POLG-related diseases are a diverse group of conditions, all caused by mutations in the gene for an important mitochondrial protein. The new molecule could be a promising treatment option. (Image credit: KATERYNA KON/SCIENCE PHOTO LIBRARY via Getty Images)
Mitochondria, which function as the powerhouses of cells, contain unique DNA that is susceptible to mutation in some diseases, starving cells of energy. Now scientists have discovered the first molecule of its kind that can reverse the effects of the common mutations that underlie these genetic diseases.
“These [mutations] can lead to many different diseases for which there are no cures,” said Carlo Viscomi, associate professor of biomedical sciences and the Padua Neuroscience Center in Italy.
“I think this paper is truly groundbreaking,” said Viscomi, who was not involved in the study but previously collaborated with some of the authors. “It could open up incredible possibilities for treating these conditions.”
One limitation of the study is the lack of data on how well the molecule functions in living organisms, Viscomi said. However, the researchers are continuing to develop a similar molecule as part of the research, which is currently undergoing clinical trials. The trials are being conducted by Pretzel Therapeutics, a company with which several of the authors of the paper are affiliated as founders, consultants, employees, or shareholders. The trial is designed to assess the drug’s safety in healthy people, and the company plans to test it in patients with mitochondrial diseases next year.
The team's preliminary study was a “significant step” toward launching the current study, study co-author Klas Gustafsson, a professor in the department of medical biochemistry and cell biology at the University of Gothenburg in Sweden, told Live Science.
“Highly variable” diseases
The study, published in April in the journal Nature, focused on polymerase gamma-associated diseases, called POLG-associated diseases for short. These rare inherited diseases affect about 1 in 10,000 people worldwide and are caused by mutations in the POLG gene, which codes for a key protein in the mitochondria.
Mitochondrial DNA must be replicated as new mitochondria are formed. Mitochondrial DNA also needs to be repaired after damage caused by factors such as oxidative stress. However, about 300 different mutations in the POLG gene disrupt this replication and repair process by interfering with the action of the enzyme responsible for this job: polymerase gamma (POLG).
POLG mutants cause harmful mutations to accumulate in mitochondrial DNA, which can lead to chunks of DNA being deleted over time, or both. POLG diseases cause a variety of symptoms that vary from patient to patient and progress at different rates depending on which mutations a person has and how many copies they inherited from their parents. “It’s extremely variable,” Viscomi told Live Science.
Alpers-Huttenlocher syndrome, one of the most severe POLG disorders, typically begins between 2 and 4 years of age; causes liver failure and seizures; and is fatal within four years of symptom onset. Some POLG disorders begin earlier, shortly after birth, while others may appear later, between 12 and 40 years of age or even after age 40. Those whose symptoms begin after age 40 usually have a better prognosis, and symptoms at the onset of the disease are often mild, including drooping eyelids and weakness of the eye muscles.
In general, people with POLG diseases live from three months to 12 years after the first symptoms appear.
Because hundreds of mutations lead to these conditions, they will be difficult to treat with gene-editing techniques such as CRISPR, noted William Copeland, a senior investigator and leader of the mitochondrial DNA replication group at the National Institute of Environmental Health Sciences in the US, who is not
Sourse: www.livescience.com
