Treatment with a small molecule called pireperone rescued cognitive and behavioral impairments in a mouse model Fragile X syndromemaking it a potential candidate for treatment of a rare genetic disorder, a study says.
It is likely that the beneficial effects of Pireperone are related to a significant increase in activity FMR1 The gene – which is deficient in fragile X – was also observed in laboratory brain cells from healthy mice.
This approach and study may provide opportunities for new therapeutic development against [fragile X syndrome] It can be expanded to another [brain and spinal cord] Disorders that also need effective treatment,” the researchers wrote, noting their work screening more than 900 genes to identify this small molecule.
Find a new treatment
Fragile X is due to mutations in FMR1 gene, which provides the instructions for making the FMRP protein. FMRP regulates the activity of genes involved in neuronal communication.
These mutations result in decreased production of FMRP, which leads to stimulation of cognition, development, and behavior symptoms It is found in people with fragile X.
Here, a research team in South Korea sought new ways to identify potential treatment for fragile X.
The team hypothesized that they could find a good therapeutic candidate by screening small molecules with the potential to normalize the altered gene activity profile associated with FMRP deficiency.
To do this, they used a connectivity map—a method and database that helps identify small molecules that enhance or revert the gene activity signature of interest.
The X-linked fragile signature was obtained by analyzing gene activity data from eight fragile X patients and 15 healthy subjects, who served as controls. Of the 924 genes analyzed, activity levels of 42 genes were altered – 17 increased and 25 decreased – and were chosen as the disease-associated profile.
Of the 5,000 small molecules included in the database, 25 have shown potential to reverse the fragile X-linked signature, and 11 of them are already approved in the US for other indications.
One of those molecules is called berenberonIt was chosen for further trials based on its known ability to easily penetrate the brain and enhance antipsychotic effects. It is a selective blocker of serotonin, a key molecule in nerve cell communication implicated in autism spectrum disorder, which is most commonly caused by the single gene fragile X.
In neurons cultured in the laboratory from the neocortex, or outer layer of the brain, of healthy mice, treatment with bereniprone was found to significantly increase brain activity. FMR1 gene, which is also regulated by FMRP. The activity of some other genes included in the disease-associated profile was also rescued.
The results indicate that [activity] gene levels in cortical neurons [altered] and reasoned to [fragile X] “Berenbiron,” the researchers wrote.
The team then evaluated whether preniprone could mitigate disease-related cognitive and behavioral problems in a mouse model of fragile X with a deficiency of FMR1 gene.
Whereas mice with fragile X-like disease showed hyperactivity, which is one of the most important features of this mouse model, these symptoms were rescued with bereniprone treatment.
Impulsive behavior, a common feature of fragile X patients, also decreased after administration of bereniprone, reaching levels similar to those observed in healthy animals.
In addition, the memory and learning abilities of the rat model benefited from the treatment. Before treatment, this ratio was reduced compared to healthy mice, but normalized after treatment.
These results indicate that bereniprone is a novel drug candidate [fragile X]
In general, pirenperone has been seen to increase FMR1 gene activity, suggesting that it could enhance FMRP production, which helps regulate neuronal communication and rescue some of the behavioral deficiencies associated with the disease.
These results indicate that bereniprone is a novel drug candidate [fragile X]which must be verified in future studies.”
Although there are still many questions to understand the mechanism of bereniprone as a potential drug candidate [fragile X]We hypothesize that the current study will provide new insights to discover effective drug candidates for the disorder.”