CLEVELAND – Genes undergo extensive editing through a process called alternative splicing, which greatly increases the size of the functional genome—the working portion of our DNA that helps make each person unique. Put simply, a single gene can be edited in different ways to produce multiple sets of instructions. This helps explain why humans differ so significantly from fruit flies and mice, despite having a similar number of genes.
In a new study, published May 21 in Molecular Cell , researchers from University Hospitals and Case Western Reserve University found that nitric oxide—a gas naturally produced in the body—can broadly regulate alternative splicing, dramatically altering how genes function.
“We further showed that nitric oxide levels are decreased in the brains of patients with Alzheimer’s disease, and that this loss of control over gene splicing correlates with worse clinical outcomes,” said lead author Jonathan Stamler, MD, president and co‑founder of Harrington Discovery Institute at UH and Distinguished University Professor and the Robert S. and Sylvia K. Reitman Family Foundation Chair of Cardiovascular Innovation at the Case Western Reserve School of Medicine. “In other words, lower nitric oxide levels lead to reduced gene-splicing activity, which is associated with increased plaque buildup and more rapid memory loss.”
The research team also found that specific enzymes remove nitric oxide from brain proteins that regulate splicing, creating a nitric oxide–deficient state. The findings suggest that targeting these enzymes could represent a new therapeutic strategy to restore nitric oxide levels in the brain and potentially treat Alzheimer’s disease.
“Interestingly, the Alzheimer’s field has long believed that nitric oxide levels were too high and contributed to the disease,” Dr. Stamler added. “This new discovery changes that paradigm.”
Next steps in this research will include studies in animals with new classes of enzyme inhibitors, which should restore nitric oxide in the brain and drive healthy splicing of genes.
The new class of drugs will be developed with the help of Harrington Discovery Institute at UH, which has a singular mission: To accelerate promising discoveries into medicines for unmet needs. Now in its 13 th year, Harrington Discovery Institute’s growing portfolio includes 239 medicines in the making; 75 institutions supported; 46 companies launched; 28 medicines in clinic; and 15 licenses to pharma.
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Schindler J, et. al, Nitric oxide drives proteomic diversity through alternative splicing, Molecular Cell , 2026; DOI: DOI: 10.1016/j.molcel.2026.04.024
About University Hospitals / Cleveland, Ohio
Founded in 1866, University Hospitals serves the needs of patients through an integrated network of more than 20 hospitals (including 5 joint ventures), more than 50 health centers and outpatient facilities, and over 200 physician offices in 16 counties throughout northern Ohio. The system’s flagship quaternary care, academic medical center, University Hospitals Cleveland Medical Center, is affiliated with Case Western Reserve University School of Medicine, NEOMED, Oxford University, Technion Israel Institute of Technology, and National Taiwan University College of Medicine. The main campus also includes the UH Rainbow Babies & Children's Hospital, ranked among the top children’s hospitals in the nation; UH MacDonald Women's Hospital, Ohio's only hospital for women; and UH Seidman Cancer Center, part of the NCI-designated Case Comprehensive Cancer Center. UH is home to some of the most prestigious clinical and research programs in the nation, with more than 3,400 active clinical trials and research studies underway. UH Cleveland Medical Center is perennially among the highest performers in national and international ranking surveys, including “America’s Best Hospitals” from U.S. News & World Report and UK Brand Finance. UH is also home to 19 Clinical Care Delivery and Research Institutes. UH is one of the largest employers in Northeast Ohio with more than 30,000 employees. Follow UH on LinkedIn , Facebook and Twitter . For more information, visit UHhospitals.org .
About Case Western Reserve University
As one of the fastest-growing research universities in the United States, Case Western Reserve University is a force in career-defining education and life-changing research. Across our campus, more than 12,000 students from around the world converge to seek knowledge, find solutions and accelerate their impact. They learn from and collaborate with faculty members renowned for expertise in medicine, engineering, science, law, management, dental medicine, nursing, social work, and the arts. And with our location in Cleveland, Ohio—a hub of cultural, business and healthcare activity—our students gain unparalleled access to academic, research, clinical and entrepreneurial opportunities that prepare them to join our network of more than 125,000 alumni worldwide. Visit case.edu to see why Case Western Reserve University is built for those driven to be a force in the world.
Molecular Cell
21-May-2026