CSO Corner Volume 16: Investigating a Gene Therapy for Kleefstra Syndrome

Hello fellow members of our KS family!

In a previous update, I shared the exciting news about our partnership with the Dickinson Lab at the University of Chicago. We talked about how Kleefstra syndrome (KS) is caused by one damaged or missing copy of the EHMT1 gene, but that everyone with KS still has one perfectly healthy copy. I compared that single healthy copy to a car factory and explained how the Dickinson Lab’s approach is designed to “turn up the volume” and run that single factory faster to make up for the missing one.

But what if, instead of speeding up the factory we already have, we could just drop in a brand-new factory?

Today, I am absolutely thrilled to share that we are exploring exactly that approach. As recently announced in our latest press release, IDefine has officially launched a two-year research collaboration with UT Southwestern (UTSW) Medical Center to advance a potential gene replacement therapy for Kleefstra syndrome!

A World-Class Partner

This new project will be led by Dr. Steven Gray, Director of the UTSW Gene Therapy Program. I cannot overstate how significant this is for us: the Gray lab is widely recognized as one of the premier labs on the planet for developing gene therapies for rare neurological diseases.

To give you an idea of their impact, Dr. Gray’s preclinical discoveries have already successfully translated into multiple human clinical trials for rare genetic disorders, including conditions like Rett syndrome and Batten disease. 

It is worth noting that while these therapies have successfully made it to human trials, none have crossed the finish line to final FDA commercial approval yet. It is important to remember that the regulatory path for gene therapies can be long and rigorous. However, getting a gene therapy out of the laboratory and into human clinical trials is arguably the most difficult hurdle in rare disease research—and Dr. Gray has a proven, repeatable roadmap for clearing it.

Partnering with a lab of this caliber is a true testament to the strength and organization of our KS community. Top-tier researchers take note of patient groups that are highly engaged, show high levels of community participation, and fundraise actively. Your efforts have helped make IDefine the kind of foundation that world-class scientists want to collaborate with.

Parallel Paths to a Treatment

So, how does this compare to the Dickinson project we discussed in a previous CSO Corner?

While the Dickinson project uses synthetic biology to boost the output of the existing healthy EHMT1 gene, the Gray lab project is exploring traditional gene replacement therapy. Using a specialized delivery system designed to target the central nervous system, the goal here is to safely deliver a completely new, functional copy of the EHMT1 gene directly into the cells that need it.

Both projects share the exact same ultimate goal: restoring EHMT1 protein levels in the brain to address the root genetic cause of KS. However, by exploring two distinctly different scientific mechanisms, we are diversifying our efforts. This is a huge step forward for our community in being “treatment focused,” as we now have a range of parallel pre-clinical programs running that could each eventually become a treatment. We aren’t putting all of our eggs in one basket; we are taking a “multiple shots on goal” approach to maximize our chances of success.

The Pre-Clinical Journey Ahead

As with all cutting-edge science, we have to pace ourselves and manage our expectations. This is a pre-clinical project to test the initial approach in model systems, and it will take time to determine if this is a safe and effective strategy that we can take to the clinic. However, the Gray lab is particularly well-equipped for this challenge, and his team will be rigorously evaluating the safety and feasibility of this specific gene replacement strategy for KS.

Moving a genetically defined neurodevelopmental syndrome like ours into a structured, funded gene therapy program with a world-renowned lab is a massive milestone. We are taking the vital first steps on a promising path.

There is more to come, stay tuned!

Until next time,

Eric Scheeff, PhD

IDefine Chief Scientific Officer