Treatment for mitochondrial diseases within reach

Mitochondrial diseases caused by POLG mutations vary in severity. In young children, these diseases can quickly result in brain damage and life-threatening liver problems while others suffer muscle weakness, epilepsy, and organ failure later in childhood. 

The POLG gene regulates the production of DNA polymerase gamma, an enzyme that copies mitochondrial DNA. Without it, the mitochondria cannot function normally and, as a result, fail to provide the cell with energy.

A breakthrough

Maria Falkenberg and Claes Gustafsson, professors at Sahlgrenska Academy at the University of Gothenburg, have led the work behind the study now being published in the journal Nature.

"We demonstrate that the molecule PZL-A can restore the function of mutated DNA polymerase gamma and improve the synthesis of mitochondrial DNA in cells from patients. This improves the ability of the mitochondria to provide the cell with energy," says Maria Falkenberg, Professor of Biomedical Laboratory Science.

"This is a breakthrough as for the first time we can demonstrate that a small molecule can help improve the function of defective DNA polymerase. Our results pave the way for a completely new treatment strategy," says Claes Gustafsson, Professor of Medical Chemistry.

From lab to medication

More than twenty years of basic research led to the discovery of PZL-A. The molecule was identified following the analysis of hundreds of chemical compounds in collaboration with Pretzel Therapeutics, where another one of the lead authors of the study, Vice President of Chemistry Simon Giroux, has led the chemical development of the molecule. So far, the molecule has been studied in cells from patients as well as in animal models.

Sebastian Valenzuela, a doctoral student at Sahlgrenska Academy, has analyzed the molecule's structure, including by means of cryo-electron microscopy.

"We demonstrate exactly where the molecule binds, between two separate chains of the enzyme. The binding site is extremely specific, which helps us understand how the enzyme works and how we can influence it," says Sebastian Valenzuela, first author of the study.

Pretzel Therapeutics will soon embark on phase I studies with a refined version of the molecule in order to test its safety on healthy volunteers. Since a lack of mitochondrial DNA is also seen in other mitochondrial, age-related, and neurodegenerative diseases, substances similar to PZL-A may gain broader therapeutic use. Pretzel Therapeutics is part of the Gothenburg region's life science cluster, with its Swedish operations conducted at GoCo Health Innovation City and its headquarters located in Waltham, Massachusetts, just outside Boston.