Pretzel Study Identifies Potential Treatment of Mitochondrial DNA Depletion Disorders

Rare Daily Staff

Pretzel Therapeutics published new research findings that describe a novel disease-modulating mechanism of action for the treatment of mitochondrial DNA depletion syndromes.

The article, published in the journal Nature, offers insights into a unique bioenergetics restoration pathway, suggesting the therapeutic potential of Pretzel’s development pipeline and supporting continued advancement of its lead therapeutic, PX578, which recently entered phase 1 clinical development.

The study, conducted in collaboration with Pretzel Therapeutics scientific co-founders from the University of Gothenburg, Sweden, describes the discovery of novel activators that restore function to mutant mitochondrial DNA polymerases, allowing repopulation of depleted mitochondrial DNA (mtDNA), and offering a promising approach for the treatment of disorders caused by mutation to the POLG gene, which encode the mitochondrial DNA polymerase. These mutations impair the replication of mitochondrial DNA and energy production.

PX578, the lead experimental therapy in the company’s energetics restoration franchise, represents a first-in-class approach to targeting and activating the mitochondrial polymerase POLG, with disease modifying potential across rare mtDNA depletion syndromes and broader degenerative diseases. PX578 is in phase 1 clinical development.

“Our collaboration with Pretzel Therapeutics has led to these exciting new insights demonstrating first-in-class small molecule activators that restore POLG function and increase mtDNA levels in patient-derived cells, representing a potential breakthrough for patients with POLG disorders, a group of severe and sometimes fatal diseases for which there are no disease modifying treatments,” said Maria Falkenberg, professor of medical biochemistry at the Sahlgrenska Academy of the University of Gothenburg and Pretzel co-founder. “Because loss of mtDNA and the accumulation of mtDNA deletions over time influences the severity of other disorders, the potential applications of these findings may extend beyond rare genetic diseases into broader areas where mtDNA maintenance is compromised, including neurodegenerative diseases such as Parkinson’s.”