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Promising Breakthrough in Treatment for Mitochondrial Diseases

A significant advancement has emerged in the field of medicine, potentially providing a groundbreaking treatment for rare yet severe diseases linked to genetic mutations that impair cellular energy production. Researchers from the University of Gothenburg have unveiled a molecule that enhances mitochondrial function.

Mitochondrial diseases, particularly those associated with mutations in the POLG gene, exhibit a wide range of symptoms and severity. In young patients, these conditions can lead to rapid neurological damage and critical liver issues, while others might experience muscle weakness, epilepsy, and organ failure as they grow older.

The POLG gene plays a crucial role in the synthesis of DNA polymerase gamma, an enzyme responsible for replicating mitochondrial DNA. In the absence of proper POLG function, mitochondria struggle to operate effectively, resulting in insufficient energy production for the cell.

A Major Breakthrough

Leading the research are Professors Maria Falkenberg and Claes Gustafsson from the Sahlgrenska Academy at the University of Gothenburg, whose findings are set to be published in the journal Nature.

“We have shown that the molecule PZL-A can rectify the function of mutated DNA polymerase gamma, thereby enhancing mitochondrial DNA synthesis in patient cells. This, in turn, significantly boosts the mitochondria’s capacity to supply energy to the cells,” explained Maria Falkenberg, a Professor of Biomedical Laboratory Science.

“This represents a pivotal breakthrough, as we are the first to demonstrate that a small molecule can ameliorate the functionality of defective DNA polymerase. Our findings lay the groundwork for an entirely new strategy in treatment development,” added Claes Gustafsson, who specializes in Medical Chemistry.

From Laboratory Discoveries to Potential Treatment

The identification of PZL-A is the result of over two decades of foundational research. This molecule was discovered after extensive analysis of numerous chemical compounds in collaboration with Pretzel Therapeutics, led by Simon Giroux, who is the Vice President of Chemistry at the company and a co-author of the study. Initial investigations of PZL-A have involved cells derived from patients as well as in vivo studies in animal models.

Researcher Sebastian Valenzuela, a doctoral student at Sahlgrenska Academy, has conducted a detailed structural analysis of the molecule, utilizing techniques such as cryo-electron microscopy.

“We have pinpointed the precise location where the molecule interacts with the enzyme, targeting a very specific binding site that enhances our understanding of the enzyme’s operations and how we may be able to modulate its activity,” noted Sebastian Valenzuela, the study’s first author.

Pretzel Therapeutics is preparing to initiate phase I clinical trials with an improved version of PZL-A, focusing on assessing its safety in healthy volunteers. Given that deficiencies in mitochondrial DNA are also implicated in various other mitochondrial conditions and neurodegenerative diseases, similar compounds to PZL-A may have broader therapeutic applications. Pretzel Therapeutics operates within the life sciences sector in the Gothenburg area, with its Swedish activities based at GoCo Health Innovation City and its main office located in Waltham, Massachusetts, just outside Boston.

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