Mouse model of LGS epilepsy shows promise for testing new therapies
Study: It successfully mimics disease, responds to approved, potential treatments
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A pair of white-gloved hands are shown holding a black laboratory mouse. (Photo by iStock)
A new mouse model of Lennox-Gastaut syndrome (LGS) accurately reproduced key features of the disease and responded to approved and investigational therapies, providing the first pharmacological validation of the model, a new study reports.
“These promising results suggest the mouse model could be a valuable tool for drug discovery in LGS,” researchers wrote.
The study, “Cannabidiol reduces atypical absence seizures and epileptic spasms in a Gabrb3+/D120N mouse model of Lennox–Gastaut syndrome,” was published in Epilepsia Open.
LGS marked by multiple seizure types
LGS is a severe form of epilepsy that belongs to a broader group of rare genetic conditions known as developmental and epileptic encephalopathies (DEEs). It is marked by multiple seizure types that are often difficult to control, including atypical absence seizures, which can cause brief staring spells and reduced awareness, along with a range of developmental issues, such as cognitive and behavioral problems.
In about 20% to 30% of cases, LGS develops after infantile epileptic spasms syndrome (IESS), a severe epilepsy of infancy marked by epileptic spasms, or sudden muscle contractions that often occur in clusters. This progression is associated with poorer neurological outcomes and a higher risk of death.
“Despite the availability of several antiseizure medications, often administered in combination, long-term seizure freedom in LGS remains rare, highlighting the urgent need for novel therapies,” the researchers wrote.
Treatment with cannabidiol reduced seizure frequency
One obstacle to developing new treatments has been the lack of animal models that closely reproduce the disease seen in people. However, the recent identification of a disease-causing mutation in the GABRB3 gene has provided a strong foundation for developing animal models of LGS.
Mice carrying the patient-derived disease-causing GABRB3 mutation develop many of the syndrome’s hallmark features, including multiple seizure types, abnormal brain activity, and cognitive and behavioral problems. They also develop epileptic spasms shortly after birth, mirroring the progression seen in some children whose IESS later develops into LGS.
Although previous studies showed the mouse model responds to several agents established in preclinical studies to suppress atypical absence seizures, the efficacy of pharmaceutical-grade cannabidiol — the active ingredient in Epidiolex, an oral therapy approved to treat seizures in LGS — remains unexplored.
In the new study, a team led by researchers in Australia sought to validate the mouse model as a platform for LGS drug discovery by testing its ability to accurately predict the effects of pharmaceutical-grade cannabidiol.
To determine whether the mouse model accurately reproduced LGS, the researchers first looked at atypical absence seizures. As expected, mice carrying the disease-causing GABRB3 mutation developed spontaneous atypical absence seizures, characterized by abnormal brain activity accompanied by brief behavioral arrest, while healthy littermates did not.
The present findings support the model’s predictive validity and its utility as a tool for identifying urgently needed therapies for DEEs.
Treatment with pharmaceutical-grade cannabidiol reduced seizure frequency by 46% and total seizure duration by 51%. Two other anti-seizure medications — ethosuximide (sold under the brand name Zarontin and generics), an approved treatment for absence seizures, and the experimental therapy ulixacaltamide — produced similar reductions, further supporting the model’s ability to predict responses to anti-seizure treatments.
The researchers then turned to epileptic spasms. As with atypical absence seizures, neonatal mice carrying the disease-causing GABRB3 experienced substantially more spasms than healthy littermates. Daily treatment with pharmaceutical-grade cannabidiol reduced spasm frequency by 45%. Vigabatrin (sold under the brand name Vigafyde, among others), a first-line anti-seizure medication for infantile epileptic spasms, produced similar results.
Not all mice responded equally to pharmaceutical-grade cannabidiol, however. Nearly half (46%) showed only modest or no improvement, whereas 54% experienced near-complete suppression of spasms.
“The … mouse model of LGS demonstrates robust, drug-responsive atypical absence seizures and neonatal spasms that recapitulate the developmental trajectory of human LGS,” the researchers wrote. “The present findings support the model’s predictive validity and its utility as a tool for identifying urgently needed therapies for DEEs.”
