Revolutionary Molecule Offers Hope as a Promising Treatment for Devastating Mitochondrial Diseases

Mitochondria are known as the powerhouses of our cells, but they can also carry unique DNA that sometimes leads to energy shortages. Researchers have recently discovered a groundbreaking molecule that might reverse the effects of certain mutations causing these issues.

“These mutations lead to various diseases with no existing cures,” says Carlo Viscomi, a professor at the University of Padova in Italy. He believes this research could open doors for new treatments.

However, there is still much to learn. Viscomi highlights that this study hasn’t tested the molecule in living organisms yet. Following the initial findings, scientists created a similar molecule that’s now being evaluated in human trials by Pretzel Therapeutics, a company linked to some of the study’s authors. This trial aims to assess the drug’s safety in healthy people, with plans to later include those with mitochondrial diseases.

According to Claes Gustafsson, a professor at the University of Gothenburg, the foundational research is crucial for these ongoing trials.

The study, published in Nature, investigates POLG-related diseases. These rare genetic disorders affect about 1 in 10,000 people globally, stemming from mutations in a gene called POLG, which is vital for mitochondrial function. Mitochondrial DNA needs to be replicated and repaired, and over 300 mutations in POLG can disrupt this process, causing harmful additions or deletions in the DNA.

Symptoms of POLG diseases can vary widely. For instance, Alpers-Huttenlocher syndrome often strikes between ages 2 and 4, leading to severe complications like liver failure and seizures. Others may not show symptoms until they are in their 20s or even later, with those beginning after age 40 generally experiencing milder symptoms.

As people with POLG conditions experience a wide range of symptoms, treatment options are limited, and current therapies mainly focus on symptom management rather than curing the diseases. Given the complexity of hundreds of different mutations, approaches like gene editing are challenging. William Copeland, a senior investigator at the National Institute of Environmental Health Sciences, emphasizes that previous attempts using small molecules have achieved only limited success. What’s different about this new research is the introduction of a specific drug targeting mutant POLG genes that shows promising results in lab experiments.

The research team aimed to find a molecule that could enhance healthy POLG activity and subsequently tested 270,000 compounds. They discovered one that significantly improved function when modified, naming it PZL-A. This optimized molecule binds to a specific area of the POLG protein, enhancing its stability and function. While the study initially focused on just four common mutations, about 70% of individuals with POLG diseases carry at least one of these.

In lab tests, cells treated with PZL-A showed faster recovery of mitochondrial DNA compared to untreated cells. “I didn’t expect to find a solution that worked for so many cases,” Gustafsson remarked. Copeland expressed surprise at how effectively this small molecule could stabilize both mutant and healthy versions of the protein.

Testing on more POLG mutations is ongoing, and early findings indicate positive effects across several types. However, Copeland cautions that thorough clinical trials will be necessary to ensure the drug’s safety and efficacy in humans. If successful, treatment may need to be ongoing, fulfilling a significant need for those with POLG diseases.

Moreover, both Viscomi and Gustafsson noted that mitochondrial DNA issues are linked to age-related diseases, including neurodegenerative disorders. This raises the possibility of broader applications for the compound beyond POLG diseases, potentially benefiting even more people in the future.

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