CSO Corner, Volume 17: Turning Up the Volume on EHMT1, Part 2

Hello fellow members of our KS family!

As you probably know, at its core, Kleefstra syndrome (KS) is caused by damage to one copy of the gene EHMT1. Since every person with KS still has one perfectly healthy copy of the gene, one approach that might lead to a treatment is to find a way to “turn up the volume” on that functional copy.

I’ve often compared this to a situation where you have two car factories making cars, but then one factory is shut down. But what if you could run the remaining factory at twice the pace? Now you have the same total output of cars! In the world of KS research, this means boosting the output of the remaining healthy EHMT1 gene copy to restore the missing protein in patients.

Today, I am incredibly excited to announce another major step forward along these lines: IDefine has announced its participation in a collaborative research initiative at Johns Hopkins University (JHU) to evaluate a novel RNA-based therapeutic platform designed to increase gene expression in rare neurodevelopmental disorders.

A Collaborative Effort

This exciting initiative is being coordinated through COMBINEDBrain, a consortium of rare disease organizations working together to accelerate therapeutic development through shared research, data and resources. By joining forces with four other rare disease organizations (the Koolen-de Vries Syndrome Foundation, MED13L Foundation, DLG4 SHINE Foundation, and DYRK1A Syndrome International) we aim to pool resources and evaluate a shared therapeutic approach that could benefit all of our patient communities. We are “stronger together” as a KS community, and even stronger when we join forces with other rare disease communities!

The research is being led by Jeff Coller, PhD, a professor at JHU. Dr. Coller’s laboratory has developed poly(A)-mimetic technology, which is also known as “mRNA boosters”. This platform is designed to enhance expression from a patient’s existing functional gene copy. In both cellular and animal models, this platform has demonstrated the ability to increase expression of multiple genes associated with neurodevelopmental disorders. Now, the Coller Lab will assess its potential to increase expression of EHMT1 and the other genes participating in the consortium.

Comparing Our Strategies

You might be wondering: isn’t this just like the previous project we’ve announced with the Dickinson Lab at the University of Chicago, which was also about “turning up the volume”? In fact, it is quite similar, but only in terms of the overall concept. The two approaches are quite distinct, and represent two possible paths to the same goal.

• Increasing the Rate (Dickinson Lab): This approach acts like a highly specialized booster designed to increase the rate at which the EHMT1 “blueprint” is read in the cell. In the analogy of a car factory, it works by making the single remaining factory run at a higher rate to produce more cars.
• Increasing the Duration (Coller Lab): This approach acts like a highly specialized booster designed to make the EHMT1 “blueprint” be read for a much longer time in the cell. In the analogy of a car factory, it works by making the single remaining factory run for much longer to produce more cars. It’s like adding a night shift.

Diversifying Our Shots on Goal

By pursuing both of these approaches to “turn up the volume”, we are diversifying our scientific methods. Biology is an unpredictable science, so it makes sense to have multiple parallel projects to maximize our chances of finding targeted therapies for KS, and getting them to clinical trials. This partnership represents exactly what our “Turn Up the Volume” campaign was designed to do. If you have contributed to our efforts in any way, you have helped make this work possible. Thank you!

Until next time,

Eric Scheeff, PhD IDefine Chief Scientific Officer