New Pathway to Treating Rheumatoid Arthritis Identified

Updated on Jun 30, 2022 | Featured, Research, Your Health

Pércio S. Gulko, MD, center, with team members Teresina Laragione, PhD, Assistant Professor of Medicine (Rheumatology), left, and Carolyn Harris, Senior Associate Researcher.

A new gene associated with disease severity in rheumatoid arthritis (RA) has been identified by researchers at the Icahn School of Medicine at Mount Sinai. This finding could provide a new pathway for treatment and a way to measure the prognosis of patients diagnosed with this autoimmune condition.

Through a series of experiments, Pércio S. Gulko, MD, Chief of the Division of Rheumatology, and the Lillian and Henry M. Stratton Professor of Medicine (Rheumatology), and his colleagues showed that Huntingtin-interacting protein 1 (HIP1) is a driver in inflammatory arthritis severity. The findings were published in July 2018 in the Annals of the Rheumatic Diseases. “It is known that this gene is expressed in some cancers, but precisely how it contributed to cancer was not known, and it has never been implicated in inflammation or arthritis. So this new discovery, that it regulates cell invasion, is completely novel,” says Dr. Gulko, senior author of the paper.

Rheumatoid arthritis is a chronic disease affecting more than 1.3 million Americans. The disease causes pain, swelling, and sometimes deformation of joints and affects about 1 percent of the world’s population. In the last 20 years, there have been major advances in the treatment of RA, but the existing treatments immunosuppress patients, increasing the risk for infections.

Dr. Gulko with images of synovial fibroblasts, cells in the joints that are central to his team’s study of rheumatoid arthritis.

“At my laboratory, we have been looking for alternative strategies,” Dr. Gulko says. “We have focused on understanding the regulation of disease severity and joint damage, and this led us to the synovial tissue and the fibroblasts.” These cells are present in all joints and produce the fluid that lubricates and nourishes the cartilage, but in patients with RA, they grow out of control, invading and destroying cartilage and bone.

Dr. Gulko’s team started with rodent models of arthritis, studying animals that were highly susceptible to RA and those that were resistant. Using a technique called positional cloning, the researchers identified gene variants that control arthritis severity and the behavior of the synovial fibroblasts, finding that HIP1 made the cells highly invasive. Next, the team studied synovial fibroblasts from patients with RA and found that HIP1 was strongly expressed in those cells.  To test the finding further, the team used a molecular biology technique to “knock down,” or remove, HIP1 from the cells of RA patients, and found that this significantly reduced the cells’ ability to invade.

The team unexpectedly found further evidence implicating HIP1 while  collaborating in a study of RA and epigenetics, the environmental influence on genetics. The study, which was published in May 2018 in Nature Communications, compared the synovial fibroblasts of patients with RA with those from patients with osteoarthritis, which is not considered an inflammatory disease. The researchers were looking for dysregulated genes and pathways that differentiated the two groups of patients.

“One key pathway found to be epigenomically dysregulated was the Huntington protein pathway, including HIP1,” Dr. Gulko says.

Going forward, Dr. Gulko has several goals: improving the understanding of how HIP1 regulates disease; finding a way to quantify HIP1 levels in the blood or synovial fluid cells with the aim of creating a predictor of disease prognosis; and developing a drug that would target the HIP1 gene. The ultimate goal is to achieve remission for RA patients.

“I treat many patients with rheumatoid arthritis,” Dr. Gulko says, “and all the work that we have done throughout my career has been centered on trying to bring a benefit to these patients.”

 

Read more Featured stories about Mount Sinai

FAMILIA Trial Teaches Healthy Habits at Early Age

Updated on Jun 30, 2022 | Community, Featured, Research

Natalia Leal and her son Gabriel are participants in FAMILIA, which instructs preschoolers and their families on cardiovascular health.

Children will listen. That is the simple premise underlying FAMILIA, a trial developed by Valentin Fuster, MD, PhD, Director of Mount Sinai Heart and Physician-in-Chief of The Mount Sinai Hospital, to promote cardiovascular health among children while reducing their chances of developing risk factors for heart disease.

The “Family-Based Approach in a Minority Community Integrating Systems-Biology for Promotion of Health” (FAMILIA) trial enrolled 600 families in Harlem, including 562 children ages 3 to 5, over the last four years. It has demonstrated that a school-based education intervention is an effective strategy for instilling healthy behaviors among preschoolers, according to an abstract that Dr. Fuster presented in November 2018 at the American Heart Association Scientific Sessions in Chicago.

Dr. Fuster is a pioneer in the study of atherosclerotic disease—the build-up of fats, cholesterol, and other substances in and on artery walls—which is the leading cause of death in the United States. It develops slowly over a lifetime and is often caused by such factors as an unhealthy diet, lack of exercise, and tobacco use.

“There is good data showing that part of our behavior as adults develops between ages 3 and 5,” Dr. Fuster says. “If this age is so important, why wouldn’t we use this window of opportunity to teach children to make health a priority for the rest of their lives?”

Funded by a $3.8 million grant from the American Heart Association, FAMILIA is based on successful health interventions that Dr. Fuster developed in Bogota, Colombia, and Spain. Like those programs, FAMILIA is exploring how a child’s behavior, environment, and genetics may lead to heart disease, with the goal of reducing the future risk of obesity, heart attack, stroke, and type 2 diabetes by creating a family-based “culture of health.”

The specific objective of the FAMILIA trial was to “assess the impact of a preschool-based health promotion education intervention in an underserved community.” It enrolled children in 15 Head Start preschools, forming a cohort that was 51 percent female, 54 percent Hispanic/Latino, and 37 percent African American. Children were randomly assigned to either a control group that received their school’s normal curriculum or a group that received 50 hours of heart-health education over four months.

At the start, each child was interviewed by a team member with experience in early childhood education, using tools that were pictorial and structured like an interactive game. Based on the results, each child was given a KAH (knowledge, attitudes, and habits) score. The children who received intervention learned lessons, including: how the heart works; how to select healthy foods; how to regulate their emotions; and how to stay physically active and encourage their families to be active, too. After four months, researchers interviewed the preschoolers again and measured the change in KAH from the baseline.

Researchers found that the overall KAH score rose 11.8 percent from the baseline in the intervention group, compared with 5.5 percent in the control group. Based on the children’s responses, their attitudes about staying active and their understanding of the human body and heart were the biggest drivers of the higher KAH scores, researchers said. The team is planning to conduct a long-term follow-up at five and ten years to assess the sustainability of the intervention effects.

FAMILIA also includes a parallel program for the parents and caregivers of children in the trial. Some adults meet in small groups to help each other get healthier through peer support, while others receive individualized lifestyle counseling and a personal activity-monitoring device. Results from that program are expected in late 2019.

“What we are finding is a significant benefit in all respects,” Dr. Fuster says of both adults and children in FAMILIA. “Their knowledge, their attitudes, and their habits are quite positive, and this is very exciting.”

Read more Featured stories about Mount Sinai

Computational Model Leads to Discovery of Gene-Activation Pathway Associated With Atherosclerosis

Updated on Jun 30, 2022 | Featured, Research

 Jun Zhu, PhD

A computational model of cells that line blood vessels in the human heart, developed at the Icahn School of Medicine at Mount Sinai, has led to the discovery of a gene-activation pathway caused by lipids associated with coronary artery disease. The findings appear in the June 12, 2018, issue of Nature Communications.

The new pathway, discovered by researchers in Mount Sinai’s Department of Genetics and Genomic Sciences, and at Goethe University in Frankfurt, Germany, could help identify new directions in research and drug development.

Atherosclerosis is caused by the buildup of a complex mixture of components, commonly referred to as plaque, within the inner lining of arteries. Oxidized phospholipids are abundant in this arterial plaque and are thought to promote atherosclerosis progression. However, the specific cellular processes caused by these lipids on the arterial surface are still not well understood. The cells composing the inner surface of blood vessels, called endothelial cells, are at the forefront of the atherosclerotic process and, therefore, are a major focus of research into coronary artery disease.

“Computational biological models such as the one we used in this study are allowing us to uncover a wealth of knowledge about complex diseases that we never could before,” says Jun Zhu, PhD, Professor of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai; Head of Data Science at Sema4, a patient-centered predictive health company that is a Mount Sinai venture; and co-senior author of the study. “Endothelial cell response to lipids has been studied extensively over the years, but it was still unknown that MTHFD2 was even functional in these cells.”

The researchers from Mount Sinai and Goethe University predicted and validated in follow-up experiments that the MTHFD2 gene plays a key role in endothelial cell response to oxidized phospholipids. They found that MTHFD2 was also activated in endothelial cells in response to other factors, such as inflammation or a change in amino acid concentration. This underscores the many factors involved in the development of atherosclerosis that must be understood and taken into consideration when approaching disease therapies.

“Our study showed that when the MTHFD2 gene is activated in endothelial cells in response to oxidized lipids, it sends out molecular ‘danger signals’ promoting inflammation and stimulating the atherosclerotic process,” says Ralf Brandes, MD, Director of the Institute for Cardiovascular Physiology and Professor of Physiology at Goethe University. “These findings suggest that MTHFD2 could be a novel target to disrupt development and progression of atherosclerosis.”

While the role of MTHFD2 in the vascular system was unknown before this study, the gene is known to be consistently activated in cancer, making it a promising target for cancer therapies. In clinical trials, MTHFD2 inhibitors are already in use as anticancer therapies. “It’s possible that these therapies could also help prevent coronary artery disease, but more research into the specific role of MTHFD2 in atherosclerosis is needed first, before proposing it as a target for potential therapy,” according to Dr. Zhu.

Read more about Research at Mount Sinai

STAT Online: Virtual Repurposing Can Speed the Discovery of New Uses for Existing Drugs

Updated on Jun 30, 2022 | Featured, Research

Inga Peter, PhD

In an essay in STAT, a leading online publication covering the life science industry, Inga Peter, PhD, Professor, Genetics and Genomic Sciences, at the Icahn School of Medicine at Mount Sinai, writes about a new approach to drug discovery—sometimes called virtual repurposing—that offers a way to discover unknown connections between “unconnected” diseases that may lead to new treatments.

Dr. Peter is a genetic epidemiologist with extensive experience designing studies aimed at identifying  genetic risk factors associated with complex diseases such as type 2 diabetes, obesity, cardiovascular disease, and Crohn’s disease.

Read the essay in STAT online

Learn more about the Peter Laboratory at the Icahn School of Medicine

Read more about Research at Mount Sinai

Two Studies Point to the Quality of Neoantigens in Determining Long-Term Cancer Survival

Updated on Nov 19, 2025 | Artificial Intelligence, Featured, Research

Benjamin Greenbaum, PhD

The quality, not quantity, of tumor neoantigens may best predict a patient’s response to cancer immunotherapy and his or her chance of long-term survival. That finding was based on two groundbreaking studies co-authored by Benjamin Greenbaum, PhD, Assistant Professor, Medicine (Hematology and Medical Oncology), and Pathology, Icahn School of Medicine at Mount Sinai. Now, it is being further explored by Dr. Greenbaum and Vinod Balachandran, MD, Memorial Sloan Kettering Cancer Center, through a Stand Up to Cancer Convergence 2.0 Grant and funding from the Lustgarten Foundation.

Their goal is to understand the underpinnings of pancreatic cancer survivorship, and their team is one of seven research groups that comprise Stand Up to Cancer’s broad $11 million initiative that was announced in January 2018. Neoantigens, or peptides found on the surface of cancer cells, are considered promising targets for cancer immunotherapy.

“Previous research has shown that T cell immunity is linked to exceptional outcomes for the few long-term survivors of pancreatic cancer, but it wasn’t clear if neoantigens played a role,” says Dr. Greenbaum. “Our newest research shows there are particular neoantigens that seem to be driving this long-term response in patients with pancreatic cancer, and further suggests that targeting those neoantigens might be a viable therapeutic strategy.”

According to Dr. Greenbaum, who was trained as a physicist and quantitative biologist, “One of the most exciting aspects of our work is collaborating with academic teams that can combine the tools and knowledge from diverse fields like theoretical physics, structural biology, mathematics, computer science, and translational genomics. We never lose sight of the fact that our combined efforts could one day result in clinical breakthroughs that benefit countless numbers of people.”

Earlier research formed the basis of the team’s efforts. In the first of two back-to-back studies published in Nature (November 2017), researchers described a mathematical model they developed—the first of its kind—to predict how a cancer patient would benefit from certain immunotherapies. Dr. Greenbaum was the senior author on this work with first author Marta Luksza, PhD, Assistant Professor of Oncological Sciences, Icahn School of Medicine at Mount Sinai.

By capturing aspects of a tumor’s evolution and ways in which it interacted with the underlying immune system, the new model appeared to offer an approach beyond previous biomarkers. Going forward, it also has the potential to uncover new therapeutic targets within the immune system, and help in the design of vaccines for patients who do not respond to immunotherapy.

The second study, whose first author was Dr. Balachandran, applied the modeling framework in order to better understand immune response in patients with pancreatic cancer and, more specifically, the unique role of neoantigens.

As part of the broad initiative, the Mount Sinai researchers are focused on better understanding what makes a neoantigen a good immune target, and the role of the microbiome in neoantigen recognition. By advancing the core science behind developing a vaccine for pancreatic cancer, the research could eventually improve treatment prospects for patients with this deadly form of the disease.

As they investigate the immune system’s response to cancers, the Convergence 2.0 team will be encouraged to draw upon the knowledge of Microsoft Research experts in machine learning and artificial intelligence. In addition to Dr. Luksza, the research team includes Nina Bhardwaj, MD, PhD, from the Icahn School of Medicine at Mount Sinai; and Eileen M. O’Reilly, MD; Taha Merghoub, PhD; and Jedd D. Wolchok, MD, PhD, from Memorial Sloan Kettering Cancer Center.

Read more about Research at Mount Sinai

FREEDOM Follow-On Study Confirms Therapy for Patients With Diabetes and Heart Disease

Updated on Jun 30, 2022 | Featured, Research

Valentin Fuster, MD, PhD

A long-term international study led by researchers at Mount Sinai Heart is helping to establish an optimal standard of care for patients with diabetes and advanced multivessel coronary artery disease—a group at high risk for heart attack and stroke.

The FREEDOM Follow-On Study found that patients in this group who are treated with coronary artery bypass grafting (CABG) survive significantly longer than those treated with percutaneous coronary intervention (PCI) with drug-eluting stents.

Over a period of seven and one-half years, mortality from all causes was 18.7 percent for the CABG group and 23.7 percent for the PCI cohort. The study found that younger patients fared the best, with the difference most significant for those under age 63. “These data support current recommendations that CABG be considered the preferred strategy for patients with diabetes and multivessel disease,” says the study’s principal investigator, Valentin Fuster, MD, PhD, Director of Mount Sinai Heart, and Physician-in-Chief of The Mount Sinai Hospital.

During CABG, a healthy artery or vein from the body is connected, or grafted, to the blocked coronary artery, providing a bypass around the blocked portion of the coronary artery. In PCI—a minimally invasive procedure also known as angioplasty—a catheter is threaded through the body to a blocked or occluded vessel in the heart. The occlusion is removed and a drug-eluting stent is often inserted to maintain flow within the blood vessel.

The FREEDOM Follow-On Study, published in the Journal of the American College of Cardiology in November 2018, is the successor to the FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial, which randomized 1,900 patients with diabetes. That original study, which concluded in 2012, found that individuals who have diabetes and advanced coronary artery disease live longer and are less likely to suffer a nonfatal heart attack when treated with CABG instead of PCI with drug-eluting stents. The median follow-up time of that trial—just under four years—was considered relatively short, however, because of the prolonged nature of atherosclerotic cardiovascular disease.

Consequently, Mount Sinai developed a longer-term follow-up study, and 25 of the original international centers agreed to participate, tracking data on the mortality of 943 patients from the original FREEDOM trial. Adults with diabetes are two to four times more likely to die from heart disease than those without it, according to the American Heart Association.

In addition to confirming a standard of care for such patients, the study’s results underscore the importance of aggressive medical treatment and prevention to keep them from reaching advanced stages of diabetes, hypertension, and high cholesterol—forestalling the need for either CABG or PCI, Dr. Fuster says.

“We have to pay attention to how we can prevent this late stage of disease by taking care of obesity,” he says. “About 70 percent of these patients were obese, and we can do a lot to prevent this.”

Read more about Research at Mount Sinai