Skin Health: New Insights from a Rare Disease

Forehead of study participant with rare form of ichthyosis

Courtesy of Keith Choate, Yale University School of Medicine, New Haven, CT

Skin is the largest organ in the human body, yet we often take for granted all of the wonderful things that it does to keep us healthy. That’s not the case for people who suffer from a group of rare, scale-forming skin disorders known as ichthyoses, which are named after “ichthys,” the Greek word for fish.

Each year, more than 16,000 babies around the world are born with ichthyoses [1], and researchers have identified so far more than 50 gene mutations responsible for various types and subtypes of the disease. Now, an NIH-funded research team has found yet another genetic cause—and this one has important implications for treatment. The new discovery implicates misspellings in a gene that codes for an enzyme playing a critical role in building ceramide—fatty molecules that help keep the skin moist. Without healthy ceramide, the skin develops dry, scale-like plaques that can leave people vulnerable to infections and other health problems.

Two patients with this newly characterized form of ichthyosis were treated with isotretinoin (Accutane), a common prescription acne medication, and found that their symptoms resolved almost entirely. Together, the findings suggest that isotretinoin works not only by encouraging the rapid turnover of skin cells but also by spurring patients’ skin to boost ceramide production, albeit through a different biological pathway.

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Rare Disease Mystery: Nodding Syndrome May Be Linked to Parasitic Worm

Rural Uganda village gathering

Caption: Village in the East Africa nation of Uganda
Credit: Centers for Disease Control and Prevention

In the early 1960s, reports began to surface that some children living in remote villages in East Africa were suffering mysterious episodes of “head nodding.” The condition, now named nodding syndrome, is recognized as a rare and devastating form of epilepsy. There were hints that the syndrome might be caused by a parasitic worm called Onchocerca volvulus, which is transmitted through the bites of blackflies. But no one had been able to tie the parasitic infection directly to the nodding heads.

Now, NIH researchers and their international colleagues think they’ve found the missing link. The human immune system turns out to be a central player. After analyzing blood and cerebrospinal fluid of kids with nodding syndrome, they detected a particular antibody at unusually high levels [1]. Further studies suggest the immune system ramps up production of that antibody to fight off the parasite. The trouble is those antibodies also react against a protein in healthy brain tissue, apparently leading to progressive cognitive dysfunction, neurological deterioration, head nodding, and potentially life-threatening seizures.

The findings, published in Science Translational Medicine, have important implications for the treatment and prevention of not only nodding syndrome, but perhaps other autoimmune-related forms of epilepsy. As people in the United States and around the globe today observe the 10th anniversary of international Rare Disease Day, this work provides yet another example of how rare disease research can shed light on more common diseases and fundamental aspects of human biology.

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Snapshots of Life: Picturing the Developing Windpipe

Mouse trachea

Randee Young and Xin Sun, University of Wisconsin–Madison

The image above shows a small section of the trachea, or windpipe, of a developing mouse. Although it’s only about the diameter of a pinhead at this stage of development, the mouse trachea has a lot in common structurally with the much wider and longer human trachea. Both develop from a precisely engineered balance between the flexibility of smooth muscle and the supportive strength and durability of cartilage.

Here you can catch a glimpse of this balance. C-rings of cartilage (red) wrap around the back of the trachea, providing the support needed to keep its tube open during breathing. Attached to the ends of the rings are dark shadowy bands of smooth muscles, which are connected to a web of nerves (green). The tension supplied by the muscle cells is essential for proper development of those neatly organized cartilage rings.

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Find and Replace: DNA Editing Tool Shows Gene Therapy Promise

Neutrophil being edited with CRISPR/Cas9

Caption: This image represents an infection-fighting cell called a neutrophil. In this artist’s rendering,  the cell’s DNA is being “edited” to help restore its ability to fight bacterial invaders.
Credit: NIAID, NIH

For gene therapy research, the perennial challenge has been devising a reliable way to insert safely a working copy of a gene into relevant cells that can take over for a faulty one. But with the recent discovery of powerful gene editing tools, the landscape of opportunity is starting to change. Instead of threading the needle through the cell membrane with a bulky gene, researchers are starting to design ways to apply these tools in the nucleus—to edit out the disease-causing error in a gene and allow it to work correctly.

While the research is just getting under way, progress is already being made for a rare inherited immunodeficiency called chronic granulomatous disease (CGD). As published recently in Science Translational Medicine, a team of NIH researchers has shown with the help of the latest CRISPR/Cas9 gene-editing tools, they can correct a mutation in human blood-forming adult stem cells that triggers a common form of CGD. What’s more, they can do it without introducing any new and potentially disease-causing errors to the surrounding DNA sequence [1].

When those edited human cells were transplanted into mice, the cells correctly took up residence in the bone marrow and began producing fully functional white blood cells. The corrected cells persisted in the animal’s bone marrow and bloodstream for up to five months, providing proof of principle that this lifelong genetic condition and others like it could one day be cured without the risks and limitations of our current treatments.

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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