Mitochondria have come to be more appreciated for their roles in health and disease. Mitochondrial dysfunction has been implicated in a direct role in more than 50 diseases. In others, mitochondrial dysfunction is an important contributing factor, including neurodegenerative diseases (e.g., Alzheimer’s disease, Parkinson’s disease), cancer, and metabolic diseases.

Mitochondria have increasingly become the focus of new biotech companies. One of those is Pretzel Therapeutics. Pretzel seeks to harness cellular energetics to treat a wide range of conditions now recognized as having a mitochondrial connection. Mitochondria are the powerhouses of the cell, and each cell contains hundreds of mitochondria. Interestingly, mitochondria have their own small genome that encodes enzymes that control mitochondrial activities. Several of the projects at Pretzel focus on controlling cellular energetics by modulating the cellular copy number of mitochondrial DNA (mtDNA).

The Pretzel researchers hope to restore cellular energetics to treat neurodegenerative and rare diseases associated with low mtDNA levels or to modify bioenergetics to treat obesity. In one program, they hope to restore energetics by activating the mitochondrial DNA polymerase. This program was disclosed in a recent Nature report (Valenzuela et al., 2025). In that publication, the researchers show that a small-molecule activator restored function to the most common mutants of the mtDNA polymerase, PolG. A lead therapeutic in this program was recently entered into Phase 1 clinical study. In another program, they hope to modulate the activity of the mitochondrial RNA polymerase. A third program employs gene editing to reduce mutated mtDNA and increase levels of healthy mtDNA.

Pretzel launched in 2022 with financing of $72.5 million. The founders include Gabriel Martinez, Claes Gustafsson, Maria Falkenberg, Michal Minczuk, Nils-Göran Larsson, and the late Paul Thurk. Their facilities are located in Waltham, Massachusetts, and Mölndal, Sweden.

For more information on Pretzel Therapeutics, visit their website (https://www.pretzeltx.com/).

 

Reference

Valenzuela S, Zhu X, Macao B, et al. (2025) Small molecules restore mutant mitochondrial DNA polymerase activity. Nature, doi.org/10.1038/s41586-025-08856-9

 

Questions for Pretzel Therapeutics

Pretzel researchers and others recently published an excellent paper in Nature that supports your therapeutic strategy. Congratulations on that publication.

 

Mitochondrial dysfunction has been implicated, directly or indirectly, in many diseases. What diseases do you see as the “low-hanging fruit” for treatments?

The lack of treatments for mitochondrial dysfunction and disease indicates to us that there really isn’t any “low-hanging fruit” in this area.  That said, diseases with a clear and direct genetic cause, such as POLG disease, offer the clearest mechanistic rationale to drug discoverers.

 

Are you considering testing approved drugs for potential off-label uses for treating mitochondrial diseases?

We are focused on our own, novel targets and drug candidates.  We do not work in re-purposing projects.

 

Neurodegenerative diseases are projected to increase rapidly with our aging population. Do you have any thoughts about how your therapies might fit into preventing or treating those diseases?

There has been substantial published research on the links between degenerative conditions of aging and declining mitochondrial function, far more than we can summarize here.  We are of course interested in investigating how our novel mechanisms may influence these conditions.  To this end, we have been awarded a grant from Parkinson’s-UK, a leading charity supporting research, to study our mechanisms in Parkinson’s disease.