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Rare diseases present a growing global health issue. Of the 7,000 or so rare diseases known to medicine, approximately 80 percent are of genetic origin—and a whopping 95 percent are without a treatment approved by the U.S. Food and Drug Administration (FDA), according to the Pharmaceutical Research and Manufacturers of America. Even monogenic diseases (disorders caused by issues concerning a single gene) often result in pathology that is difficult understand and even more difficult to treat. Recently, researchers at Case Western Reserve University developed an induced pluripotent stem cell (iPSC) model for a rare neurological disease called Pelizaeus-Merzbacher disease (PMD). The model could offer a proof of concept for how to better understand the origin of other rare brain diseases, as well as a way to test targeted pharmacological treatments in the future.
One Gene, Different Subtypes
PMD is a genetic disorder characterized by a lack of myelin, the fatty white substance made up of oligodendrocytes that insulate neural circuits in the brain. Myelin is crucial to successful brain signaling, helping to quickly, efficiently transmit signals across the cortex. PMD is a rare and often fatal disease, but those who do live with it show varied symptoms of impaired motor and intellectual function. Paul Tesar, a professor of innovative therapeutics at Case Western Reserve University, says that PMD is an interesting disorder because it is actually more complex than one might first think a single gene disorder might be.
“It is a so-called rare monogenic disorder that affects a gene called the proteolipid protein 1 (PLP1) gene. But it’s a disease that’s had hundreds of different mutations identified, spanning hundreds of individual point mutations—duplications, deletions, triplications, partial deletions,” he says. “All those different types of changes converge on this same endpoint, a phenotype where the patients have this lack of myelin. We wanted to understand whether all these different mutations are really all the same disease, or if there may be different subtypes, with different underlying cellular and molecular pathologies, that might help better inform clinical care in the future.”
To investigate, Tesar and colleagues grew oligodendrocytes from iPSCs from 12 people with PMD, including those with mutations, duplication, triplication, and deletion of the PLP1 gene. The researchers then looked at the molecular and cellular processes affected by the specific genetic changes in the generated oligodendrocytes. The results were published in the April 6, 2017, issue of The American Journal of Human Genetics.
“This is the first disease we tackled in the laboratory in relation to myelin disorders. By looking at these different genotypes, we could link defects in the brain cell function to the individual patient genetics,” he says.
Some of those discoveries were surprising, he says, showing that there are distinct subgroups within the disorder. “It was striking to us that the deletion of the gene was typically the mildest form of the disorder. For such an extraordinarily important gene that can have such devastating effects with just small mutations, it was peculiar that a full deletion had the least effect.”
Understanding such differences, says Lawrence Goldstein, director at the Sanford Stem Cell Clinical Center at the University of California, San Diego, is important to being able to ultimately develop effective treatments for these rare disorders.
“Studies like this are an illustration that we are developing an ability to prospectively generate multicellular disease in a dish model,” he says. “With this method using truly human biochemistry, we are moving towards valuable models that can help us distinguish between different forms of a disease, better understand the risk factors, and also identify potential molecules that could potentially treat these disorders. These models have enormously powerful potential.”
A Promising Future
Tesar says that iPSC models are not limited solely to rare diseases—they could also help elucidate the mechanisms of other neurological disorders as well.
“In the past, we’ve really only been left with the option of understanding a disease from post-mortem material, especially when it comes to neurological disease. After all, you can’t take a direct sample of the brain from a living person,” he says. “In the past, trying to understand some of these disorders is like trying to understand an accident after it happens. The tissue is already damaged and dysfunctional. But with this kind of method, we can better understand how disease initiates and the underlying molecular and cellular dysfunction.”
That’s why these new iPSC models are exciting, says Marcus Wernig, a researcher at Stanford University’s Stem Cell Institute. They allow scientists to move away from animal model research, whose molecular and cellular findings don’t always directly translate to human medicine.
“These kinds of models can give us a lot of confidence because we are essentially dealing with the patient’s cells,” he says. “They are changing the way we, as the biomedical research field, are able to investigate disease processes and pattern mechanisms in real human cells. They also are changing how we think about potential treatments. It’s a very powerful approach.”
Goldstein agrees—and says these new technologies are rapidly advancing. In doing so, they are allowing researchers to build more and more complex models of disease. Those models, ultimately, will have the most to offer when it comes to fielding potential pharmacological treatments.
“You see labs that are already identifying drug candidates on a small scale using these kinds of models. Our ability to do that is only going to grow,” he says. “We’ve got a stem cell revolution unfolding here. On one side, you see stem cells to make replacement tissues and organs. That’s moving along nicely with some clinical trials. And then on the other side, you have these disease-in-a-dish models where we can really track how diseases develop and then identify and test potential drug candidates. These things are really going to revolutionize the way we develop treatments for genetic disorders in the future.”