A research team at NYU Langone Health reported that, in mouse studies, a drug candidate successfully prevented two proteins from interacting: RAGE and DIAPH1. When these proteins come together, they contribute to heart and kidney injury linked to diabetes and slow the healing of wounds.

Blocking a Key Protein Interaction Boosts Healing

The findings, recently featured as a cover story in Cell Chemical Biology, show that keeping DIAPH1 from attaching to RAGE can ease swelling in diabetic tissues and promote more efficient repair. Tests conducted in human cells and mouse models revealed that the compound significantly reduced both immediate and long-term complications in Type 1 and Type 2 diabetes. The compound, known as RAGE406R, is a small molecule named for the protein it targets.

"There are currently no treatments that address the root causes of diabetic complications, and our work shows that RAGE406R can -- not by lowering the high blood sugar, but instead by blocking the intracellular action of RAGE," said co-senior study author Ann Marie Schmidt, MD, the Dr. Iven Young Professor of Endocrinology at the NYU Grossman School of Medicine. "If confirmed by further testing in human trials, the compound could potentially fill gaps in treatment, including that most current drugs work only against Type 2 diabetes."

How RAGE and DIAPH1 Contribute to Damage

RAGE is a receptor, a type of protein that responds to signaling molecules known as advanced glycation end products (AGEs). These molecules form when proteins or fats bind to sugars, a process that occurs more frequently in people with diabetes. AGEs accumulate in the bloodstream in individuals with diabetes and obesity, and also naturally increase with age.

Experiments showed that RAGE406R competes for the binding site on RAGE that DIAPH1 normally occupies. DIAPH1 helps form actin filaments, which are part of the cell's internal structure. The researchers demonstrated that DIAPH1 connects to the inner tail of RAGE, and this pairing increases the formation of actin structures that intensify diabetic complications.

Developing a Safer and More Effective Molecule

Schmidt's team previously screened a library of more than 58,000 molecules and identified several that interfered with the RAGE-DIAPH1 pathway. Their earlier lead compound, RAGE229, did not pass a standard safety test designed to flag structural features that might alter DNA and raise cancer risk. RAGE406R removes the part of the structure that created this concern.

The team then tested RAGE406R in a widely used model for chronic diabetes complications: delayed wound healing in obese mice with Type 2 diabetes. In both male and female mice, applying RAGE406R directly to the skin accelerated wound closure.

Reducing Misplaced Inflammation to Support Repair

Many of the compound's benefits stem from its effects on the immune system. The immune response is designed to detect and eliminate harmful invaders such as bacteria and viruses. When activated, it can cause inflammation, which includes swelling triggered by immune cells gathering at an injured area. In diabetes, inflammation often occurs in the wrong places or lasts too long.

RAGE406R lowered the levels of CCL2, a major proinflammatory signaling molecule. Reducing CCL2 activity calmed inflammation in macrophages, a type of immune cell. This shift helped support structural remodeling in tissues, an essential part of the healing process.

"Our findings point to a promising new pathway for treating diabetes in the future," said co-senior study author Alexander Shekhtman, PhD, a professor in the Department of Chemistry at the State University of New York (SUNY) at Albany. "The current study results serve as a springboard for the development of therapies for both types of diabetes, and for designing markers that can measure how well the new treatment works in live animals."

Contributors and Funding Support

Along with Schmidt, contributors from the Diabetes Research Program in the Department of Medicine at NYU Langone Health include co-first author Michaele Manigrasso, as well as Gautham Yepuri, Kaamashri Mangar, and Ravichandran Ramasamy. Additional NYU Langone collaborators include Sally Vanegas from the Department of Medicine and Yanan Zhao and Huilin Li from the Division of Biostatistics in the Department of Population Health. Shekhtman's group at SUNY at Albany includes first author Gregory Theophall, Parastou Nazarian, Aaron Premo, Sergey Reverdatto, and David Burz. Robert DeVita, PhD, from RJD Medicinal Chemistry and Drug Discovery Consulting LLC, also contributed to the research.

This work was funded by U.S. Public Health Service grants 1R24DK103032, 1R01DK122456-01A1, P01HL146367, and 5R01GM085006. The NYU Histology Core receives partial support from the Perlmutter Cancer Center support grant P30CA016087. Additional backing came from the Diabetes Research Program at the NYU Grossman School of Medicine. Drs. Manigrasso, Ramasamy, and Schmidt are listed on patent applications owned by NYU Langone Health related to this research. Their relationship to this intellectual property is being managed in accordance with NYU Langone Health policies. Dr. DeVita, who consults for NYU Technology Opportunities & Ventures' Therapeutics Alliances and for Intercept Therapeutics, was compensated for his involvement.

A study in Scientific Reports describes how scientists used CRISPR gene-editing tools to restore a gene that disappeared from the human lineage millions of years ago. Bringing this gene back lowered uric acid, the substance responsible for gout and several other health problems.

The long-lost component is uricase, an enzyme that most other animals continue to carry.

Uricase breaks down uric acid, a waste product that routinely forms in the blood. If uric acid levels rise too much, it can crystallize in the joints and kidneys, causing gout, kidney disease and a number of related conditions.

Why Humans Lost Uricase

Humans and other apes shed the uricase gene roughly 20 to 29 million years in the past. Some experts argue this change may have once offered an advantage. According to research cited in Seminars in Nephrology, scientists including Dr. Richard Johnson of the University of Colorado have suggested that elevated uric acid helped early primates convert fruit sugars into fat, providing a survival boost during lean times.

Today, however, that ancient adaptation contributes to a range of modern metabolic issues. This is the challenge that Georgia State biology professor Eric Gaucher and his team aimed to test.

"Without uricase, humans are left vulnerable," said Gaucher, a co-author of the study. "We wanted to see what would happen if we reactivated the broken gene."

Reintroducing an Ancient Gene With CRISPR

Working with postdoctoral researcher Lais de Lima Balico, Gaucher relied on CRISPR-Cas9, often referred to as molecular scissors, to insert a reconstructed version of the ancient uricase gene into human liver cells. This allowed the team to observe how the enzyme functioned in a modern biological environment.

The results surprised them. Uric acid levels fell sharply, and liver cells no longer accumulated fat when exposed to fructose. Because experiments in individual cells cannot always predict what will occur in more complex systems, the researchers advanced to a more sophisticated model.

They tested the gene in 3D liver spheroids, which are small, lab-grown structures that more closely resemble actual organ function. The reintroduced uricase gene again reduced uric acid. The enzyme also moved into peroxisomes, the cellular compartments where uricase naturally operates, suggesting the therapy might behave safely and appropriately in living organisms.

"By reactivating uricase in human liver cells, we lowered uric acid and stopped the cells from turning excess fructose into triglycerides -- the fats that build up in the liver," Gaucher said.

The Wider Impact of High Uric Acid

The findings extend well beyond gout. High uric acid, known as hyperuricemia, is associated with many modern health disorders. Research highlighted in the journal Hypertension has linked elevated uric acid to hypertension and cardiovascular disease, and the risks have been compared to those of high cholesterol.

These concerns are reflected in patient statistics. Between one-quarter and one-half of people with high blood pressure also have high uric acid, and in newly diagnosed hypertension, that overlap rises to 90 percent, according to the study.

"Hyperuricemia is a dangerous condition," Gaucher said. "By lowering uric acid, we could potentially prevent multiple diseases at once."

Toward Future Therapies

Current treatments for gout are not effective for everyone, and some individuals experience adverse reactions to existing uricase-based medications. A CRISPR method that restores uricase directly in liver cells could avoid these issues.

"Our genome-editing approach could allow patients to live gout-free lives and potentially prevent fatty liver disease," Gaucher said.

Animal studies are the next step, followed by human trials if early results hold up. Potential delivery methods include direct injections, returning modified liver cells to patients, or using lipid nanoparticles (the same technology employed in some COVID-19 vaccines).

If the strategy proves safe, Gaucher believes it could reshape the way gout and related metabolic disorders are treated. However, several challenges still need to be addressed.

"Genome-editing still faces substantial safety concerns," he said. "Once those are addressed, society will be faced with contentious ethical discussions about who should and should not have access."