Researchers at WashU Medicine are developing therapies for the Ashkenazi Jewish subtype of Wolfram syndrome, a rare inherited condition in which about one in every 30 – 40 people of Ashkenazi Jewish ancestry carries the WFS1 variant. The lab’s long-term goal is to find a cure, and current work focuses on gene-editing technologies that address the root cause of the disease rather than just managing symptoms.
Gene-editing technologies are transforming the treatment of rare genetic diseases by correcting the underlying mutations. Base-editing, a second-generation gene-editing technology, has the potential to provide a one-time, lasting treatment. In their current project, the team created brain cells from patient-derived induced pluripotent stem cells (iPSCs) — a type of stem cell generated from patients’ blood cells — carrying the Ashkenazi Jewish WFS1 variant. Using base-editing, they successfully corrected the variant in those brain cells. The corrected brain cells demonstrated healthier energy production, reduced cellular stress, and improved survival, providing evidence that base-editing may help protect nerve cells in the brain and eyes and slow disease progression.
The researchers also used structural modeling to study how the p.R558C change affects the WFS1 protein. Their results suggest that this alteration destabilizes the protein, and this knowledge is guiding efforts to design new drugs that may restore its function.
Future Directions
The next step for the team is to test this gene-editing approach on insulin-producing pancreatic cells made from iPSCs, which will allow them to assess whether diabetes can be reversed “in a dish.” They also plan to repeat these studies with iPSCs from other patients, evaluate the approach in a mouse model of this subtype to improve vision, diabetes, and neuronal dysfunction, and use iPSC-derived brain cells to screen for new medicines.
At the same time, the lab is refining computer models of the WFS1 protein to aid in the design of stabilizing drugs. Together, these efforts are bringing the field closer to clinical trials and new treatments for people with Wolfram syndrome.