Scientists Unveil Molecule with Potential to Treat Devastating Mitochondrial Diseases

Mitochondria – often referred to as the power stations within our cells – possess distinctive DNA that can mutate, leading to particular illnesses which result in cellular energy deprivation. Recently, researchers have identified an unprecedented compound capable of reversing the impacts of frequent mutations responsible for such hereditary conditions.

"The mutations can lead to various illnesses for which no cures currently exist," he stated. Carlo Viscomi , an associate professor at the University of Padova's Department of Biomedical Science and Padua Neuroscience Center in Italy.

“I believe this paper truly represents a significant advancement,” stated Viscomi, who wasn’t part of the study but had earlier worked alongside several of the researchers. “It could potentially unlock extraordinary opportunities for treating these conditions.”

One drawback of this study is that it failed to show how effectively the molecule performs in a living organism or human, according to Viscomi. However, building upon these findings, researchers proceeded to create a comparable molecule that has improved characteristics. currently undergoing human trials That clinical trial is being conducted by Pretzel Therapeutics, where multiple authors from this paper serve as founders, consultants, employees, or shareholders. The study will test the safety Regarding the use of the drug in healthy participants, next year, the firm intends to conduct a study involving individuals with mitochondrial disorders.

The team's preliminary research served as "a crucial stage" in initiating the current trial, according to study co-author Claes Gustafsson , a professor from the Department of Medical Biochemistry and Cell Biology at the University of Gothenburg in Sweden, explained to Live Science.

Related: An initial study suggests that malfunctioning mitochondria might be behind Crohn's disease.

"Extremely variable" diseases

The research, released in April in the journal Nature , concentrating on disorders associated with polymerase gamma, known as POLG-related diseases In brief, these uncommon, hereditary disorders impact approximately 1 in 10,000 individuals globally. They arise from alterations in the POLG gene, responsible for producing a crucial protein within mitochondria.

The DNA inside mitochondria has to be duplicated when new mitochondria are produced. Additionally, mitochondrial DNA should undergo repair following influences such as oxidative stress damage it. However, around 300 different mutations In the POLG gene, this replication-and-repair mechanism can be disrupted by interfering with the enzyme responsible for it: polymerase gamma (POLG).

POLG mutations lead to the accumulation of detrimental changes in mitochondrial DNA, trigger deletions within segments of this genetic material over time, or do both. The conditions associated with POLG can manifest as a broad spectrum of symptoms that differ significantly between individuals based on the specific mutations present and the number of copies inherited from their parents. As Viscomi explained to Live Science, "The variability is immense."

Alpers-Huttenlocher syndrome One of the most serious POLG disorders usually begins manifesting symptoms between ages 2 and 4, leading to liver failure and seizures, and proving fatal within approximately four years from when symptoms first appear. Certain POLG-associated conditions can present themselves at an even younger age. shortly after birth While some appear earlier, others emerge later, typically between the ages of 12 and 40, or sometimes even after 40. Individuals who develop their symptoms after turning 40 generally have the most favourable outlook with relatively minor initial signs such as sagging eyelids and weakened eye muscles.

Typically, individuals affected by POLG disorders have shorter lifespans. ranging from three months to 12 years once their symptoms initially start.

Due to the numerous mutations causing these disorders, tackling them using gene-editing techniques would be quite difficult. CRISPR , said William Copeland , a senior investigator and leader of the Mitochondrial DNA Replication Team at the National Institute of Environmental Health Sciences in the U.S., who did not participate in the research. Therefore, several teams have explored using small molecules to treat the diseases , achieving only modest success, as he informed Live Science via email.

The novel aspect of this research is the introduction of what is described as "the first medication designed explicitly for mutations in the POLG gene," according to Copeland. Additionally, preliminary tests suggest that this drug can "substantially" enhance the functionality of the POLG protein, he noted further.

Related: We now understand why the brain consumes such large amounts of energy.

Search for a promising medication

The researchers hypothesized that discovering a medication capable of boosting the function of normal POLG might also make it effective against mutated forms. To test this theory, they started by examining over 270,000 different substances for their effect on the performance of regular POLG. Their search yielded an encouraging compound which they subsequently modified to boost its effectiveness before testing it on prevalent mutations. The refined variant was named PZL-A.

In this research, the scientists concentrated on only four POLG variants instead of examining all 300. Nonetheless, approximately 70% of individuals with POLG disorders possess at least one of these four mutations, as they pointed out.

The team employed a method known as cryogenic electron microscopy to provide an intricate view of how the molecule engaged with each mutant and with normal POLG proteins. This protein comprises three sections that interlock: one "A" segment and two "B" segments. Their investigation uncovered that the PZL-A compound occupies a space located between the A section and one of the B sections. Notably, this particular site remains “untouched” by the prevalent disease-inducing [POLG] mutations, as stated by the researchers in their publication.

Through its interaction at that site, the molecule increases the general stability of the protein; consequently, this improves its capacity for replicating and repairing DNA, irrespective of whether a mutation exists. "Although not every single mutation was examined, those that were looked at appear to have been 'restored' in some way when this compound was used," stated Viscomi.

The scientists supported these preliminary observations by conducting laboratory tests using cells derived from individuals affected by the four prevalent mutations under investigation. They began by removing the mitochondrial DNA within these cells to assess how swiftly the cells would be able to restore this missing genetic material. The cells exposed to the compound regained their DNA considerably more rapidly compared to those not treated, and in certain cases, matched the recovery rate seen in normal versions of the proteins.

I was not ready for this result — that we would indeed discover one stone capable of eliminating all these birds," Gustaffson stated. "Yet, we found it nonetheless.

Copeland concurred, stating, "I'm astonished that a minuscule molecule can stabilize the mutated variants of POLG," along with stabilizing and modifying the function of the normal forms of the protein.

The team has started testing the compound on further POLG mutants. Up until now, they have observed impacts across many of these other mutations, according to Gustafsson. This latest research hasn’t been published yet. In parallel, the clinical trial has only recently commenced to assess a molecule that bears close structural similarities to PZL-A, he mentioned additionally.

Clinical trials will be necessary to determine if the newly discovered compound induces any undesirable side effects and confirms its anticipated impact on humans, according to Copeland. Should it demonstrate safety and efficacy, "It’s presumed that the patient would require constant therapy throughout their lifetime," he further noted.

This approach would address a gap in care for individuals suffering from these ailments, since existing therapies primarily focus on managing symptoms rather than providing a cure. managing patients' symptoms .

Furthermore, Viscomi and Gustafsson pointed out that the reduction in mitochondrial DNA is linked to age-related disorders, such as neurodegenerative illnesses. Therefore, it might be possible that apart from treating POLG-associated diseases, researchers could investigate further uses for this compound.

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