disease.
Credit: Darin J. Falk, A. Gary Todd, Robin Yoon, and Barry J. Byrne, University of Florida, Gainesville

Mistletoe? Holly? Not exactly. This seemingly festive image is a micrograph of nerve cells (green) and nerve-muscle junctions (red) in a mouse model of Pompe disease. Such images are helping researchers learn more about this rare form of muscular dystrophy, providing valuable clues in the ongoing search for better treatments and cures.

People with Pompe disease lack an enzyme that cells depend on to break down a stored sugar, known as glycogen, into smaller glucose molecules that can be readily used for energy. Without enough of this enzyme, called acid alpha-glucosidase (GAA), glycogen can accumulate destructively in the liver, heart, and skeletal muscles, making it increasingly difficult to walk, eat, and even breathe.

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