Inhibition of mitochondrial RNA polymerase (POLRMT) drives significant weight loss and improved metabolic markers in obese mouse models.

Findings underscore the promise of targeting mitochondrial transcription as a new approach to modulating energy balance and metabolism.

Pretzel Therapeutics, a leader in harnessing cellular energetics to develop novel treatments for a range of conditions spanning neurological, muscle, metabolic and rare diseases, today announced that new preclinical data supporting mitochondrial RNA polymerase (POLRMT) as a novel target for the treatment of metabolic disease will be presented at ObesityWeek 2025 in Atlanta, Georgia. The POLRMT program, the lead initiative in Pretzel’s energetics modulation franchise, represents a novel liver-targeted mechanism for the treatment of metabolic conditions, including obesity, and is currently in preclinical development.

The data demonstrate that inhibition of POLRMT—an enzyme essential for mitochondrial transcription and oxidative phosphorylation (OXPHOS) biogenesis—led to significant weight loss and improved metabolic parameters in diet-induced obese (DIO) mouse models. Targeted knockdown of POLRMT using a liver-directed antisense oligonucleotide (ASO) resulted in increased energy expenditure, improved glucose homeostasis, and enhanced body composition, with weight loss primarily driven by reductions in fat mass while lean mass remained stable. The presentation will include additional analyses of metabolic parameters observed in DIO mice.

“Inhibition of mitochondrial transcription through POLRMT modulation produced meaningful metabolic effects, including weight loss and improved glucose balance,” said Gabriel Martinez, Ph.D., Chief Scientific Officer and Co-Founder of Pretzel Therapeutics. “These results, which build upon groundbreaking research published in Nature Metabolism by Pretzel Therapeutics co-founder Nils-Goran Larsson, further validate our bioenergetics platform’s ability to uncover first-in-class therapeutic targets within mitochondrial biology.”

“The identification of POLRMT as a novel metabolic disease target deepens Pretzel’s scientific reach into obesity, a pressing global health challenge,” said Jay Parrish, Ph.D., Chairman and Chief Executive Officer of Pretzel Therapeutics. “These findings reinforce our mission to translate mitochondrial science into transformative treatments across a range of rare and common conditions.”

The oral presentation, titled “Antisense Oligonucleotide Targeting POLRMT Reduces Weight and Increases Energy Expenditure in Mice,” will be delivered by David Ehmann, Ph.D., Vice President, Head of Biology, on Tuesday, November 4, from 1:45–2:00 p.m. ET in room A411-A412. A copy of the presentation will be available on the Pretzel Therapeutics website following presentation.

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, muscle, metabolic and rare diseases. PX578, the lead therapeutic in Pretzel’s bioenergetics restoration franchise, represents a first-in-class approach to targeting mitochondrial DNA polymerase (POLG) across primary mitochondrial disorders (PMD), including mitochondrial DNA depletion syndromes (MDDS) and broader neurodegenerative disease. 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.

Forward-Looking Statements

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"The identification of POLRMT as a novel metabolic disease target deepens Pretzel’s scientific reach into obesity, a pressing global health challenge,” said Jay Parrish, Ph.D., Chairman and Chief Executive Officer of Pretzel Therapeutics.