News

URMC Drug to be Tested for Delirium and Dementia Following Surgery; Also Brain Disorder ALS

For those caring for elderly parents or grandparents, this scene may be familiar: Grandma falls and fractures her hip. Grandma has surgery to repair the broken hip. Grandma comes out of surgery delirious and confused; she can’t remember simple things, or focus on more than one thing at a time.

More than half of older adults suffer from delirium after surgery that may progress to dementia, a condition called postoperative cognitive dysfunction (POCD). There are no good treatments for postoperative cognitive dysfunction, which is associated with increased illness and death. Estimates suggest that caring for patients with POCD costs more than $150 billion a year.

A team of researchers from the University of Rochester Medical Center (URMC) and Duke University Medical Center is addressing the problem, with the help of a five-year, $2.8 million grant from the National Institutes of Aging at the National Institutes of Health.

What causes postoperative cognitive dysfunction?

What causes postoperative cognitive dysfunction is not entirely understood, but the body’s immune response to surgery and subsequent inflammation throughout the body – including in the brain – likely play a role. The team, led by Niccolo Terrando, Ph.D. at Duke, will test in animal models a drug developed in the laboratory of Harris A. “Handy” Gelbard, M.D., Ph.D. at URMC. Called URMC-099, the drug tamps down the body’s immune response and reduces inflammation.

A drug developed at the University of Rochester Medical Center protected mice from one of the many ills of our cheeseburger and milkshake-laden Western diet – non-alcoholic fatty liver disease.

In a study out today in the journal JCI Insights, scientists report that a drug called “URMC-099” reversed liver inflammation, injury and scarring in animals fed a diet high in fat, sugar and cholesterol. The diet was designed to replicate the Western fast food diet and recreate the features of non-alcoholic fatty liver disease found in people. The drug was well tolerated and the research team plans further testing in order to move URMC-099 into early phase human trials.

Obesity often leads to non-alcoholic fatty liver disease, and estimates suggest that 64 million people have the disorder in the U.S. alone. Individuals with the most severe form of the disease, called non-alcoholic steatohepatitis (NASH), have inflammation and liver cell damage, which can lead to scarring, cirrhosis and liver cancer. Other than weight loss, there are no treatment options.

Eating lots of fatty and sugary foods triggers inflammation in the liver and the body responds by sending immune cells to neutralize the threat. Unfortunately, the immune response can rage out of control, creating even more inflammation and further damaging the liver. URMC-099, which was discovered in the laboratory of URMC scientist Harris A. (Handy) Gelbard, M.D., Ph.D., dials back the immune response to a normal level.

“URMC-099 seems to break this vicious cycle of persistent inflammation by restoring balance between immune cells and liver cells,” said Gelbard, professor and director of the Center for Neurotherapeutics Discovery at URMC. “The drug’s ability to turn down the volume on the immune response allows the liver to regain its normal functions.”

A new therapy for non-alcoholic fatty liver disease is needed now more than ever: according to the Centers for Disease Control and Prevention, more than a third of adults in the U.S. are obese and that number is expected to climb.

Gelbard, working with scientists at the Mayo Clinic and University of Cincinnati, fed mice the high fat, sugar and cholesterol diet for six weeks. After five-and-a-half weeks on the diet, half of the mice received URMC-099 and half received placebo. The mice given the drug had less immune-related inflammation and less liver injury and fibrosis compared to placebo-treated mice and didn’t experience any major side effects.

The research, funded by the National Institutes of Health, was conducted in partnership with Samar H. Ibrahim, senior study author from the Mayo Clinic in Rochester, Minnesota and Burns C. Blaxall from the University of Cincinnati. Gelbard, who originally developed URMC-099 to treat neurological disorders, is working with UR Ventures to pursue different opportunities to develop URMC-099 for clinical trials for non-alcoholic fatty liver disease. URMC-099 is protected by 10 national and international patents to URMC.

The Center for Neural Development and Disease, led by Harris A. (Handy) Gelbard, M.D., Ph.D., since 2008, will now be the Center for NeuroTherapeutics Discovery, reflecting an increased emphasis on translation and the creation of intellectual property that will lead to new therapies for nervous system disorders.

Gelbard, professor of Neurology, Pediatrics, Neuroscience and Microbiology & Immunology, will continue as director. His research, coupled with the work of Charles Thornton, M.D., professor of Neurology and Neuroscience, and Marc Halterman, M.D., Ph.D., associate professor of Neurology, Neuroscience and Pediatrics, will serve as the anchor of the new center. The trio has a strong track record of grants, publications, and patents, as well as academic and commercial relationships that they are actively pursuing to bring new treatments to the public.

“The Center for NeuroTherapeutics Discovery was developed out of the Center for Neural Development and Disease to create more visibility for academic and commercial partnerships as a necessary bridge for bringing new therapeutics forward,” said Gelbard. “This represents a way to do the best and most cutting edge science possible in a time when the traditional avenues towards funding academic research are changing rapidly.”

The center will bring together many investigators from across the Medical Center and River Campus to identify the mechanisms that lead to various neurological disorders, including HIV-associated neurocognitive disorder (Gelbard lab), myotonic dystrophy (Thornton lab) and stroke (Halterman lab). The center remains committed to its members that investigate the molecular signaling events that lead to nervous system disease during development and aging. Industry partnerships and resources will be sought to fast-track existing therapies or create new molecules that affect these disease mechanisms.

Treatments that harness the immune system to help regenerate damaged cells will be a major focus at the center; the team believes that this approach is broadly applicable to a range of acute and chronic neurodegenerative disorders, such as Parkinson’s disease, multiple sclerosis and Alzheimer’s disease.

Major Step toward Longer-Lasting HIV Treatment

A drug developed at the University of Rochester Medical Center extends the effectiveness of multiple HIV therapies by unleashing a cell’s own protective machinery on the virus. The finding, published today in the Journal of Clinical Investigation, is an important step toward the creation of long-acting HIV drugs that could be administered once or twice per year, in contrast to current HIV treatments that must be taken daily.

The drug, called URMC-099, was developed in the laboratory of UR scientist Harris A. (“Handy”) Gelbard, M.D., Ph.D. When combined with “nanoformulated” versions of two commonly used anti-HIV drugs (also called antiretroviral drugs), URMC-099 lifts the brakes on a process called autophagy.

Normally, autophagy allows cells to get rid of intracellular “trash,” including invading viruses. In HIV infection, the virus prevents cells from turning on autophagy; one of the many tricks it uses to survive. When the brake on autophagy is lifted, cells are able to digest any virus that remains after treatment with antiretroviral therapy, leaving cells free of virus for extended periods of time.

Harris A. (“Handy”) Gelbard, M.D., Ph.D.

“This study shows that URMC-099 has the potential to reduce the frequency of HIV therapy, which would eliminate the burden of daily treatment, greatly increase compliance and help people better manage the disease,” said Gelbard, professor and director of UR’s Center for Neural Development and Disease, who has studied HIV/AIDS for the past 25 years. The finding builds on previous research that Gelbard conducted with Howard E. Gendelman, M.D., professor and chair of the Department of Pharmacology/Experimental Neuroscience at the University of Nebraska Medical Center.