Researchers at WashU Medicine are working on new treatments for the Ashkenazi Jewish subtype of Wolfram syndrome, a rare genetic condition. About one in every 30–40 people of Ashkenazi Jewish ancestry carries the genetic variant that causes this disease. The lab’s ultimate goal is to find a cure, and their current work focuses on fixing the genetic mistake at its source rather than just treating the symptoms.
Gene-editing is changing the way rare diseases can be treated, offering the possibility of long-lasting or even one-time cures. One of the most promising approaches is called base-editing, which can correct tiny errors, or mutations, in DNA. In their latest project, the team created brain cells in the lab using stem cells made from the blood of Wolfram patients. These lab-grown cells carried the Ashkenazi Jewish Wolfram variant. With base-editing, the researchers were able to correct the variant in those cells. The repaired brain cells showed healthier energy production, less stress inside the cells, and better survival. This is strong evidence that base-editing could help protect brain and eye cells and slow down the progression of the disease.
The team also studied how this specific mutation in the WFS1 gene, called p.R558C, affects the protein it produces. They found that this change makes the protein unstable. Understanding this weakness is helping them design new medicines that may stabilize and restore the protein’s function.
Looking Ahead
Next, the researchers will test this same gene-editing approach on insulin-producing pancreatic cells made from patient stem cells. This will help them see if they can reverse diabetes in a lab dish. They also plan to repeat these experiments with cells from other patients and test the approach in mice to study its effects on vision, diabetes, and nerve problems, and use lab-grown brain cells to search for new medicines.
At the same time, the team is improving computer models of the WFS1 protein to design drugs that could stabilize and strengthen it. Together, these efforts are moving the field closer to clinical trials and, ultimately, new treatments for people living with Wolfram syndrome.