Seventeen-year-old Maddie Niles has a rare metabolic disease with no name, no known cause, and — at least for most of her life — no clear treatment plan. By the time she was in second grade, she was dependent on a wheelchair and a central line that fed her fluids and nutrients.

For most of her childhood, a packed suitcase stood permanently at the ready for the inevitable and recurring hospitalizations. She attended school — when that was even possible — with a private nurse attendant or a service dog.

Endless testing by a merry-go-round of medical specialists could not get to the bottom of a perplexing array of symptoms: Gastrointestinal bleeding, choking, fatigue, low oxygen levels, and an auditory processing disorder, among other things.

"We were just compiling this list of weird things," says Maddie's mother, Cheryl Niles. "I always described her life as 'medical whack-a-mole.' Every time we thought we had something settled, something else would pop up," says Niles, who lives with her family in Woodbridge, VA.

As Maddie entered her teenage years, says Cheryl Niles, "We knew we were losing her."

Then, 2 years ago, almost by chance, Maddie and her family stumbled upon something that would change their lives forever.

One of Maddie's doctors did a routine switch of medicines for a recurring symptom: kidney stones. Within a week or two of starting that medication, Maddie started to feel better than she had in a while. She had more energy and could concentrate for longer periods of time.

Her doctors took notice. Over the next year, with changes in dosing, Maddie's symptoms improved even more dramatically: She ate what she wanted, no longer required an oxygen tank during the day, and — after 9 years of wheelchair dependence — walked on her own.

Doctors at the Rare Disease Institute at Children's National Hospital in Washington, DC — one of the preeminent rare disease centers in the world — were surprised. They'd seen no sign that the drug would help with anything other than Maddie's kidney stones.

Was it just a lucky fluke? Perhaps.

But Maddie's story also raises an important issue: In the expensive and time-consuming race for new treatments for people with rare diseases, how many viable treatments are already sitting on the shelf at the local pharmacy?

'Rare' Disease?

In the U.S., a rare disease is one that affects fewer than 200,000 people. But with around 10,000 rare diseases, that number adds up quickly. There are about 30 million people in the U.S. living with a rare disease. That's about 1 in 10 people — about the same number that have diabetes or depression.

And those numbers may be low. Scientists are identifying about 10 to 12 new genetic diseases per week, says Marshall L. Summar, MD, director of the Rare Disease Institute Laboratory at Children's National Hospital in Washington, DC.

"Imagine a field of medicine where, every Friday, you've got 10 new diseases to learn about," says Summar, whose lab works on devices and treatments for patients with genetic and biochemical diseases.

"We're really witnessing the emergence of a new field of medicine that has its own unique rules," he says.

Many of these diseases have no cure and treatment, and for many patients, there is not even a full diagnosis.

Most rare diseases lack treatments partly because it is often unprofitable for pharma companies to develop drugs for small populations. Some very rare diseases, such as Jansen's disease (Jansen's metaphyseal chondrodysplasia), may affect less than a hundred people.

Government incentives have helped (see The Orphan Drug Act above), but basic logistics make it hard to develop drugs for a population that may be very small and spread all around the world. Even if you can get traction in research and development, the wait can be 10 to 15 years — and it can cost $1 billion or more.

Many people with rare diseases won't make it that long.

Using What We Have

David Fajgenbaum, MD, an assistant professor of medicine at the University of Pennsylvania, believes there's an easier answer.

Fajgenbaum was a third-year medical student in 2010 when doctors diagnosed him with a rare condition called idiopathic multicentric Castleman disease, which causes cell overgrowth in multiple lymph nodes and often leads to life-threatening infections or organ failure. Life expectancy: About 1 year.

Doctors had known about the disease since the 1950s. There was no known cure. Over the next 3 years, Fajgenbaum spent months in the hospital where he almost died five times, he says. At one point, he bade farewell to loved ones, and a priest came in to give him last rites.

All the while, Fajgenbaum and a small team of researchers continued to examine his own blood to search for clues about existing drugs that might help. They found an overactive pathway in his immune system and, after a couple of dead ends, they decided to test an inexpensive 25-year-old kidney transplant drug called sirolimus that appeared to work on some of the same pathways.

As with Maddie, the drug had a profound effect. Since then — about 9 years ago — Fajgenbaum has been in near perfect health and the drug has saved the lives of others with the disease.

After finding sirolimus, Fajgenbaum made a disappointing discovery. "I learned it doesn't help all Castleman patients. It only helps some of us."

So he continued to work with a team at the University of Pennsylvania, where he is now the director of the Center for Cytokine Storm Treatment & Laboratory (CSTL), to repurpose medications. The team advanced research on 9 more treatments for different forms of Castleman disease over the following years, he says. Four of these treatments are now often used off-label, and one of them is slated for a clinical trial at CSTL, Fajgenbaum says.

The team has also helped repurpose treatments for a number of other illnesses, including angiosarcoma (a rare and particularly virulent form of cancer), and COVID-19, among others. In every case, they used medications already on the market.

Still, says Fajgenbaum, he knew it was just a drop in the ocean. There are thousands of rare diseases with few or no viable treatments.

That's why, in September 2022, Fajgenbaum joined forces with longtime friend and fellow doctor Grant Mitchell, MD, and a group of experts at the University of North Carolina and beyond to leverage the power of machine learning to sift through the ocean of existing medical research to connect rare diseases to existing drugs. Their organization is called Every Cure.

Recently, through a partnership with Penn State University, Every Cure used its powerful software to look for connections between each of 3,000 FDA-approved drugs and approximately 12,000 diseases. The result was 36,000,000 ranked scores. The top hits look very promising, Fajgenbaum says, and the team is going through them to identify promising opportunities for further study.

Why isn't this already being done? "The problem is there's zero financial incentive for anyone to figure out a new use for them," Fajgenbaum says.

One reason is that drug companies make far more money on new drugs compared to older drugs no longer protected by a patent or exclusivity rights. In addition, drug companies may be wary of further clinical research because it can occasionally expose previously unknown side effects, says Fajgenbaum. So, instead of researching current medications, drug companies move on to the next big thing.

Beyond Rare Disease

Though already prescribed "off label" for certain forms of Castleman disease, sirolimus (the drug that saved Fajgenbaum) is not yet FDA-approved for this use. (Clinical phase II trials are underway.) If successful, it will make the fourth rare disease approved for treatment with sirolimus, says Christine Colvis, PhD, director of the Office of Drug Development Partnership Programs at the National Center for Advancing Translational Sciences (NCATS), in Bethesda, MD.

"This is like the dream-use case, where you have one drug that actually could treat many different conditions," says Colvis. "The number of rare diseases makes it ridiculous to think about finding treatments for one disease at a time, even through repurposing, so we would like to figure out any time there may be many diseases that could be treated with just one drug."

How many other existing drugs could have similarly broad uses? Like Fajgenbaum at Every Cure, Colvis and her team at NCATS want to find out. Her team is building a tool called the Biomedical Data Translator, that, like Every Cure, aims to forge connections among vast pieces of information in the hope of finding viable treatments.

Colvis cautions the computerized system will only be able to point to what might work. And it won't be able to predict all the potential dangers. That's where further research is key. Still, she sees incredible promise.

"It's gonna turn on a lot more light bulbs for researchers," she says.

Research like this could have benefits well beyond just those with rare disease, says Joni Rutter, PhD, the director of NCATS.

Scientists are breaking down more common conditions like breast cancer into subtypes with much smaller populations. Increasingly, the rules of rare disease diagnosis and treatment apply to common diseases as well, she says.

"So the more we can understand about rare diseases, the more we might be able to understand those nuances in common diseases and then help understand how we can deliver better therapeutics for those common diseases as well," Rutter says.