- Restores function to mutant mitochondrial DNA polymerases with potential to target broad range of rare and common diseases
- First-in human clinical study recently initiated with PX578, lead POLG activator therapeutic in Pretzel’s bioenergetics restoration franchise
Pretzel Therapeutics, a leader in harnessing cellular energetics to develop novel treatments for a range of conditions spanning neurological, muscular atrophies, metabolic and rare disease, today announced the publication of new research findings in Nature elucidating a novel disease-modulating mechanism of action for the treatment of mitochondrial DNA (mtDNA) depletion syndromes. The article, “Small Molecules Restore Mutant Mitochondrial DNA Polymerase Activity” (Valenzuela et al., Nature, 10.1010.1038/s41586-025-08856-9) provides critical insights into a unique bioenergetics restoration pathway, reinforcing 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 University of Gothenburg, Sweden, describes the discovery of novel activators that specifically restore function to mutant mitochondrial DNA polymerases, allowing repopulation of depleted mtDNA, and offering a promising approach for the treatment of POLG disorders and other severe conditions linked to mtDNA depletion, a significant unmet medical need.
“This publication in Nature underscores our commitment to pioneering novel scientific discoveries that have the potential to transform patient care,” said Gabriel Martinez, Ph.D., Chief Scientific Officer and Co-Founder of Pretzel Therapeutics. “These compelling results not only support the recently initiated clinical study for PX578, the lead therapeutic in our bioenergetics restoration franchise, but also expand the promise of our pipeline in broader disease indications, further reinforcing Pretzel’s position as a leader in harnessing cellular bioenergetics.”
Maria Falkenberg, Ph.D., Professor of Medical Biochemistry at the Sahlgrenska Academy of the University of Gothenburg and Pretzel co-Founder, added: “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. 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.”
About Pretzel Therapeutics
Pretzel Therapeutics is dedicated to developing life-changing medicines with a broad pipeline of first-in-class treatments addressing novel targets within the mitochondria. By harnessing cellular energetics to modulate disease processes and improve survival, function and quality of life, we are ushering in a new treatment paradigm for a breadth of conditions spanning neurological, muscular atrophies, metabolic and rare disease. PX578, the lead development program in Pretzel’s bioenergetics restoration franchise, represents a first-in-class approach to targeting mitochondrial DNA polymerase (POLG) across mitochondrial DNA depletion syndromes (MDDS). PX578 is in Phase 1 clinical development. POLRMT, the lead program in our energetics modulation franchise, targets mitochondrial RNA polymerase for the treatment of metabolic conditions including obesity. POLRMT is in late preclinical development. The company is headquartered in Waltham, MA and has research facilities in Mölndal, Sweden. For more information, visit www.pretzeltx.com.
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This publication in Nature underscores our commitment to pioneering novel scientific discoveries that have the potential to transform patient care.
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Gina Nugent, Nugent Communications
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