U of U Health’s original post can be viewed here.

In recognition of Rare Disease Day, which falls on Feb. 29, University of Utah Health published this feature article highlighting research at the U exploring potential treatments for disorders afflicting small numbers of people. By themselves, these diseases don’t impact that many patients, but collectively they affect 10% of the U.S. population.

You can also explore U of U Heath’s multi-media report, Beacon of Hope, which highlights spinal muscular atrophy (SMA), the top genetic killer of infants. In December 2016, gene therapy stopped SMA in its tracks. Infants who received those revolutionary treatments now live life to the fullest at home, at school and at play.

“Doug, you’ve got to see this!” Jill Hawkins motions to her husband excitedly. They’re standing in the lab of geneticist Clement Chow, at the Spencer Fox Eccles School of Medicine. With their 20-year-old son Nash beside them, Jill and Doug squint into a glass vial teeming with fruit flies. Each tiny insect represents hope.

The feeling of optimism is so intense, Jill thinks, that it must have made its way to 18-year-old Charlotte and 13-year-old Cooper, her two younger children back home in Seattle. Both have a disease so rare that only a dozen people worldwide have been diagnosed with it.

Jill and Doug had been searching for answers for their children for years. Their quest reached a milestone in 2019 when scientists discovered the disease’s cause. Two errors in a single gene, FAM177A1, gave rise to Charlotte and Cooper’s global developmental delay, seizures, and motor issues. But knowing that critical link was not enough. There was no cure and no treatment. In the following years, the kids’ symptoms continued to worsen. Jill and Doug wondered what more they could do.

The challenge

In the medical field, rare diseases pose significant challenges. As defined by the U.S. Food & Drug Administration (FDA), each rare disease impacts fewer than 200,000 in the country. That small number makes it difficult for pharmaceutical companies to use standard approaches to develop and test treatments—or justify the expense of finding new ways to do it.

Yet collectively, rare diseases are a significant burden. More than 7,000 rare diseases—and possibly as many as 10,000—affect 10% of the U.S. population. The treatment gap leaves individuals who have rare diseases with few places to turn.

Chow’s lab is one such place, tucked in a quiet building hundreds of yards from the bustle of University of Utah Hospital. Seven years ago, Chow took on a research project that connected him to the world of patients and medicine. His lab had established foundational knowledge needed to move a dietary supplement into testing in human clinical trials as a treatment for a symptom of the rare disease NGLY1 deficiency.

Before then, there had been no immediate application for Chow’s research in disease genetics. After finding that his lab’s expertise could directly benefit people, there was no turning back

Now, in between teaching students and running his lab, his work week includes exchanging emails and taking Zoom meetings with parents from across the country and beyond. His small research team works with a handful of families at a time, searching for treatments for their children.

Learning from flies

When Chow explains to parents that his lab looks to fruit flies for answers, they’re often surprised. Yet, there are good reasons why. Despite obvious differences, flies and humans share 60% of their genes, making the household pest a good model for researching the genetics of disease. What’s more, the insect is easy to experiment with. And since it takes about two weeks for flies to reach adulthood, that allows scientists to get results quickly.

“How can this fly that we shoo away tell us so much about human disease?” Jill Hawkins marvels. Motivated by her children and other families who are contending with the same condition, she founded the FAM177A1 Research Fund with a mission to accelerate research and patient-focused treatments. “We could very well come up with something we could treat our kids with in the near future,” she says.

When Jill thinks about her children Cooper and Charlotte, her face softens and she can’t help but smile. She describes Charlotte as delighting in “all things ridiculous.” Animals sneezing and cartoon characters falling on their heads never fail to get her daughter giggling. Cooper is a gentler child who craves closeness and comfort. “They are so pure,” Jill says. “You can look straight into their souls and it is so beautiful.”

They have a disease so rare that only a dozen people worldwide have been diagnosed with it.

But every day is a battle for them, she continues. Between seizures, declining motor skills, and a limited ability to communicate, her younger children need assistance with all aspects of daily living.

To search for drugs that could help them, Katherine Beebe, a research scientist in Chow’s lab, makes a kind of “fly avatar” by engineering them to have the same disease-causing genetic changes that the kids have. Then, she and her lab colleagues put the flies in glass vials along with food mixed with FDA-approved drugs, testing 1,600 medicines altogether. Days later, they search the vials for drug “hits” that have made the avatars healthier. Additional screens narrow down the hits to the most promising candidates.

Compared to the years and hundreds of millions of dollars it takes for pharmaceutical companies to develop new drugs, fly screens yield results for a fraction of the cost in a fraction of the time. Since the drugs have already been proven safe for humans, a child’s medical team can immediately evaluate whether to try giving a child a drug that performed well in the screen.

“These screens don’t work for all diseases, but it’s something we should be doing,” Chow says. “We get results that are meaningful, and it’s so fast.”

A glimpse of hope

Once Chow set up operations to perform fly screens on demand, it didn’t take long for results to come in. One of the first screens the lab ran was for a boy named Jake Carroll, now 7 years old. He’s a happy child who reads, is good with numbers, and gets lost in music, from Miley Cyrus to the Grateful Dead. “He’s a Renaissance man,” his mom Claire Fast says. His biggest challenges are his limited interests and developmental delays that, among other things, result in him having a 10-word vocabulary.

After consulting with their pediatrician, Jake went on a low dose of a top hit from a screen tailored to his rare disease. His parents and teachers reported changes in his disposition: he became open to new experiences, was more social, and increased participation in school.

However, because of the nature of the drug, he could not stay on it long-term. And when he stopped taking it, his behavior regressed. While discouraging, the initial boost leads Claire to believe that there is something out there that can improve Jake’s quality of life. “These families go from nothing to having a list of things that could potentially work,” Chow says. “It’s certainly the most exciting thing I’ve done.”

Jake will be trying other hits from the screen. At the same time, Chow’s group is performing additional experiments in an attempt to identify other candidate treatments. Jake’s is just one of the stories that has shifted from frustration to hope.

From bench to bedside

As Jill, Doug, and Nash tour Chow’s lab, they pepper Beebe with questions. “There is an expression, ‘from bench to bedside,’” Jill remarks as she gazed into a microscope. “Until now, I’ve never actually seen the bench.” Her voice trails off, caught up in emotion.

After years of being told there was nothing anyone could do, she and her family were witnessing a team of people doing something—and making progress.

Charlotte and Cooper’s screen turned up 33 drug hits. The remarkable thing was that Chow and his team had no preconceived notion of which compounds might work. However, a group of those drugs had similar molecular targets. “The biology is trying to tell us something,” Beebe says. That information can help further refine the types of treatments that could work best.

There are more screens and tests to be done, but the Hawkinses finally feel a hint of promise when there had been none. Jill and her family know it’s unlikely they will ever be able to reverse their children’s disease. Yet for them, a treatment that could slow or stop their decline would make all the difference in the world.

“Repurposing is the best hope for finding a drug in the short immediate term for any of these disorders,” Chow says. “For so many rare diseases, the answer is sitting out there, and we just don’t know it.”