A rare mutation in the IQSEC2 gene results in a phenotype of severe intellectual disability, autism spectrum disorder, and drug resistant epilepsy. Herewith is a set of technologies and capabilities centered around the goal of finding a therapy to improve the lives of children with IQSEC2 mutations. Several targetable nodes for treatment have been identified.
The lab has created a CRISPR murine model of the mutation which recapitulates the learning, behavioral and epileptic phenotypes seen in the child with the IQSEC2 mutation and have demonstrated that AMPA receptors, whose trafficking to and from the membrane are regulated by Arf6, are markedly downregulated in the IQSEC2 mutation providing an important link between the mutation and its associated cognitive impairment. It was demonstrated that the said mutation results in a constitutive activation of the GEF activity of IQSEC2 resulting in increased Arf6-GTP.
They have also studied human induced pluripotent stem cells (iPSC) derived hippocampal neurons from a child with the mutation (as well as a CRISPR corrected wild type line from the child) which corroborate the biochemical and electrophysiological findings observed in mice, validating their role as a platform for drug discovery.
While the mutation in IQSEC2 is an orphan rare disease, the pathways which are affected by this mutation overlap considerably with common disorders affecting cognition such as Alzheimer’s disease (for Arf6) and epilepsy (affecting the excitatory/inhibitory balance).
- Novel targets
Applications and Opportunities
- Novel targets for rare/orphan neurological disorders
- Potential new drug targets for epilepsy and neurodegenerative diseases
- Platform for drug discovery and drug screening