Pretzel Therapeutics Unveils POLRMT as Novel Obesity Target with Promising Preclinical Results
Key Insights
Pretzel Therapeutics (search) presented preclinical data at ObesityWeek 2025 showing that inhibition of mitochondrial RNA polymerase (search) (POLRMT (search)) drives significant weight loss and improved metabolic markers in obese mouse models.
The liver-targeted antisense oligonucleotide approach resulted in increased energy expenditure, improved glucose homeostasis, and enhanced body composition with weight loss primarily from fat mass reduction while preserving lean mass.
The POLRMT (search) program represents a novel liver-targeted mechanism for treating metabolic conditions including obesity (search) and is currently in preclinical development as part of Pretzel's energetics modulation franchise.
Pretzel Therapeutics (search) announced promising preclinical data supporting mitochondrial RNA polymerase (search) (POLRMT (search)) as a novel therapeutic target for metabolic disease (search) treatment at ObesityWeek 2025 in Atlanta, Georgia. The company's lead energetics modulation program demonstrates a liver-targeted mechanism for addressing obesity (search) and other metabolic conditions.
Significant Weight Loss Through Mitochondrial Targeting
The preclinical studies revealed that inhibition of POLRMT (search)—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. The targeted knockdown of POLRMT using a liver-directed antisense oligonucleotide (ASO) resulted in increased energy expenditure, improved glucose homeostasis, and enhanced body composition.
Notably, the weight loss was primarily driven by reductions in fat mass while lean mass remained stable, indicating a favorable therapeutic profile for metabolic intervention.
Scientific Validation and Platform Advancement
"Inhibition of mitochondrial transcription through POLRMT (search) 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 (search). Martinez emphasized that these results build upon groundbreaking research published in Nature Metabolism by Pretzel Therapeutics co-founder Nils-Goran Larsson, further validating the company's bioenergetics platform's ability to uncover first-in-class therapeutic targets within mitochondrial biology.
Expanding Therapeutic Reach
Jay Parrish, Ph.D., Chairman and Chief Executive Officer of Pretzel Therapeutics (search), highlighted the broader implications of the research. "The identification of POLRMT (search) as a novel metabolic disease (search) target deepens Pretzel's scientific reach into obesity (search), a pressing global health challenge," Parrish stated. "These findings reinforce our mission to translate mitochondrial science into transformative treatments across a range of rare and common conditions."
Conference Presentation Details
The research was presented in an oral presentation titled "Antisense Oligonucleotide Targeting POLRMT (search) Reduces Weight and Increases Energy Expenditure in Mice," 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. The presentation includes additional analyses of metabolic parameters observed in DIO mice, with a copy made available on the Pretzel Therapeutics (search) website following the presentation.
Company Pipeline and Development Status
Pretzel Therapeutics (search) focuses on developing first-in-class treatments addressing novel targets within the mitochondria across neurological, muscle, metabolic and rare diseases. The POLRMT (search) program represents the lead initiative in the company's energetics modulation franchise and is currently in preclinical development. The company also has PX578 (search), a first-in-class approach targeting mitochondrial DNA polymerase (search) (POLG (search)) for primary mitochondrial disorders (search), which is in Phase 1 clinical development.
The company is headquartered in Waltham, Massachusetts, with research facilities in Mölndal, Sweden.