Understanding Pediatric Epilepsy and the PIK3-AKT-MTOR Pathway

Using mouse models to screen potential drugs that could treat the most common forms of epilepsy and seizures

Technical Overview

Overgrowth of cells in the brain during development can cause severe neurological pathologies such as autism, impaired cognition and epilepsy. Epilepsy from brain overgrowth provides a model for understanding the genetics of pediatric epilepsy and how it might be treated. Kathleen J. Millen, PhD, has created mouse models that are ready to screen drugs for their ability to treat epilepsies.

Dr. Kathleen Millen

The most common forms of focal epilepsy are caused by mutations in the PIK3-AKT-MTOR pathway. The mutations overlap those seen in cancers, in the catalytic subunit of phosphoinositide 3-kinase (PIK3CA) and other PI3K-AKT-MTOR pathway components. For cancer, commercially accessible targeted inhibitors for the PI3K/AKT/mTOR pathway include mTOR inhibitors everolimus, sirolimus and temsirolimus. PI3K inhibitors include alpelisib, duvelisib, copanlisib, idelalisib and umbralisib.

Millen and team are interested in repurposing drugs that affect the PIK3-AKT-MTOR pathway. Most of the drugs cannot be used for cancer because they either do not kill cancer cells or are too toxic at the levels needed. To modulate epilepsy, however, the drug does not need to turn off the PIK3-AKT-MTOR pathway but rather turn it down like a rheostat. Her team is looking for drugs that affect the PIK3-AKT-MTOR pathway but do not cause cell death.

Millen is interested in industry partnerships to collaborate on developing a platform for testing drugs for epilepsy treatment. The animal models she developed at Seattle Children’s Research Institute are ready for screening drugs for efficacy in treating epilepsy.

Stage of Development

• Pre-clinical in vitro or in vivo

Partnering Opportunities

• Collaborative research and development
• Sponsored research agreement
• Tissue samples, cell lines, animal models, data
• Drug development opportunity

Publications

1. Roy A, Skibo J, Kalume F, ... Millen KJ. Mouse models of human PIK3CA-related brain overgrowth have acutely treatable epilepsy. Elife. 2015;4:e12703.
2. Roy A, Millen KJ, Kapur RP. Hippocampal granule cell dispersion: a non-specific finding in pediatric patients with no history of seizures. Acta Neuropathologica Communications. 2020;8(1):54.
3. Roy A, Deng M, Aldinger KA, … Millen KJ. Laser capture micro-dissection (LCM) of neonatal mouse forebrain for RNA isolation. Bio-protocol. 2020;10(1):e3475.
4. Roy A, Murphy RM, Deng M, … Millen KJ. PI3K-Yap activity drives cortical gyrification and hydrocephalus in mice. eLIFE .2019;8:e45961. https://doi.org/10.7554/eLife.45961

Learn More

• Kathleen J. Millen, PhD
• UW Neuroscience Institute presentation, 2021