Mayo Clinic researchers have developed a new way to predict whether existing drugs could be repurposed to treat heart failure, one of the world’s most pressing health challenges. By combining advanced computer modeling with real-world patient data, the team has created "virtual clinical trials" that may facilitate the discovery of effective therapies while reducing the time, cost, and risk of failed studies.

"We've shown that with our framework, we can predict the clinical effect of a drug without a randomized controlled trial. We can say with high confidence if a drug is likely to succeed or not," says Nansu Zong, Ph.D., a biomedical informatician at Mayo Clinic and lead author of the study, which was published in npj Digital Medicine.

An urgent need

Heart failure affects more than 6 million Americans and is a leading cause of hospitalization and death. Despite decades of research, treatment options remain limited and many clinical trials fail. Traditional drug development is costly and slow, often taking more than a decade and $1 billion to bring a single therapy to market.

Drug repurposing — finding new uses for medicines already approved for other conditions — could offer a faster, less costly pathway. Because the safety of these drugs is already established, researchers can move directly to studying their potential benefits for new diseases. Yet determining which drugs are worth pursuing remains a major challenge.

Dr. Zong led efforts with a multidisciplinary team of experts in biochemistry, molecular pharmacology, cardiovascular medicine and quantitative health sciences to combine two powerful tools: computer models that predict how drugs interact with biological systems, and electronic health records (EHRs) from nearly 60,000 patients with heart failure.

Using these tools, the researchers designed virtual clinical trials — also called trial emulations — that mimic the structure of a randomized clinical trial. Instead of recruiting participants, they used existing patient data to create comparison groups and measure outcomes such as changes in biomarkers that track heart failure progression.

To strengthen the accuracy of these predictions, the team added drug-target modeling, a method that uses AI to analyze chemical structures alongside biological data, such as protein sequences or genes. This addition helped bridge the gap between real-world patient data and traditional randomized trials.

The team tested this approach with 17 drugs that had already been studied in 226 Phase 3 heart failure clinical trials. Seven had shown benefit, while 10 had not. The virtual clinical trials accurately predicted the "direction" of those real-world results.

"This model has the potential to guide drug development pipelines at scale," says Dr. Zong. "Right now, it can tell us the direction of efficacy — whether a drug will be beneficial — but not yet the level of that effect. That's our next step."

Faster, smarter clinical research

By identifying which repurposed drugs are most promising, researchers can prioritize them for further clinical testing and focus resources where success is most likely. That could mean faster access to therapies for patients and lower costs for healthcare systems.

Originally developed as an AI-enabled framework for virtual clinical trials, this technology has now led to a broader initiative within Mayo Clinic under the guidance of Cui Tao, Ph.D., the Nancy Peretsman and Robert Scully Chair of Department of Artificial Intelligence and Informatics and vice president of Mayo Clinic Platform Informatics. The new effort is exploring three complementary approaches:

• Trial emulation — replicating the design and analysis of a completed or hypothetical trial using real-world data to validate findings or generate evidence
• Trial simulation — creating a mock trial with real-world data to estimate how an existing treatment would perform in a different population or for a new indication
• Synthetic trials — constructing a trial that replaces or augments one or more arms with real-world or modeled patient data

"Clinical trials will always remain essential," says Dr. Tao. "But this innovation demonstrates how AI can make research more efficient, affordable and broadly accessible. Integrating trial emulation, simulation, synthetic trials and biomedical knowledge modeling opens the door to a new paradigm in translational science."

Looking ahead, these innovations could become an integral part of Mayo Clinic's enterprise strategy. They could support Mayo's strategic efforts such as Precure by advancing proactive risk prediction and prevention and Genesis by informing intelligent transplant care delivery and personalized interventions.

The post ‘Virtual clinical trials’ may predict success of heart failure drugs appeared first on Mayo Clinic News Network.

At the first U.S. 'Undiagnosed Hackathon,' scientists from around the world will team up at Mayo Clinic to solve unsolved medical mysteries. 

Young Julian Limon clutches his blanket wherever he goes, a source of comfort during hospital stays, procedures and tests. At 17 months, he has not yet reached walking or talking milestones. His brittle hair and unexplained neurological symptoms compound his challenges. He has endured pneumonia and other respiratory illnesses, and his weak immune system leaves him vulnerable. Despite extensive evaluations and genetic testing, Julian's condition remains a mystery.

This September, Julian's family will travel to Mayo Clinic in Minnesota to take part in the Undiagnosed Hackathon, a global effort to solve rare diseases that have long gone unexplained. 

The Hackathon was inspired by Helene and Mikk Cederroth, founders of the Wilhelm Foundation, who lost two young sons and a daughter to an undiagnosed condition. Their grief became a call to action. Over the past two decades, they've built a global network of scientists, clinicians and advocates committed to finding answers. 

An unprecedented collaboration

Over three days at Mayo Clinic, more than 125 scientists, clinicians and AI experts will gather for the first U.S.-based Undiagnosed Hackathon. They will come from 30 countries across six continents. Their goal: to uncover answers for Julian and 28 others whose conditions have eluded diagnosis. 

Having families in person at the Hackathon allows researchers to observe traits and ask questions that data alone can't capture. 

"If you put a molecular biologist next to a bioinformatician next to a clinician who have come from different parts of the world, each will bring a unique lens to the same investigation shaped by their training and lived experience," Dr. Klee says. "That's how breakthroughs happen." 

Unlocking hidden clues with advanced tools 

Among the international team are Mayo Clinic's Dr. Cherisse Marcou, assistant professor and co-director of the Clinical Genomics laboratory, and Dr. Eric Klee, the Everett J. and Jane M. Hauck Midwest Associate Director of Research and Innovation. After participating in last year’s Undiagnosed Hackathon in the Netherlands, they return with momentum to co-lead this year’s event. 

Working with global colleagues, they’ll explore DNA, RNA and other signals using tools that reveal what standard tests can miss. This includes examining long DNA stretches, studying RNA to see which genes are active and identifying chemical changes that turn genes on or off — a process called methylation.

This complex approach, known as omics, combines layers of biological information to better understand how the body works and why disease occurs. Bringing multiple omics together is more like a moving picture than a still photo, where hidden patterns emerge. Artificial intelligence will help scientists integrate these layers and interpret the results.

Breaking silos to spark breakthroughs 

"I come from a place where many families are not afforded the access to the latest and greatest diagnostic testing options in their diagnostic journey," Dr. Marcou says. "To be part of something that brings hope worldwide is deeply personal."

The idea behind the Hackathon is bringing people together who might not otherwise work side by side. 

"If you put a molecular biologist next to a bioinformatician next to a clinician who have come from different parts of the world, each will bring a unique lens to the same investigation shaped by their training and lived experience," Dr. Klee says. "That's how breakthroughs happen." 

Fueled by passion, and personal connection 

Now in its third year, the Hackathon has become a global engine for rare disease discovery. The Cederroths have co-led every one. 

"They've poured their lives into this mission," Dr. Marcou says. "Their energy is transformative. You leave the Hackathon changed." 

For Dr. Marcou, the work is personal. She grew up in the Bahamas, where access to advanced diagnostics is limited. 

"I come from a place where many families are not afforded the access to the latest and greatest diagnostic testing options in their diagnostic journey," she says. "To be part of something that brings hope worldwide is deeply personal." 

Dr. Marcou clinically interprets and decodes genomic data to deliver real-time insights for patients every day and has been involved in the development of AI tools at Mayo Clinic to advance this work. Dr. Klee, a leader in rare disease research, is building the Research Data Atlas to accelerate discoveries by unifying Mayo Clinic's extensive research data. 

Hope for families, and ripple effects worldwide

The Hackathon's goal is ambitious: solve as many cases as possible. Last year, 10 of 26 participants received diagnoses, with promising leads for nine more. One person's diagnosis can also unlock recognition, testing and potential treatment options for others with the same condition. 

"Our ultimate goal is to find answers for all our participants. That said, if we can find an answer for even one person, that would be amazing. If we find answers for 10 or 12 participants, that would be incredible," Dr. Klee says. "And for the participants where a clear answer eludes us, we hope to find strong leads that guide future research and testing for others." 

The Hackathon doesn't end when the event does. The findings must be clinically confirmed before they become diagnoses. For those who receive answers, the next goal is treatment, if one exists. For cases that remain unsolved, the work continues. 

It's also a powerful exchange of knowledge. Collaborators from places with fewer resources gain exposure to advanced techniques, while all experts have the opportunity to learn new approaches from those working alongside them. 

"It's peer-to-peer learning at its best," Dr. Marcou says. "We're all better for it." 

Julian's diagnostic journey

Even after long days of doctor visits and tests, Julian still breaks into bright smiles. He is working with physical therapists to build strength as his family continues to hope for a diagnosis. 

"I feel incredibly grateful that we'll have so many experts looking closely at Julian," says his mother, Jasmine Limon. "I just want to know what we're facing so we can give him the best possible care." 

At its heart, the Hackathon is where some of the world's brightest minds gather around families like Julian's, determined to give all they can and to open new doors in medicine. 

The post When diagnosis hits a wall, this global hackathon opens new doors  appeared first on Mayo Clinic News Network.

Mayo Clinic researchers have pinpointed how excessive alcohol consumption contributes to fatty liver disease, a condition that affects more than one in three people in the U.S. Also known as Metabolic Dysfunction Associated Steatotic Liver Disease, it is a long-lasting disease that can lead to type 2 diabetes and even liver cancer. Excessive alcohol can contribute to this fatty disease as well — and Mayo Clinic researchers recently discovered a reason why.

The researchers found that exposure to excessive alcohol alters an important enzyme that recycles damaged proteins.

How the liver works

The liver is the primary filter for everything you ingest. Liver cells, or hepatocytes, support this organ's giant job by releasing dozens of various proteins while collecting, sorting, degrading and recycling nearly everything that passes through this massive, sieve-like organ. Fat coming from the gut, for example, is absorbed then stored in hepatocytes as lipid droplets, which are globular structures that store fat. The body can use these lipid droplets as an energy source, especially during periods of fasting. However, too many lipid droplets can lead to fatty liver disease.

The researchers found the key lies with an important enzyme called the valosin-containing protein (VCP). VCP plays a role in many important processes including recycling unwanted proteins and is found in cells throughout the body.

"We were surprised to see VCP removing a specific protein from the surface of the lipid droplet. When that particular protein called HSD17β13 accumulates, the fat content in liver cells balloons and contributes to fatty liver disease," says Mark McNiven, Ph.D., senior author on the study, which was published and highlighted in the Journal of Cell Biology.

In people without fatty liver disease, the enzyme, VCP, appears to keep the protein, HSD17β13, in check to prevent lipid droplets from over-accumulating in the liver cells.

However, the researchers found that exposure to excessive alcohol removes VCP almost completely from the lipid droplet surface, allowing HSD17β13 to significantly accumulate.

Watch: The Mayo Clinic Minute

The researchers also saw and captured the elaborate recycling mechanism of VCP. They witnessed VCP working with a chaperone protein to deliver damaged proteins to an organelle called a lysosome, which then broke apart the unwanted proteins.

"It was astounding to see this. We tried several experiments to confirm what we were seeing, and every result indicated VCP directs the HSD17β13 protein from the lipid droplet to the lysosome," says Sandhya Sen, Ph.D., a Mayo Clinic research fellow and lead author of the study.

Their findings mean HSD17β13 is a target for potential new therapies to prevent or treat fatty liver disease, says Dr. McNiven.

"This study increases our understanding of the biology of lipid droplets, the central culprit of fatty liver, and how the hepatocyte works in an effort to reduce its fat content," Dr. McNiven says. "It also could help predict which patients are prone to the detrimental effect of excessive alcohol consumption on their liver if this cellular system is compromised."

The research is part of a larger effort at Mayo Clinic called the Precure initiative focused on developing tools that empower clinicians to predict and intercept biological processes before they evolve into disease or progress into complex, hard-to-treat conditions.

Review the study for a complete list of authors, disclosures and funding. 

The post New research reveals a link between excessive alcohol and fatty liver disease appeared first on Mayo Clinic News Network.

ROCHESTER, Minn. — Clinicians typically classify meningiomas — the most common type of brain tumor — into three grades, ranging from slow-growing to aggressive.

But a new multi-institutional study suggests that appearances may be deceiving. If a tumor shows activity in a gene called telomerase reverse transcriptase (TERT), it tends to recur more quickly, even if it looks low-grade under the microscope.

"High TERT expression is strongly linked to faster disease progression," says Gelareh Zadeh, M.D., Ph.D., a neurosurgeon at Mayo Clinic and senior author of the study. "This makes it a promising new biomarker for identifying patients who may be at greater risk of developing aggressive disease."

An early warning sign

Meningiomas — tumors of the meninges, the protective tissue that surrounds the brain and spinal cord — are generally considered benign. But a small subset of these tumors has a mutation in the TERT gene, which is linked to faster growth and a shorter time before the tumor returns after treatment.

TERT is the active part of telomerase, an enzyme that maintains telomeres, the protective ends of chromosomes. In most healthy adult cells, TERT is switched off. But if it becomes switched back on, it can fuel cancer development by driving unchecked cell growth.

In this study, the researchers wanted to see whether high TERT expression, even in the absence of the TERT genetic mutation, also predicted worse outcomes. They looked at more than 1,200 meningiomas from patients across Canada, Germany and the U.S., and they found that nearly one-third of them had high TERT expression despite not having the mutation.

These patients had earlier tumor regrowth compared to those without TERT expression, though their outcomes were better than patients with full-blown TERT mutations.

"TERT-positive tumors behaved like they were one grade worse than their official diagnosis," says Dr. Zadeh. "For example, a grade 1 tumor with TERT expression acted more like a grade 2."

Guiding treatment decisions

The findings suggest that testing for TERT activity could help doctors predict which patients are at higher risk for recurrence and may need closer monitoring or more intensive treatment.

"Because meningiomas are the most common primary brain tumor, this biomarker could influence how thousands of patients are diagnosed and managed worldwide," says Dr. Zadeh.

"TERT expression can help us more accurately identify patients with aggressive meningiomas," Chloe Gui, M.D., a neurosurgery resident at the University of Toronto, Mayo Clinic research collaborator and the study's lead author, explains on a podcast hosted by The Lancet Oncology. "This information allows us to offer treatment tailored to the tumor's behavior." "This information allows us to offer treatment tailored to the tumor's behavior."

The team is currently investigating ways to incorporate TERT expression into the clinical workflow. The research is part of a larger effort at Mayo Clinic called the Precure initiative, focused on developing tools that empower clinicians to predict and intercept biological processes before they evolve into disease or progress into complex, hard-to-treat conditions.

Review the study for a complete list of authors, disclosures and funding. 

###

About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and to providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.

Media contact:

• Tia Ford, Mayo Clinic Communications, newsbureau@mayo.edu

The post New genetic biomarker flags aggressive brain tumors appeared first on Mayo Clinic News Network.

ROCHESTER, Minn. — The immune system is meant to protect the body from infection and disease. But with age, it can become less capable of doing so. However, Mayo Clinic researchers have found that some older people maintain "immune youth" – a new term coined by Mayo researchers to explain a young immune system in someone over age 60.

"We are studying why some individuals have a 'fountain of youth' in their immune systems. We want to learn from them," says Cornelia Weyand, M.D., Ph.D., a Mayo Clinic rheumatologist and clinician-scientist. She is a lead author on a perspective paper published in Nature Aging.

Dr. Weyand's research team discovered this cellular fountain of youth in more than 100 older patients who came to Mayo Clinic to receive treatment for an autoimmune disease that affects the arteries, including the aorta, called giant cell arteritis. Dr. Weyand and colleagues found in the diseased tissue of these patients specialized immune cells, called stem-like T cells. These immune cells behave like young stem cells that usually regenerate and aid healing and growth; but in this case, they were spreading the disease. This team of researchers also discovered autoimmune stem cells in humans previously.

"We observed that these patients have very young immune systems despite being in their 60s and 70s. But the price they pay for that is autoimmunity," she says.

Autoimmunity is when the immune system mistakenly attacks healthy tissues and organs.

In addition, the researchers saw that the immune checkpoint inhibitors that regulate the immune system were not working properly.

Benefits of immune system aging

"Contrary to what one may think, there are benefits to having an immune system that ages in tandem with the body," says Jörg Goronzy, M.D., Ph.D., a Mayo Clinic researcher on aging who is a co-lead author of the paper. "We need to consider the price to pay for immune youthfulness. That price can be autoimmune disease."

Immune aging is a sophisticated adaptation mechanism that the immune system can use to prevent autoimmune disease, say the researchers.

They are in the process of developing new diagnostic tests that will help find patients and healthy individuals who carry high numbers of immune stem cells and may be predisposed to autoimmune disease later in life. The research is part of a larger effort at Mayo Clinic called the Precure initiative, focused on developing tools that empower clinicians to predict and intercept biological processes before they evolve into disease or progress into complex, hard-to-treat conditions.

Review the study for a complete list of authors, disclosures and funding. 

Additional resources:
Mayo Clinic advances research on mysterious blood vessel disease

###

About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.

Media contact:

• Alison Satake, Mayo Clinic Communications, newsbureau@mayo.edu

The post Mayo Clinic researchers discover the immune system’s ‘fountain of youth’ appeared first on Mayo Clinic News Network.

ROCHESTER, Minn. — Scientific breakthroughs in one disease don't always shed light on treating other diseases. But that's been the surprising journey of one Mayo Clinic research team. After identifying a sugar molecule that cancer cells use on their surfaces to hide from the immune system, the researchers have found the same molecule may eventually help in the treatment of type 1 diabetes, once known as juvenile diabetes.

Type 1 diabetes is a chronic autoimmune condition in which the immune system errantly attacks pancreatic beta cells that produce insulin. The disease is caused by genetic and other factors and affects an estimated 1.3 million people in the U.S.

In their studies, the Mayo Clinic researchers took a cancer mechanism and turned it on its head. Cancer cells use a variety of methods to evade immune response, including coating themselves in a sugar molecule known as sialic acid. The researchers found in a preclinical model of type 1 diabetes that it's possible to dress up beta cells with the same sugar molecule, enabling the immune system to tolerate the cells.

"Our findings show that it's possible to engineer beta cells that do not prompt an immune response," says immunology researcher Virginia Shapiro, Ph.D., principal investigator of the study, published in the Journal of Clinical Investigation.

A few years ago, Dr. Shapiro's team demonstrated that an enzyme, known as ST8Sia6, that increases sialic acid on the surface of tumor cells helps tumor cells appear as though they are not foreign entities to be targeted by the immune system.  

"The expression of this enzyme basically ‘sugar coats' cancer cells and can help protect an abnormal cell from a normal immune response. We wondered if the same enzyme might also protect a normal cell from an abnormal immune response," Dr. Shapiro says. The team first established proof of concept in an artificially-induced model of diabetes.

In the current study, the team looked at preclinical models that are known for the spontaneous development of autoimmune (type 1) diabetes, most closely approximating the process that occurs in patients. Researchers engineered beta cells in the models to produce the ST8Sia6 enzyme.

In the preclinical models, the team found that the engineered cells were 90% effective in preventing the development of type 1 diabetes. The beta cells that are typically destroyed by the immune system in type 1 diabetes were preserved.

Importantly, the researchers also found the immune response to the engineered cells appears to be highly specific, says M.D.-Ph.D. student Justin Choe, first author of the publication. Choe conducted the study in the Ph.D. component of his dual degree at Mayo Clinic Graduate School of Biomedical Sciences and Mayo Clinic Alix School of Medicine.

"Though the beta cells were spared, the immune system remained intact," Choe says. The researchers were able to see active B- and T-cells and evidence of an autoimmune response against another disease process. "We found that the enzyme specifically generated tolerance against autoimmune rejection of the beta cell, providing local and quite specific protection against type 1 diabetes."

No cure currently exists for type 1 diabetes, and treatment involves using synthetic insulin to regulate blood sugar, or, for some people, undergoing a transplant of pancreatic islet cells, which include the much-needed beta cells. Because transplantation involves immunosuppression of the entire immune system, Dr. Shapiro aims to explore using the engineered beta cells in transplantable islet cells with the goal of ultimately improving therapy for patients.

"A goal would be to provide transplantable cells without the need for immunosuppression," says Dr. Shapiro. "Though we're still in the early stages, this study may be one step toward improving care."

The research was funded by grants from the National Institutes of Health.

Please see the study for the full list of authors.

###

About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.

Media contact:

• Kelley Luckstein, Mayo Clinic Communications, newsbureau@mayo.edu

The post Mayo Clinic researchers find ‘sugar coating’ cells can protect those typically destroyed in type 1 diabetes appeared first on Mayo Clinic News Network.

For nearly three decades, Mayo Clinic researcher Christopher Evans, Ph.D., has pushed to expand gene therapy beyond its original scope of fixing rare, single-gene defects. That has meant systematically advancing the field through laboratory experiments, pre-clinical studies and clinical trials.

Several gene therapies have already received approval from the U.S. Food and Drug Administration (FDA), and experts predict that 40 to 60 more could be approved over the next decade for a range of conditions. Dr. Evans hopes a gene therapy for osteoarthritis — a form of arthritis affecting more than 32.5 million U.S. adults — will be one of them.

Recently, Dr. Evans and a team of 18 researchers and clinicians reported the results of a first-in-human, phase 1 clinical trial of a novel gene therapy for osteoarthritis. The findings, published in Science Translational Advances, demonstrated that the therapy is safe, achieved sustained expression of a therapeutic gene inside the joint and offered early evidence of clinical benefit.

"This could revolutionize the treatment of osteoarthritis," says Dr. Evans, who directs the Musculoskeletal Gene Therapy Research lab at Mayo Clinic.

In osteoarthritis, the cartilage that cushions the ends of bones — and sometimes the underlying bone itself — degenerates over time. It is a leading cause of disability, and notoriously difficult to treat. "Any medications you inject into the affected joint will seep right back out in a few hours," says Dr. Evans. "As far as I know, gene therapy is the only reasonable way to overcome this pharmacologic barrier, and it's a huge barrier." By genetically modifying cells in the joint to produce their own pharmacy of anti-inflammatory molecules, Evans aims to engineer knees that are more resistant to arthritis.

The Evans laboratory found that a molecule called interleukin-1 (IL-1) plays an important role in fueling inflammation, pain and cartilage loss in osteoarthritis. As luck would have it, the molecule had a natural inhibitor, aptly named the IL-1 receptor antagonist (IL-1Ra), that could form the basis of the first gene therapy for the disease. In 2000, Dr. Evans and his team packaged the IL-1Ra gene into a harmless virus called AAV, which they tested in cells and then pre-clinical models. The results were encouraging.

In pre-clinical testing, his collaborators at the University of Florida demonstrated that the gene therapy successfully infiltrated the cells that make up the synovial lining of the joint as well as the neighboring cartilage. The therapy protected the cartilage from breakdown. In 2015, the team got investigational new drug approval to start human testing. But regulatory hurdles and manufacturing challenges kept them from injecting their first patient for another four years. Mayo Clinic has since established a new process for accelerating clinical trial activation that could help researchers launch studies more quickly.

In the recent study, Dr. Evans and his team gave the experimental gene therapy to nine patients with osteoarthritis, delivering it directly into the knee joint. They found that the levels of the anti-inflammatory IL-1Ra increased and remained elevated in the joint for at least a year. Participants also reported reduced pain and improved joint function, with no serious safety issues. Dr. Evans says the findings suggest the treatment is safe and may offer long-lasting relief from osteoarthritis symptoms. "This study provides a highly promising, novel way to attack the disease," he says.

Dr. Evans has co-founded an arthritis gene therapy company called Genascence to drive the project forward. The company just completed a larger phase Ib study and is in discussions with the FDA about launching a pivotal phase IIb/III clinical trial to evaluate the therapy's effectiveness, the next step before FDA approval for the therapy.

Review the study for a complete list of authors, disclosures and funding. 

Additional resources:

• Pushing the limits of gene therapy for osteoarthritis

The post Progress in gene therapy offers hope for long-term knee pain relief appeared first on Mayo Clinic News Network.

ROCHESTER, Minn. — Mayo Clinic researchers have discovered a key reason some cancer patients relapse after receiving chimeric antigen receptor T-cell therapy, or CAR-T cell therapy. Over time, the engineered immune cells age and lose their ability to fight cancer.  

Published in Molecular Cancer, the study identifies this aging process, known as senescence, as a previously unrecognized mechanism of CAR-T failure.   

The researchers also showed that senescence is influenced by how CAR-T cells are engineered. Certain intracellular features — such as how the cell recognizes cancer and how strongly it activates — can overwork the cells. The researchers found that if the activation signal is too intense or prolonged, it can push CAR-T cells into premature aging.  

The discovery may guide the development of next-generation CAR-T therapies that last longer and are more effective across a broader range of cancers.  

"This is one of the most clinically relevant discoveries we've made because it doesn't just explain the cause of relapse, it gives us a biological target to possibly prevent it," says Saad Kenderian, M.B., Ch.B., a principal investigator and hematologist at Mayo Clinic.  

CAR-T therapy reprograms a patient's own immune cells to recognize and destroy cancer. It has led to long-term remission for patients, including some with aggressive or treatment-resistant diseases. But many patients eventually relapse, and the causes have remained poorly understood. 

Modeling CAR-T cell stress over time 

To investigate why CAR-T therapy can fail, the Mayo team developed a novel lab model that simulates long-term biological stress, offering a clearer view of how the engineered cells behave after infusion. Over time, some CAR-T cells lost their ability to multiply and attack cancer. Specifically, they showed hallmark signs of senescence, including distinct genetic changes.  

The researchers found that senescence occurred more often in CAR-T cells built with a signaling feature, known as 4-1BB, which affects how the cells respond to cancer. In comparison, cells designed with an alternative domain, called CD28, were less affected by aging. These cells activate more quickly and persist for a shorter time, reducing the cumulative stress that drives senescence.

The researchers confirmed the results in multiple laboratory models and validated them in patient samples.

Engineering CAR-T cells for longevity 

That discovery was driven in part by the work of Ismail Can, Ph.D., who helped lead the molecular analysis behind the finding. 

"Efforts to make CAR-T cell therapy more durable will likely fail without fully understanding the reasons behind CAR-T cell failure. This study represents a significant step toward understanding why CAR-T cells fail," says Dr. Can, first author of the study and a senior research fellow at Mayo Clinic’s T Cell Engineering Laboratory. "By identifying the early molecular triggers of senescence, we can begin to refine CAR-T design to potentially improve long-term function and reduce relapse." 

The findings highlight a new direction for CAR-T research, with potential implications not only for blood cancers but also for expanding cell therapy into solid tumors.  

The study builds on Dr. Kenderian's broader efforts to identify resistance mechanisms and design more durable and personalized immunotherapies.   

This work was supported in part by Mayo Clinic Comprehensive Cancer Center, the Eagles 5th District Cancer Telethon Funds for Cancer Research, the State of Minnesota, and benefactors Georgia and Michael Michelson. For a complete list of authors, disclosures and funding information, review the study.    

### 

About Mayo Clinic 
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news. 

Media contact:  

• Sharon Theimer, Mayo Clinic Communications, newsbureau@mayo.edu 

The post Mayo Clinic researchers link CAR-T cell aging to cancer relapse  appeared first on Mayo Clinic News Network.

Just one day after undergoing brain shunt surgery at Mayo Clinic, 75-year-old Minoo Press put his wheelchair aside and walked out of the hospital on his own. For the first time in two years, his mind was clear. His balance had returned. He was no longer losing control of his bladder. 

The significant turnaround followed two years of steady cognitive and physical decline. A retired engineer known for his sharp mind and independence, Press gradually withdrew from daily life. Even simple routines became impossible. 

He visited leading medical centers across the country, undergoing spinal taps, surgical procedures and advanced imaging to evaluate for conditions ranging from Alzheimer's disease to Parkinson's. 

Some clinicians at those institutions also considered normal pressure hydrocephalus, a condition in which excess fluid builds up in the brain. But because Mr. Press' symptoms overlapped with signs of neurodegenerative disease, the doctors could not confirm the diagnosis or recommend surgery. They told him there was nothing more they could do. 

From rapid diagnosis to life-changing care

After an exhaustive search for answers, Press' family brought him to Mayo Clinic where he was evaluated by Dr. David Jones, a neurologist and director of Mayo Clinic's Neurology Artificial Intelligence Program.   

Dr. Jones used an innovative artificial intelligence tool developed by his team, called StateViewer. The tool works with a widely available brain scan known as fluorodeoxyglucose positron emission tomography, or FDG-PET, comparing a patient's brain activity to thousands of confirmed dementia cases. It highlights patterns linked to nine types of the disease — from Alzheimer's and frontotemporal dementia to less common forms with overlapping symptoms. 

In a recent study published in Neurology, the tool identified the correct dementia type in 88% of cases and helped clinicians interpret scans up to three times more accurately and twice as fast as standard methods.  

In Press' case, the tool helped Dr. Jones rule out Alzheimer's and other types of dementia. That was the turning point.  

With neurodegenerative disease ruled out, Dr. Jones diagnosed Press with normal pressure hydrocephalus and confirmed that he was a candidate for a shunt procedure to relieve the pressure on his brain and potentially reverse the symptoms.  

A last-minute surgical cancellation made it possible for Press to have the procedure that same week.

Within three days at Mayo Clinic, he had a clear diagnosis, a treatment plan and underwent brain surgery to place a shunt that would drain excess fluid from his brain. The procedure was performed by Dr. Ben Elder, a neurosurgeon and clinician-scientist.  

Press, who traveled from Chicago, noticed immediate improvements. His thinking was sharper, his steps steadier and he felt like himself again. 

A clear mind, steady steps and hope

Dr. Jones says Press' case highlights the promise of combining AI with clinical care to accelerate diagnosis, scale expert clinical knowledge and help guide treatment planning.  

"When you're looking at overlapping symptoms, it's easy to miss the underlying cause," Dr. Jones says. "StateViewer gave us the clarity we needed to make an informed diagnosis and take action." 

Press continues physical therapy and says he's improving every day. He hopes his story can help others who are navigating the same often misdiagnosed and debilitating condition. 

"I can enjoy time with my family again and I can go out with my friends. I can even do my own taxes. These are the moments I thought I had lost forever," Mr. Press says. "Mayo Clinic gave me my life back." 

Related article:

Mayo Clinic's AI tool identifies 9 dementia types, including Alzheimer's, with one scan

Mayo Clinic researchers have developed a new artificial intelligence (AI) tool that helps clinicians identify brain activity patterns linked to nine types of dementia, including Alzheimer's disease, using a single, widely available scan — a transformative advance in early, accurate diagnosis. Read more.

The post How a Mayo Clinic neurologist used AI to help restore a patient’s health appeared first on Mayo Clinic News Network.

ROCHESTER, Minn. — Mayo Clinic researchers have developed a new artificial intelligence (AI) tool that helps clinicians identify brain activity patterns linked to nine types of dementia, including Alzheimer's disease, using a single, widely available scan — a transformative advance in early, accurate diagnosis. 

The tool, StateViewer, helped researchers identify the dementia type in 88% of cases, according to research published online on June 27, 2025, in Neurology, the medical journal of the American Academy of Neurology. It also enabled clinicians to interpret brain scans nearly twice as fast and with up to three times greater accuracy than standard workflows. Researchers trained and tested the AI on more than 3,600 scans, including images from patients with dementia and people without cognitive impairment. 

This innovation addresses a core challenge in dementia care: identifying the disease early and precisely, even when multiple conditions are present. As new treatments emerge, timely diagnosis helps match patients with the most appropriate care when it can have the greatest impact. The tool could bring advanced diagnostic support to clinics that lack neurology expertise. 

The rising toll of dementia 

Dementia affects more than 55 million people worldwide, with nearly 10 million new cases each year. Alzheimer's disease, the most common form, is now the fifth-leading cause of death globally. Diagnosing dementia typically requires cognitive tests, blood draws, imaging, clinical interviews and specialist referrals. Even with extensive testing, distinguishing conditions such as Alzheimer's, Lewy body dementia and frontotemporal dementia remains challenging, including for highly experienced specialists. 

StateViewer was developed under the direction of David Jones, M.D., a Mayo Clinic neurologist and director of the Mayo Clinic Neurology Artificial Intelligence Program.  

"Every patient who walks into my clinic carries a unique story shaped by the brain's complexity," Dr. Jones says. "That complexity drew me to neurology and continues to drive my commitment to clearer answers. StateViewer reflects that commitment — a step toward earlier understanding, more precise treatment and, one day, changing the course of these diseases." 

To bring that vision to life, Dr. Jones worked alongside Leland Barnard, Ph.D., a data scientist who leads the AI engineering behind StateViewer. 

"As we were designing StateViewer, we never lost sight of the fact that behind every data point and brain scan was a person facing a difficult diagnosis and urgent questions," Dr. Barnard says. "Seeing how this tool could assist physicians with real-time, precise insights and guidance highlights the potential of machine learning for clinical medicine." 

Turning brain patterns into clinical insight 

The tool analyzes a fluorodeoxyglucose positron emission tomography (FDG-PET) scan, which shows how the brain uses glucose for energy. It then compares the scan to a large database of scans from people with confirmed dementia diagnoses and identifies patterns that match specific types, or combinations, of dementia. 

Alzheimer's typically affects memory and processing regions, Lewy body dementia involves areas tied to attention and movement, and frontotemporal dementia alters regions responsible for language and behavior. StateViewer displays these patterns through color-coded brain maps that highlight key areas of brain activity, giving all clinicians, even those without neurology training, a visual explanation of what the AI sees and how it supports the diagnosis. 

Mayo Clinic researchers plan to expand the tool's use and will continue evaluating its performance in a variety of clinical settings. 

For a complete list of authors, disclosures and funding, review the study.

### 

About Mayo Clinic 
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news. 

Media contact:  

• Tia Ford, Mayo Clinic Communications, newsbureau@mayo.edu 

The post Mayo Clinic’s AI tool identifies 9 dementia types, including Alzheimer’s, with one scan  appeared first on Mayo Clinic News Network.