Over the course of 12 years, Brendon Paradis lost his eyesight to a disease with no name. Starting in his mid-20s, his symptoms puzzled one doctor after another, leaving him bouncing between specialists as his vision faded. By age 37, he was completely blind, and no one knew why.
The answer finally came in 2019, when his young son, Keegan, received a diagnosis: . Fewer than 70 people worldwide have been diagnosed with this inherited autoimmune disorder, which inflames the optic nerve, joints, and spleen. Left untreated, it causes retinal damage and vision loss, as it did with Brendon. He hopes Keegan’s future will be different.
Keegan was in first grade when a routine exam detected mild eye inflammation. Multiple specialists later, he was referred to the (UDN), a National Institutes of Health-funded program on a mission to solve the rarest and most confounding of medical cases, illuminate the processes that fuel these diseases, and generate broader insights about human health.
With Keegan’s diagnosis, the pieces of the puzzle finally fell into place, Brendon says. It explained why Brendon's own father’s vision loss was attributed to retinitis pigmentosa, a genetic condition Brendon did not have.
“Keegan’s diagnosis led to Brendon getting diagnosed and other family members getting tested and diagnosed, and it’s altered the trajectory of the treatment,” says Keegan’s mother, Andria Paradis. “Keegan is getting treated in the hopes of keeping inflammation at bay to avoid the same outcome as Brendon.”
Stories like Brendon’s are common among those with rare diseases. Patients often spend years searching for answers, frustrated and scared, as their diseases progress relentlessly. But since the UDN’s inception in 2014, nearly 100 new conditions, and diagnosed 855 individuals with previously unknown diseases. The progress made by the UDN — and the broader field of rare disease research — could also bring about insights into more common conditions and benefit the field of medicine more broadly.
The lessons of rare disease research
Although each rare disease occurs in a relatively small number of people — fewer than 200,000 per condition in the U.S. — collectively, they affect an estimated in this country and . Of the , 95 percent have no treatment. Identifying the cause of a condition — the exact molecular glitch that ignites it — is key to developing treatments that go beyond symptom relief and target the disease at its very root. This is the UDN’s reason for being.
The work takes place across nationwide. HMS helms the UDN’s research activities and leads its data operations. Under principal investigator , head of the department of biomedical informatics in the Blavatnik Institute, HMS oversees the collection, management, and storage of research data emanating from participating hospitals. HMS also leads activities such as AI tool development, genomic analysis, and outreach and engagement at UDN centers across the U.S.: Morehouse School of Medicine, University of Alabama at Birmingham, University of Utah, Washington University in St. Louis, and Stanford University.
The UDN embodies the principles of precision medicine, tailoring diagnoses and treatments to individual patients based on their unique genetic and molecular profiles. This model could serve as a blueprint for improving standard medical care as a whole.
“When conventional medicine does not have the answer, deeper and focused research turns into action to diagnose many of these patients for the first time in years and start them on treatments,” says Kohane. “This demonstrates how research and clinical care can be productively linked.”
The UDN’s approach streamlines complex medical evaluations, compressing them into several days of intensive testing with a multidisciplinary team. Data and biological samples collected from patients are stored and shared, enabling future research and collaboration. Unlike standard medical practice, which often lacks a direct link between clinicians and researchers, the UDN fosters continuous interaction between the two, enhancing both diagnosis and treatment strategies.
“We see these types of collaborations in rare disease research, but in mainstream medicine, they’re far less common,” says , senior director of the UDN Coordinating Center at HMS. “By working closely together, clinicians and researchers gain deeper insights that improve both patient care and scientific discovery.”
Beyond its impact on individual patients, rare disease research can also reveal fundamental biological mechanisms that apply to more common diseases and lead to insights that can transform medical understanding and treatment.
Take Mitchell syndrome, a UDN-identified disorder named after the first patient to be diagnosed with a never-before-seen mutation in a gene called ACOX1, which plays a key role in fat metabolism. At Baylor College of Medicine — a UDN Model Organism Screening Center that receives funds through HMS — that this novel mutation causes the protein made by the ACOX1 gene to become overactive, which leads to an overabundance of harmful molecules called reactive oxygen species that damage glial cells supporting the brain and spinal cord.
Glial cell damage is also a hallmark of other neurodegenerative diseases, such as multiple sclerosis (MS). Indeed, the loss of ACOX1 causes defects that are observed in patients with MS that are different from those seen in Mitchell syndrome, where the ACOX1 protein is too active. Instead, the missing protein causes a toxic buildup of a lipid called S1P, which damages glial cells and activates the immune system. The Baylor team showed that dampening the production of S1P alleviated neurologic symptoms in a mouse model of MS. This finding, the team said, arose from research into a rare condition that identified a novel mechanism — and possible pathway for treatment — of a common neurodegenerative disease.
Another example comes from research on PLA2G6, a gene linked to the rare neurodegenerative disorder infantile neuroaxonal dystrophy. At Baylor, UDN that mutations in this gene disrupt the proper recycling of membrane fats, leading to a harmful buildup of fat molecules called ceramides. By lowering ceramide levels with existing drugs, they were able to reduce nerve cell damage. The scientists also found that similarly elevated levels of ceramides occur in Parkinson’s disease models — a clue that rare and common neurodegenerative diseases may share a pathway and that lowering levels of ceramides may benefit patients with Parkinson’s disease.
Looming uncertainty over federal funding
After WWII, a by President Franklin D. Roosevelt formulated the vision for the future of science and laid the foundation of modern U.S. science policy. The landmark report was based on the premise that government-funded basic research was essential for national security, economic growth, and the nation’s health. Over the decades, the vision has spurred scientific breakthroughs and fueled a boom in multiple fields of science and a range of industries.
Now, a vigorous debate over federal funding for academic research has created uncertainty about the future of biomedical discovery. In the meantime, programs such as the UDN hang in the balance.
“The uncertainty has had a serious effect on team morale and is causing fear among patients and their families who rely on this work,” LeBlanc says. “Without stable funding, our ability to diagnose and treat rare diseases diminishes. A secure funding source is imperative for future discoveries.”
To date, Congress has allocated about $18 million per year to the UDN. About $10 million of this money supports hospital sites that care for patients and conduct research that yields critical evidence for scientists to comb for clues in their efforts to identify disease and possible treatments.
HMS receives roughly $8.5 million — more than half (nearly $5 million) of which is distributed among UDN centers across seven states, in addition to Massachusetts: Alabama, California, Georgia, Missouri, Oregon, Texas, and Utah. The UDN’s Model Organism Screening Centers at Baylor College of Medicine, Washington University in St. Louis, and the University of Oregon study animal models to map disease mechanisms — a crucial step in making diagnoses and identifying treatments. Baylor also runs a genetic sequencing program, which offers DNA analyses for uninsured patients or those whose insurance won’t cover testing. Without sequencing, diagnoses become impossible.
AI and rare disease research
Over the past two decades, advances in genomics, molecular biology, and proteomics have revolutionized medicine and generated vast amounts of data. Now, researchers use AI to reap the benefits of these earlier advances in several ways. AI can analyze reams of data at never-before-seen speed and in record time to disease-causing gene mutations and benign variations, and it can uncover possible treatments. For the first time, AI can be used to diagnose previously undiagnosable patients, identify new biological drivers of rare diseases, and inform the design of treatments for them.
In 2024, scientist developed an that identifies treatments for thousands of rare diseases from already approved drugs and experimental compounds. The AI model is already being used by rare disease foundations and by clinicians who treat patients with rare diseases.
“Reducing research support for rare diseases now would severely disrupt the momentum created by AI,” says Zitnik, who is an associate professor of biomedical informatics in the Blavatnik Institute at HMS. “AI-driven discovery relies on continuous, iterative cycles of hypothesis generation, experimentation, and data refinement. Patients awaiting diagnosis and treatment would face longer waits, and we risk losing our current edge precisely when AI is beginning to produce tangible results.”
The personal and collective stakes
For Brendon Paradis, the stakes are deeply personal. Thanks to the UDN, his son now has a chance at a different future because the rigorous follow-up and timely treatment will stave off eye-damaging inflammation even in the absence of a cure.
“I hope Keegan will live a long healthy life with good vision and not face the obstacles I did. Even though there’s no cure, the doctors know what they are treating,” Brendon says. “I am confident that researchers will continue to work toward new therapies and give my son a chance to take advantage of them in the future.”
Yet, given the uncertainty around federal funding support, the next family searching for answers may not be as lucky.
“It’s saddening to think about what happens if we lose momentum,” Kohane says. “How many Keegans won’t get diagnosed? How many diseases will remain undiscovered? The consequences are unknowable — but they could be profound.”
RSS