August 27, 2025 

Andrew P.  Levy MD PHD 

 IQSEC2 is a protein which is critical for normal brain development.  Without a properly functioning IQSEC2 molecule children will develop seizures, poor language skills, and a moderate to severe learning disability.  All children with IQSEC2 disease have a change in their DNA (mutation). We and our collaborators have created mice with the same DNA mutations found in children with IQSEC2 disease.  These mice display seizures, behavioral changes, and learning disabilities similar to children with IQSEC2 disease.      

In this research study we set out to test whether providing a normal copy of the IQSEC2 DNA could prevent or rescue mutant mice from developing the disease.  We introduced the IQSEC2 DNA using a special type of virus which doesn’t infect people (adeno associated virus).   We also used genetic methods to make sure IQSEC2 would only be made in the brain.  

After the mice received the virus we monitored their growth, seizure activity, and behavior.   In all cases we were able to demonstrate that mice that received the virus had a dramatically improved condition.   The treated mice grew to be larger, had fewer seizures, and showed improved social behavior.  

Another important finding in the study was that treated adult mice, not just young mice, showed improvement.  This suggests that the window for this type of therapy may be quite broad, allowing teenagers or young adults with IQSEC2 mutations to be helped.  

One of the most important aspects of this study is that it was done in three different laboratories, increasing the reliability and confidence of the generated data. 

This does not represent a cure for IQSEC2 disease.  It does, however, represent a major step forward in providing a treatment that could significantly improve the lives of many children with IQSEC2 disease.   Our next step is to carry out a clinical trial within the next year which will depend on fund raising and regulatory compliance to make sure the study is done safely.  Our goal is to make treatment available to all children with IQSEC2. More details will be discussed in an upcoming webinar for the IQSEC2 community.

The research projects selected for funding were selected based on their ability to develop new therapeutics for treating our children with IQSEC2 mutations. Each project is funded for one year. 

The project let by Dr Cheryl Shoubridge will be generating brain cortical neurons derived by genetic reprogramming of skin cells taken from children with three different IQSEC2 mutations. It is known that cortical neurons from mice with IQSEC2 mutations display abnormalities in the way they can spontaneously discharge (the in vitro correlate of a seizure). This study will compare how neurons from children with IQSEC2 human mutations may differ in this abnormality and will allow the assessment of multiple anti-epileptic drugs on their ability to restore the normal electrical activity of the cells and may suggest which drugs would be best for which IQSEC2 mutations. As many parents with children with IQSEC2 mutations know, the search for an epilepsy drug is generally done by trial and error on the child with some children needing to go thru 10-20 medications. This would represent a personalized approach to the epilepsy treatment of children with IQSEC2 mutations and allow mixing and matching of multiple different treatments to help find the optimal approach for a given child’s mutation.  

The project led by Dr Takuma Mori will be to design a female model of IQSEC2 mutation associated disorders in mice. Virtually all IQSEC2 research to this point has been done in male mouse disease models. As the IQSEC2 gene is on the X chromosome, males have only one copy of the IQSEC2 gene and females have two copies. In general one of the two X chromosomes is inactivated in a cell in females and this is generally random so that if a female had one mutated copy of a gene on the X chromosome and one normal copy of the gene on the other X chromosome half of the cells would express only the mutated copy and half would express the normal copy.   In mice, this is indeed how the IQSEC2 gene is regulated on the mouse X chromosome (X inactivation). However, in humans it appears that IQSEC2 at least partially escapes X inactivation- the inactivation is skewed and both copies of the IQSEC2 gene may be expressed in a given cell. This means that currently available mouse models of IQSEC2 mutations may not mimic what is going on in female IQSEC2 patients. Dr Mori will be developing a model to introduce heterogeneity (resulting in variable degrees of IQSEC2 dysfunction) between neurons in IQSEC2 expression in the mouse brain similar to what occurs in human female brains and assessing how this heterogeneity influences disease in the mice. Furthermore, Dr Mori will assess the ability of viral mediated gene therapy to rescue abnormalities in this female model of IQSEC2 disease in the mice.  

The project led by Dr Sahar Daas will be to develop a zebrafish model of the IQSEC2 mutation.  The IQSEC2 gene is remarkably conserved in its structure and function in every known vertebrate organism. The zebrafish is a model organism that is transparent allowing one to visualize the development of the nervous system in a living animal. Furthermore, zebrafish have been used to study seizures, neurodevelopment, behavior and learning. Dr Daas and his group will first eliminate the expression of IQSEC2 from the zebrafish and then will study how this influences development, seizures and learning.  The zebrafish with IQSEC2 mutations will  then be used as a high throughput system for screening small molecules (drugs) that can block seizures and allow more normal development in these organisms.    The zebrafish has been used in a similar capacity to identify drugs to treat other genetic epilepsy conditions (i.e. Dravet Syndrome).

The project led by Dr Donald Joseph will investigate the abnormal neural circuits, which exist in a mouse model of IQSEC2 mutation in which the mice have seizures. The triggers for the start of the seizures and how the seizures propagate in the brain will be investigated. This basic mechanistic understanding of how IQSEC2 seizures are generated is critical for the development of new treatments to prevent these seizures. Dr Joseph will may use this system to assess the efficacy of new treatments (small molecules or viral gene therapy) to restore the normal neural networks and prevent seizures. Theoretically, this model may also allow for the ability to change abnormal neural circuits associated with IQSEC2 mutations and the developmental time window during which this change may be possible.