Researchers at Wake Forest University School of Medicine Receive $3.3 Million Grant from NIH to Study Rare Kidney Disease

BYLINE: Myra Wright

WINSTON-SALEM, N.C. – Jan. 23, 2025 – Wake Forest University School of Medicine has been awarded a $3.3 million grant from the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health, to study and develop a treatment for primary hyperoxaluria (PH). This rare genetic disorder causes kidney stones and other serious health problems. 

“Primary hyperoxaluria is a challenging disease that affects patients from a young age,” said Todd Lowther, Ph.D., professor of biochemistry at Wake Forest University School of Medicine. “We hope this funding will allow us to make significant strides in understanding the disease and developing targeted treatments that can make a real difference in patients’ lives.” 

Primary hyperoxaluria causes the body to produce excessive oxalate, which can combine with calcium to form kidney stones. This condition arises from a deficiency in multiple enzymes that break down glyoxylate, causing it to be converted into oxalate. Glyoxylate is a substance that plays a role in the body’s metabolism. It is produced when the body breaks down certain amino acids. 

Consequently, oxalate levels in the kidneys gradually increase and stones develop in the kidneys and urinary tract. Repeated stone formation and calcium oxalate buildup in kidney tissue can lead to kidney failure over time. 

The disorder impacts between one and three in 1 million individuals worldwide, although the exact prevalence is difficult to estimate. Lowther said there are three different types of primary hyperoxaluria, known as PH 1, PH 2 and PH 3, each caused by different genetic mutations. 

The grant will fund a study to develop new treatments for PH 2 and PH 3, which currently have no approved therapies. The research will focus on an enzyme called hydroxyproline dehydrogenase (HYPDH). 

By inhibiting this enzyme, Lowther said the formation of oxalate can be significantly reduced.  

In previous research, the study team developed a mouse model that lacked the HYPDH enzyme. These mice are healthy and do not produce oxalate from hydroxyproline, indicating that inhibiting HYPDH could be a promising treatment.  

“Our goal of this project is to design new compounds to understand how they bind to HYPDH and to test their efficacy in various PH mouse models,” said Terrence Smalley, Ph.D. assistant professor of biochemistry at Wake Forest University School of Medicine. “We hope to find a treatment that will reduce oxalate levels and prevent kidney stones in affected patients.” 

The research team also highlighted the broader implications of the research. “There’s potential here for a discovery that could treat kidney stones in the general population in addition to patients with primary hyperoxaluria,” Lowther said. 

Pilot funding for this research was provided by the Catalyst Fund, an Atrium Health Wake Forest Baptist program managed by Wake Forest Innovations that accelerates the development of innovative life science technologies such as medical devices, drugs, vaccines, restorative medicines, diagnostics and digital health.  

“We are excited Dr. Lowther’s team has secured the grant to continue developing the technology,” said Osama Zahid, Ph.D., director of licensing at Wake Forest Innovations. “We hope these compounds will translate into the clinic and help patients suffering from kidney stones and associated complications.”  

The team also secured a Translational Research Grant from the North Carolina Biotechnology Center (NCBC) in 2023 to continue development of this novel therapy. The NCBC grant program funds projects that explore commercial applications of university-held life sciences inventions. 

Additional research supporters and collaborators include the Oxalosis and Hyperoxaluria Foundation and the University of Alabama at Birmingham. 

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Wake Forest University School of Medicine (school.wakehealth.edu) is the academic core of Advocate Health and a recognized leader in experiential medical education and groundbreaking research that includes Wake Forest Innovations, a commercialization enterprise focused on advancing health care through new medical technologies and biomedical discovery.