Mitochondrial disease researchers uncover potential single compound for therapy
Scientists have discovered a new molecule named PZL-A with the potential to reverse genetic disorders caused by mutations in the POLG gene. These rare, inherited diseases, also known as POLG-related diseases, affect an estimated 1 in 10,000 people worldwide.
The molecule has shown promise in laboratory studies by enhancing the activity of the POLG protein, which is crucial for mitochondrial DNA replication and repair. Over 300 different mutations in the POLG gene can disrupt this process, leading to various symptoms and disease progression rates.
The new study, published in April in the journal Nature, focused on four common POLG mutations, as they account for about 70% of cases. In lab-dish experiments, cells with these mutations treated with PZL-A recovered their mitochondrial DNA far faster than untreated cells. In some cases, the treated cells performed as well as cells with the healthy version of the POLG protein.
According to William Copeland, a senior investigator at the National Institute of Environmental Health Sciences who wasn't involved in the study, this breakthrough introduces the "first drug specifically targeted against mutant forms of the POLG gene." He emphasized that the compound works by binding to a pocket in the POLG protein that remains unaffected by the most common disease-causing mutations.
Researchers at Pretzel Therapeutics, which is affiliated with several authors of the paper as founders, consultants, employees, or shareholders, are conducting a clinical trial with PZL-A or a similar molecule. The trial will test the drug's safety in healthy individuals, with plans for testing it with people with mitochondrial diseases next year.
This potential treatment would offer a new avenue for those living with POLG diseases, as current treatments merely manage symptoms rather than cure the conditions. Additionally, the depletion of mitochondrial DNA is linked to diseases of aging, making it possible that scientists may explore additional applications for the compound beyond POLG diseases.
The new molecule, PZL-A, might pave the way for targeted therapies and treatments for POLG-related diseases, a group of rare, genetic disorders affecting approximately 1 in 10,000 people worldwide. By binding to an unaffected pocket in the POLG protein, this compound could introduce the first drug specifically designed to counteract mutant forms of the POLG gene, potentially reversing these conditions, and also demonstrating potential for health-and-wellness improvement in managing medical-conditions linked to the depletion of mitochondrial DNA, such as certain diseases of aging.
