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Published on: June 12, 2018
Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy
Achira Roy1, Jonathan Skibo1, Franck Kalume1
1Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States.
Abstract:
Mutations in the catalytic subunit of phosphoinositide 3-kinase (PIK3CA) and other PI3K-AKT pathway components have been associated with cancer and a wide spectrum of brain and body overgrowth. In the brain, the phenotypic spectrum of PIK3CA-related segmental overgrowth includes bilateral dysplastic megalencephaly, hemimegalencephaly and focal cortical dysplasia, the most common cause of intractable pediatric epilepsy. We generated mouse models expressing the most common activating Pik3ca mutations (H1047R and E545K) in developing neural progenitors. These accurately recapitulate all the key human pathological features including brain enlargement, cortical malformation, hydrocephalus and epilepsy, with phenotypic severity dependent on the mutant allele and its time of activation. Underlying mechanisms include increased proliferation, cell size and altered white matter. Notably, we demonstrate that acute 1 hr-suppression of PI3K signaling despite the ongoing presence of dysplasia has dramatic anti-epileptic benefit. Thus PI3K inhibitors offer a promising new avenue for effective anti-epileptic therapy for intractable pediatric epilepsy patients.
Insights
Activating mutations in PIK3CA cause brain overgrowth and epilepsy. PI3K inhibitors show promise for treating intractable pediatric epilepsy, even with existing brain dysplasia.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Mutations in PIK3CA are linked to cancer and overgrowth syndromes.
- PIK3CA-related overgrowth in the brain causes conditions like hemimegalencephaly and focal cortical dysplasia, leading to pediatric epilepsy.
Purpose of the Study:
- To create and analyze mouse models of PIK3CA-related brain overgrowth.
- To investigate the mechanisms underlying PIK3CA-related brain malformations and epilepsy.
- To evaluate the therapeutic potential of PI3K inhibitors for pediatric epilepsy.
Main Methods:
- Generated mouse models with common activating Pik3ca mutations (H1047R, E545K) in neural progenitors.
- Characterized pathological features including brain size, cortical development, and white matter.
- Assessed the anti-epileptic effects of acute PI3K signaling suppression.
Main Results:
- Mouse models recapitulated human features: brain enlargement, cortical dysplasia, hydrocephalus, and epilepsy.
- Phenotypic severity correlated with the specific mutation and timing of activation.
- PI3K inhibition provided significant anti-epileptic benefits despite persistent dysplasia.
Conclusions:
- PIK3CA mutations drive key pathological features of brain overgrowth and intractable pediatric epilepsy.
- PI3K signaling is a critical target for therapeutic intervention.
- PI3K inhibitors represent a promising treatment strategy for pediatric epilepsy associated with PIK3CA mutations.
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