Pretzel Therapeutics Launches with $72M to Advance Mitochondrial Therapies

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Biotech start-up Pretzel Therapeutics launched Monday with $72.5 million in Series A financing to develop novel, mitochondria-based therapies for rare genetic disorders and diseases of aging.  

Pretzel plans to target mitochondrial diseases, a highly heterogenous group of conditions caused by DNA mutations in the mitochondria or the nucleus. These disorders are very rare, afflicting around one in 5,000 people. 

Pretzel CEO Jay Parrish told BioSpace the funding "should enable us to get close to the clinic if not into the clinic with one or more programs." 

Using Mitochondrial Pathology to Treat Age-Related Diseases

The Waltham, MA-based biotech is also looking to tackle diseases like Alzheimer’s and lupus, whose origins may not be rooted in the mitochondrion but shows signs of dysfunction in this organelle.

Mutations to the mitochondrial DNA accrue over time, making this a prime target for other aging-related diseases such as Parkinson’s disease. The approach could also be used in other conditions with a genetic or cellular dysfunction like cancer, multiple sclerosis and metabolic disorders.

ARCH Venture Partners and Mubadala Capital led the Series A financing. Pretzel’s backers include HealthCap, Cambridge Enterprise, Eir Ventures and Karolinska Institutet Holding.

Pretzel’s approach to mitochondrial pathology has three paths. The first is what the company calls genome correction. This involves using cutting-edge genome editing technologies to silence faulty copies of mitochondrial DNA while helping the healthy DNA proliferate. 

However, instead of using CRISPR, arguably the hottest genome editor, Pretzel will leverage a more classic technology: zinc-finger nuclei, delivered using adeno-associated virus vectors.

In a 2018 paper published in Nature Medicine, researchers demonstrated that these nuclei could reach deep into cardiac tissue and remove the mutant mitochondrial DNA, restoring healthy molecular and biochemical phenotypes. The study was led by one of Pretzel’s co-founders.

Aside from directly correcting the genetic errors in DNA, Pretzel also plans to address mitochondrial diseases by modulating gene expression inside these organelles, targeting enzymes and other cofactors involved in the process of replicating, translating and transcribing mitochondrial DNA.

The company is also looking at modulating the innate quality control system of mitochondria, allowing it to fine-tune this function to therapeutic effect.

Pretzel is eyeing the development of small-molecule drugs for expression modulation and quality control rather than taking a biologics-based approach. However, it has yet to disclose which diseases it plans to work on or which specific molecules it has in its pipeline.

"In the 5-10-year horizon, we’d like to have programs in the clinic representing all three of our platform approaches – genome correction, genome expression modulation and mitochondrial quality control – across a variety of different indications," Parrish said. 

While the company is not disclosing indications at this time, "it’s likely that that first clinical program will be in the area of mitochondrial rare diseases," Parrish revealed. 

A Deep Bench

At the core of Pretzel are three leading scientists in the field of mitochondrial biology. The first, Michal Minczuk, Ph.D., is a group leader and investigator at the MRC Mitochondrial Biology Unit at the University of Cambridge. Minczuk is also the lead investigator in the 2018 Nature Medicine paper.

He is joined by Claes Gustafsson, M.D., Ph.D., professor of medical biochemistry at the University of Gothenburg, and Nils-Göran Larsson, M.D., Ph.D., professor of mitochondrial genetics at the Department of Medical Biochemistry and Biophysics at Karolinska Institutet.

Providing crucial biotech industry knowledge and experience are Gabriel Martinez, Ph.D. and Paul Thurk, Ph.D., both also Pretzel co-founders. Martinez will also serve as Pretzel’s chief scientific officer. 

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