How Close to SYNGAP1 Treatments Are We?

Article Reviewed and Approved by the BTG Scientific Advisory Board

"How close are we to Clinical Trials and what will it take to get there?"

There has been quite a “buzz” around the SYNGAP1 community these days. Everyone is asking “just how close we are to getting therapies to help improve the quality of life for our SYNGAP1 children? This is a difficult and complex question to answer. There are many steps in the therapy development process and each step MUST be completed, get us where we want to be. As with many rare diseases, the pathway is very similar to ours.

A Winding Pathway

Regardless of the type of therapy being developed (gene therapy, ASO's, and/or small molecules) drug development is a complicated process. However, to ensure proper and effective clinical study design, all therapies follow a similar path.

First – Basic Science Data: We must have SYNGAP1 Basic Science Studies. SYNGAP1 Basic Science Data gained from Basic Science Studies is already helping us understand how the SYNGAP1 gene creates SynGAP protein. It cannot be emphasized enough that the reason for your child’s disorder is a problem with SynGAP protein, which is made from the SYNGAP1 gene. For example, new basic science studies are helping us connect how a specific SYNGAP1 genetic defect present in each child impact SynGAP protein function or expression. Studies like these are critical because they help to identify which children will benefit from emerging treatments. 

Second – Human Clinical Data:  Next, we must have HUMAN Clinical Data that can be compiled and studied. SYNGAP1 Patient data is critical to understanding SYNGAP1 clinical characteristics and symptoms.

Third – Translational Data:  Translational Studies are designed by using data obtained from basic science studies and performing new research into their application to patients.  

• Translational studies are needed to determine how the SYNGAP protein functions in humans and to develop biomarkers and outcome measures.
• The understanding of how the SynGAP HUMAN protein works is an essential step in the drug development/research process. 
• The data gained from a well-designed Translational Study can enable researchers and clinicians to identify/target repurposed or new drugs that will be the best potential candidates for therapies.

How do we understand how the protein works in HUMANS?

It is vital that we understand how SynGAP protein functions. The ONLY way to understand how SYNGAP1 functions in a person is to collect clinical and real-world data from SYNGAP1 patients. This data is currently being collected by the SYNGAP1 (MRD5) Registry and Natural History Study and through the BTG Clinical Studies being run at our Centers of Excellence. Participation in these studies is incredibly important.

One possible approach to therapy and hope for SYNGAP1 patients is based on the work being done in Dravet Syndrome. We must remember that these two genes have different functions altogether. Dravet Syndrome has applied an approach called “antisense oligonucleotide” or “ASO” therapy, which work to raise deficient protein levels. In theory, there may be an opportunity to increase the amount of functional SynGAP protein that is missing within the cells of children with SYNGAP1 mutations. Based on successes using mouse models of Dravet syndrome, it will take at least 2-4 years to determine if ASOs work in SYNGAP1 mouse models. However, if they do work to raise SynGAP protein in a mouse model, then a clinical trial MAY be started shortly after.

Currently, there is no public data about ASO's working in Syngap1 mice. Thus, we must move cautiously forward, understanding the reality that they, may or may not work. We have hope, but we do not have the data yet.

Do ASO's work for every type of mutation?

This is not known because so few genes have been targeted by ASO's. There are several factors we need to understand before we will know if an ASO will work for SYNGAP1 disorders. First, we must know HOW the SynGAP protein works in humans. Second, we need to understand that each ASO is designed for ONLY one selected disorder (the Dravet ASO will not work for SYNGAP1). Third, SYNGAP1-related disorder has a spectrum of symptoms and severities and researchers must tease out the genetic spectrum and the impact on protein function. Fourth, the types of studies needed will cost millions of dollars and many years to complete. One of the biggest challenges we face as a small community is funding. If we keep our focus on filling the needed scientific gaps, the faster the path will be to a clinical trial. Just one functional analysis of one gene mutation can cost no less than a million dollars. This cost does not include the cost of actual drug development or a clinical trial.

So how will a mutation and SYNGAP1 patient be chosen for a Clinical Trial?

First, we must have a successful SYNGAP1 mouse model, that responds to an ASO, improving the quality of life, have human outcome measures, and VALIDATED biomarkers. Then, we can move to a clinical setting, where clinicians and researchers determine which individuals, will likely respond the best. This determination can be based upon mutation type, presence, or severity of certain symptoms, absence of certain exclusion criteria.

Currently, scientists do not know which SYNGAP1 patients are the best candidates. Researchers/clinicians need patient data from the SYNGAP1 (MRD5) Natural History Study Registry and other clinical studies to help them determine which type of mutations, in SYNGAP1 mutated genes, are good candidates to be treated with an (ASO) antisense oligonucleotide gene therapy approach. We are working on creating the best patient data for the registry and participate in other clinical studies.

We are Moving Closer to SYNGAP1 Clinical Studies

Basic Science Studies + Human Clinical Data + Translational Studies =

Human Clinical Research Trial