Experimental therapy improves behavior, cognition in fragile X mice
High-dose treatment produced the strongest effects, some lasting after treatment
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Marvel Biosciences’ lead experimental oral therapy MB-204 moved multiple measures of behavior and cognitive function toward normal levels in a mouse model of fragile X syndrome (FXS), with some signs of a potential carry-over effect after treatment was discontinued.
“This is now the third ASD [autism spectrum disorder] model and second independent group that has demonstrated the potential of MB-204 to restore behavioural and cognitive function to near normal levels in mice regardless of the genetic cause of the neurodevelopmental disorder,” Mark Williams, PhD, Marvel’s chief science officer, said in a company press release.
Fragile X is the most common known single-gene cause of ASD, an umbrella term used for conditions characterized by difficulties with social communication and restricted, repetitive patterns of behavior and interests.
The preclinical research was conducted through the FRAXA Drug Validation Initiative, a research program run by the FXS-focused advocacy group the FRAXA Research Foundation.
FRAXA collaboration supports preclinical testing
“We are very grateful to FRAXA for this collaboration and look forward to advancing MB-204 to the clinic,” Williams said.
Fragile X is a genetic disorder caused by mutations in the FMR1 gene. Symptoms can include developmental, cognitive, and behavioral problems. About one in three people with FXS are also diagnosed with ASD.
Marvel is developing MB-204 as a potential treatment for multiple disorders that are associated with autistic features. The experimental therapy is designed to block the activity of the A2A receptor, a signaling protein in the brain. According to Marvel, research suggests that blocking this protein may help treat ASD and other psychiatric conditions.
Researchers tested low- and high-dose MB-204 in a mouse model of fragile X that lacks the FMR1 gene. These mice show abnormalities on tests assessing memory, locomotor activity, anxiety, nesting, and grooming behaviors.
Results showed that approximately two weeks of once-daily MB-204 treatment “restored every behavioural and cognitive [outcome] studied in Fragile X mice toward wild-type (normal) levels,” the release stated.
There was a clear dose-dependent effect, with the high dose producing the strongest and most consistent effects.
Two weeks after treatment ended, the researchers retested the mice using the same battery of tests. Even after treatment had stopped, mice given high-dose MB-204 showed lingering improvements in memory, grooming, and locomotor activity.
“Overall, results support robust on-treatment efficacy and a measurable, though reduced, post-washout effect in the high-dose treatment group, while the low-dose treatment was insufficient to produce a durable post-treatment benefit,” the release stated.
MB-204 has previously shown similar benefits in a mouse model of Rett syndrome, a genetic disorder that can involve autistic-like features, and another mouse model of genetic ASD.
According to Marvel, the consistent results across multiple disease models support MB-204’s potential across a range of neurodevelopmental disorders and its advancement toward clinical trials.
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