Use of cancer drug vorinostat shown to ease symptoms in Rett mice
Developer seeking to repurpose Zolinza lymphoma therapy for genetic disease
Vorinostat, an approved lymphoma treatment sold as Zolinza, was found to ease both neurological and non-neurological symptoms in a mouse model of Rett syndrome in a new study.
When an oral formulation of vorinostat was administered after symptom onset, the drug was even more effective than Daybue (trofinetide), the only approved treatment for Rett, which showed no effects on disease progression when started at this stage.
According to the researchers, these findings support the continued development of RVL001, Unravel Biosciences‘ investigational oral formulation of vorinostat, for treating Rett syndrome.
“To our knowledge, this represents the first effective treatment of [Rett] mice when treatment is initiated after the onset of symptoms,” the researchers wrote.
Their study, “AI-enabled drug prediction and gene network analysis reveal therapeutic use of vorinostat for Rett Syndrome in preclinical models,” was published in the journal Communications Medicine. Several of the researchers work for or hold equity in Unravel.
Unravel is already seeking regulatory clearance in Colombia to launch proof-of-concept clinical trials testing RVL001 in Rett patients. The company has partnered with Quality Chemical Laboratories to manufacture materials for the trials.
Rett syndrome is primarily caused by mutations in the gene encoding MeCP2, a protein that regulates the activity of hundreds of other genes by switching them on or off.
Because MeCP2 is critical for brain development and function, people with Rett can experience cognitive, emotional, sensory, and motor disturbances, as well as frequent seizures. Beyond brain dysfunction, symptoms can include problems with breathing, digestion, sleep, bone density, and heart and kidney function.
Researchers used artificial intelligence-based discovery platform
The drug vorinostat is approved by the U.S. Food and Drug Administration (FDA), under the name Zolinza, to treat skin manifestations caused by a cancer known as cutaneous T-cell lymphoma. The therapy belongs to a class of medicines that block histone deacetylases, enzymes that regulate gene activity within cells.
In this report, a team led by researchers at Harvard University in Massachusetts described how vorinostat was identified as a potential therapy for Rett — in part with the help of artificial intelligence (AI), as well as the use of tadpoles. The researchers then validated it in a Rett mouse model.
First, the team combined AI and human gene activity analyses to identify molecules, including FDA-approved drugs, predicted to reverse the impact of MeCP2 mutations in a tadpole model.
The Rett tadpoles were then dosed with the top compounds before and after the onset of symptoms. The researchers recorded their swimming patterns and seizures, with seizure severity used as a screening metric.
Among all the compounds tested, vorinostat and another approved drug called ivermectin — used to treat parasitic infections — were found to reduce seizure scores, which rose after the drugs were stopped.
Because vorinostat showed more consistent results in all subsequent studies, the researchers focused additional analyses on this drug alone and compared it with Daybue. Both therapies reduced seizure-like symptoms, increased viability, and improved swimming abilities.
Vorinostat rescued deficiencies in mobility, walking in mice
Vorinostat was then assessed in an established MeCP2-deficient mouse model of Rett syndrome. The therapy was administered via an injection into the abdominal cavity daily for two weeks, starting before symptom onset.
Treatment was found to significantly ameliorate multiple disease-related features, as indicated by a reduction in the Bird score, which measures a broad range of neurological and non-neurological Rett symptoms.
When tested beside Daybue, animals responded favorably to both drugs, showing relief from diarrhea and enhanced performance on the Y-maze test, which assesses spatial recognition memory. However, vorinostat improved neurological function more effectively than Daybue, as determined by elevated plus maze (EPM) performance, a test used to assess anxiety.
This AI-based computational discovery platform demonstrates the possibility of rapidly identifying alternative uses for existing FDA approved drugs for treatments of patients with complex genetic disorders.
To better mimic a clinically relevant scenario, Rett mice were dosed with an oral formulation of vorinostat about one week after the onset of symptoms.
Data showed that the oral medication prevented a significant worsening of the Rett symptom severity score, improved weight gain, and enhanced performance in the EPM and Y-mazes. In comparison, Daybue was found to be ineffective when given at this stage, “similar to the moderate efficacy observed in human clinical trials,” the team wrote.
Vorinostat treatment also rescued deficiencies in mobility, walking, and hindlimb clasping among the mice. Breathing was also significantly improved with vorinostat compared with Daybue. Moreover, all animals treated with oral vorinostat were alive after three weeks of treatment, similar to untreated Rett mice, whereas approximately 60% of Daybue-treated Rett animals survived.
Overall, the results support the further development of the repurposed cancer therapy, according to Unravel.
“This AI-based computational discovery platform demonstrates the possibility of rapidly identifying alternative uses for existing FDA approved drugs for treatments of patients with complex genetic disorders,” the researchers wrote in a plain-language summary of the study.
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