In human heart tissues, investigators found that the mechanism associated with heart failure can be reversed and Dicer activity can be restored when AD-9308 was used.
A new synthetic molecule compound, AD-9308, has been tested for the treatment of heart failure (HF), demonstrating the ability to restore activity to aldehyde dehydrogenase 2 (ALDH2) in the mitochondria, according to a study published in the European Heart Journal.
“The study lasted more than 10 years and included both laboratory experiments and samples from patients [with HF] with the aim of understanding a novel mechanism involved in [HF] progression. In parallel with our experiments, the biopharmaceutical company worked on improving the efficacy of a molecule described back in 2014, which has potential to treat cardiac diseases,” Julio Cesar Batista Ferreira, a professor at the Institute of Biomedical Sciences in São Paulo, Brazil, said in a press release.
Previously, the prototype compound, Alda-1, was found to increase heart function in rats with HF by 40%, according to the press release. Investigators said the effect was because of the activation of ALDH2 in cardia cells. The investigators made modifications to the original molecule, with the newest version activating the enzyme more than 3 times than the original molecule, according to Ferreira.
Investigators have proven that HF is associated with mitochondrial malfunction, with the mitochondria producing 4-hydroxynonenal in those with HF. The compound is also in the class of aldehydes, according to the press release.
“Every cell has hundreds or sometimes thousands of mitochondria, which produce enough aldehyde to poison the entire cell when they aren’t running properly. We discovered in this latest study that too much of 4-hydroxynonenal switches off a vital event for the cell: processing of microRNAs [small non-coding RNAs that regulate the activity of other genes],” Ferreira said in the press release.
In the study, the investigators found that 4-hydroxynonenal binds to a protein that is essential to microRNA formation, called Dicer, and inactive in the protein. AD-9308 helped to improve mitochondrial filtration to eliminate 4-hydroxynonenal, according to Ferreira.
In rodents and humans who had the accumulation of aldehyde caused by HF, investigators were able to identify the chemical alterations that inactivated Dicer, which would limit the formation and maturation of the microRNAs, Ferreira said in the press release. This interruption in microRNAs has also been associated with cancer, metabolic syndrome, neurodegenerative disorders, and cardiovascular disease.
In the animal models, investigators gathered cell cultures and heart tissue samples, finding that aldehyde binding to Dicer reduces the amount of microRNA availability in the heart, according to the press release. In human heart tissues, investigators have found that the mechanism associated with HF can be reversed, with Dicer activity restored when AD-9308 was used.
“In summary, AD-9308 stimulates the removal of aldehyde from sick cells, reducing the likelihood that it will ‘switch off’ Dicer and hence protecting the heart cells. This tends to keep the microRNA profile closer to that of a healthy heart,” Ferreira said in the press release. “The results show that the synthetic molecule is well tolerated by healthy [individuals]. These are the required steps to apply to the FDA for permission to test the drug in heart failure patients. However, it requires more volunteers and more time, but it’s the only way to find out which kind of [HF] it could treat and at what stage of the disease.”
Molecule tested at University of São Paulo, in Brazil, proves able to mitigate heart failure. News release. EurekAlert. November 8, 2023. Accessed November 14, 2023. https://www.eurekalert.org/news-releases/1007398