Republished with permission from Fragile X News Today, written by Marisa Wexler, MS.
Treating Fragile X syndrome will likely require a combination of drugs, as a single medication may not address all symptoms.
At FRAXA-DVI, Dr. Patricia Cogram and her team recently tested a combination of two investigational new drugs in Fragile X mice, with support from Healx. Together ibudilast and gaboxadol rescued a wide array of symptoms in the mice.
The therapies have been shown to have good effects individually.
A combination of therapeutic candidates gaboxadol and ibudilast normalized behavior and improved memory in a mouse model of Fragile X syndrome in a new study.
The study, “A novel combination treatment for Fragile X syndrome predicted using computational methods,” was published in Brain Communications. The work was led by scientists at the drug discovery company Healx, which funded the study.
Fragile X is caused by mutations in the FMR1 gene, which leads to disruptions in different signaling systems in the brain that result in developmental problems. Since many systems are affected in Fragile X, the best treatment likely involves a number of medications that target different processes.
Healx has developed a computational model that seeks to predict how different drug combinations will affect the activity of cells in the body. With it, the company identified combining gaboxadol and ibudilast as a promising treatment.
Gaboxadol, a compound designed to activate proteins called gamma-aminobutyric acid (GABA) in the brain, was shown to safely and effectively ease behavioral and functional problems in Fragile X patients who participated in a Phase 2 clinical trial (NCT03697161). Healx secured the exclusive option to license the rights to develop and commercialize gaboxadol two years ago and planned to test the therapy with other compounds in Fragile X syndrome and other conditions.
Ibudilast is an anti-inflammatory medication shown “to have several beneficial effects in the brain,” the researchers wrote. While not approved in the U.S., it’s cleared in Japan and Korea for certain inflammatory conditions and is being tested in other neurological disorders, including multiple sclerosis and amyotrophic lateral sclerosis. Treatment with BPN14770, a molecule with a similar mechanism of action, improved cognitive skills and daily functioning in men with fragile X in a previous Phase 2 trial (NCT03569631).
“Both drugs have a good safety and tolerability profile in the clinic, making them attractive candidates for repurposing,” the researchers wrote.
Combining Therapies
Here, Healx scientists, along with colleagues in Chile and at FRAXA Research Foundation, tested the effects of gaboxadol and ibudilast individually in a mouse model of Fragile X, which, like people with the condition, displays behavioral abnormalities and issues with cognitive ability and memory.
Treatment with gaboxadol normalized behavior in the Fragile X model. Specifically, treated mice showed significantly less hyperactivity, aggression, and anxiety, as well as fewer atypical repetitive movements, called stereotypies. Gaboxadol didn’t have any noteworthy effects on the animals’ cognitive performance, however.
Treatment with ibudilast did lead to significant improvements in cognitive function, with treated mice performing much better on memory tests, but there was no notable changes in behavior.
The researchers then tested a combined treatment using the dose of each that showed the greatest effect when used on its own. Combining them led to both normalization of behaviors and gains on cognitive tests.
“This work demonstrates for the first time that by targeting multiple pathways, with a combination treatment, we were able to rescue more [disease features] in a Fragile X syndrome mouse model than either ibudilast or gaboxadol could achieve as single therapies],” the researchers wrote. “When these two drugs are administered as a combination treatment, we were able to rescue both the cognitive deficits and the behavior abnormalities in [Fragile X] mice.”
Ibudilast alone appeared more effective than the combination on some cognitive tests, and this may be because gaboxadol has anxiety-relieving properties that may have affected the animals’ cognitive performance.
Both drugs, alone or combined, showed consistent effects when given chronically over time, and no major safety issues were identified.
“This combination treatment approach holds promise for addressing the wide spectrum of diverse symptoms” in Fragile X, wrote the scientists, who emphasized that additional testing should verify the combination’s safety.
Original article: Two-med combo normalized behavior, improved memory in fragile X mice
Written by
Fragile X News Today is a digital platform started in early 2018 providing updates on research, science and advice news for Fragile X patients and caregivers.
Marisa Wexler, MS Marisa holds a Master of Science in cellular and molecular pathology from the University of Pittsburgh, where she studied novel genetic drivers of ovarian cancer. Her areas of expertise include cancer biology, immunology, and genetics, and she has worked as a science writing and communications intern for the Genetics Society of America.
