WALTHAM, Mass.– Pretzel Therapeutics has published groundbreaking research in the journal Nature, detailing a novel approach to treating mitochondrial DNA (mtDNA) depletion disorders through the use of small molecule activators. The study marks a significant advance in the treatment of rare genetic diseases linked to defective mitochondrial DNA polymerase gamma (POLG) and opens the door to potential therapies for a broader range of neurological and degenerative conditions.
The peer-reviewed article, titled “Small Molecules Restore Mutant Mitochondrial DNA Polymerase Activity” (Valenzuela et al., Nature), showcases the discovery of compounds capable of restoring the function of mutated POLG enzymes. These enzymes are essential for maintaining healthy mitochondrial DNA levels, and their dysfunction is associated with a spectrum of severe, often fatal disorders for which no disease-modifying treatments currently exist.
Developed in partnership with researchers from the University of Gothenburg in Sweden, the study demonstrates that these first-in-class small molecules can repopulate depleted mtDNA in patient-derived cells. This therapeutic approach could have far-reaching implications, not only for rare mitochondrial conditions but also for more common diseases like Parkinson’s, which involve mtDNA damage and depletion.
“Our publication in Nature underscores Pretzel’s mission to transform how we treat diseases rooted in cellular energetics,” said Dr. Gabriel Martinez, Chief Scientific Officer and Co-Founder of Pretzel Therapeutics. “These findings validate the science behind our lead candidate, PX578, and bolster our efforts to address a broad range of diseases through our bioenergetics restoration platform.”
PX578, the company’s lead POLG activator, recently entered a Phase 1 clinical trial, marking the first time this therapeutic approach is being tested in humans.
Dr. Maria Falkenberg, Professor of Medical Biochemistry at the University of Gothenburg and Pretzel co-founder, highlighted the potential scope of the findings: “Restoring POLG function with these small molecules could revolutionize the treatment of POLG-related disorders and other conditions tied to mtDNA maintenance. This research represents a promising step toward disease-modifying therapies where currently none exist.”
The announcement positions Pretzel Therapeutics at the forefront of mitochondrial medicine, with a development pipeline that spans both rare diseases and common degenerative disorders affected by impaired bioenergetics.
