#SRFWebinar Summary: Rumbaugh on a Roadmap for SYNGAP1

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Sébastien Laverrière of SYNGAP1 Switzerland has been part of the SynGap Global Network (SGN) since its inception and is active in generating content.  Sebastien’s daughter is now 15 and since the diagnosis 6 years ago, he has tried to explain to his family the very complex and intricate world of genetic and rare disease using the most accessible terms. These explanations are often converted to lay terms which are shared with the SynGAP community in multiple languages.  We are glad to be able to repost his work here.  This blog has been revised and updated by SRF to make it more relevant for the US audience.

This is a parent’s summary of Dr Gavin Rumbaugh’s SRF Webinar from June available below. He has been researching Syngap for over 15 years.

In this webinar, Dr. Rumbaugh discusses Syngap research progress made to this date and the 3 different types of therapeutics currently being studied. These 3 therapies are being explored for a number of other rare diseases and fortunately for our Syngap community, the symptomatic specifications of SYNGAP1 suggest that we are in a good position to study one of the treatments at depth for our unique patient population.

The recent Nature paper by the team at Stoke Therapeutics that Dr. Rumbaugh describes is focused on gene therapy, specifically.

Technique 1: Repurpose already existing drugs on the market as well as the corresponding molecules for the Syngap patient population.

Several tens of thousands of drug molecules already exist in the current treatment market but they need to now be tested one by one to possibly find one applicable to our unique patient population that works to limit or inhibit the impact of the genetic mutation (or abnormality) of Syngap. It is possible in the years to come to repurpose one of these existing drug molecules. That said, as is the case with the various anti-epileptic drugs that our children take, that different drug molecules, especially those repurposed for Syngap, may vary between Syngap patients in terms of their efficacy. While these tests and the corresponding research are long, these testing methods nevertheless exist and the delay in making this type of testing and research possible is caused only by the lack of resources (human – interested labs and scientists) and of course, funding. In essence, if adequate funding is made available, then more drug molecules can be tested at the same time and the discovery of a treatment option is made faster. Consequently, it is important to point out that these “repurposed drug molecules” have already gone through the rigorous safety approval process (by the FDA, EMA, TGA), and thus discovery could be brought to market more quickly than finding or experimenting with a brand new drug (molecule).

Technique 2: Repairing the genetic mutation at the DNA level
While the idea of repairing the actual genetic mutation of the DNA is certainly the most complete solution, it is also the most complex and unfortunately the technology is quite ready for this yet. Certain techniques such as the CRISPR method (which stands for “Clustered regularly interspaced short palindromic repeats”) do exist, in which technology is used to identify and alter individual genes or strands of DNA. However, at this point in time, the CRISPR technique has only been studied and developed to be used for a small number of mutations. While this type of method of intervention would be permanent and would in fact “repair” the genes of our Syngapians, we are challenged further in the use of such methods by the fact that each mutation of our Syngap children is different and therefore each genetic “repair” would have to be different or uniquely tailored to each type of mutation. Furthermore, this gene-altering solution also involves risks because if the repair is “wrong” it can have a disastrous impact. In fact, these poorly understood methods lead researchers to include in their plans for genetic alterations a kind of “genetic emergency button” which would make the modification inoperative in the event of a problem. Gene-altering genetic therapies that can be widely used and applied to a variety of genetic mutations will not be safely available for many years to come (some scientists say 10 to 15 years).

Technique 3: The ASO technique (Antisense Oligonucleotides – gene therapy) – Empowering the healthy gene to produce more Syngap protein!
This new technique is studied massively throughout the world. Instead of focusing on trying to repair the faulty copy of the Syngap gene, this therapeutic approach aims to make the good copy of the gene work harder. Since the Syngap1 mutation affects only one of the two chromosomes, our Syngap patients are great candidates for ASOs.  In our Syngapians, the SynGAP protein is needed to regulate brain functioning and is only being produced properly by the one copy of the gene – the gene that is working. With ASOs, the idea is to get the healthy gene to produce more Syngap protein than normal, basically, twice as much. The SYNGAP1 gene is the same in all humans and if we find a way to make it work more, the treatment will be generic and may eventually be the same for all of our children. Consequently and fortunately, it doesn’t matter which mutation type your Syngapian has, as this therapy is meant to work on the healthy copy of the gene irrespective of the mutation of the faulty gene.

What form does this treatment take? Currently, the vision is that the treatment would take the form of an injection every 2 to 6 months throughout the Syngapian’s life (injection into the spine). This is similar to the pain relief used during labour (Epidural), so typically very safe with a small risk of infection.

One of the risks of this method is that it could produce too much Syngap protein and it is still unknown whether that could be toxic for the brain. Researchers are looking at a mechanism to modulate the production of the protein (such as a volume control button). The technology is advancing rapidly and there are already 2 rare genetic diseases which have an existing ASO treatment (Spinal muscular atrophy and Duchenne muscular dystrophy). Another challenge for SYNGAP1 is finding a way to deliver the treatment to the brain (it is not as simple as for other gene defects that can see positive effects at the blood levels – for neurological diseases, treatments have to cross the “blood brain barrier” to go to the right place.)

The latest paper confirms the following:

  • Their testing in vitro (outside the body, in the lab) works on several proteins, one of which is SynGAP.
  • The technology they use is called TANGO and they are “reactivating” proteins that have already been created but that human body “deactivate” at first (surely because too much is produced and the body auto-regulates itself). So, instead of trying to create more Syngap protein, they use the ones that are “unused.”
  • The current method of treatment (injection) and the duration of the treatment (2-6 month after which you would need new injection), based on current knowledge however this may evolve with new technology and research.
  • The technique tested by Stoke will eventually work for thousands of different genetic mutations like Syngap1 where one gene copy is bad and the other one is available for boosting up (the therapy is the booster). This would not work on a genetic mutation on the X or Y chromosomes.

What will make them choose SYNGAP1 over other thousands of genetic mutations?

  1. A significant, connected, communicative and motivated patient population.
  2. High quality data describing the natural history of the Syngap population. (To join the SYNGAP1 Digital Natural History Study in the US, go to Ciitizen.com/SYNGAP1/SRF)
  3. Evidence that raising SYNGAP1 levels will resolve significant aspects of the disease.

We as a community can help make SYNGAP1 a more attractive target by:

  1. Finding and connecting with more patients.
  2. Participating in high quality patient registries (To join the SYNGAP1 Digital Natural History Study in the US, go to Ciitizen.com/SYNGAP1/SRF).
  3. Funding science to answer those basic science questions like ‘what happens if there is too much Syngap protein?’ (SRF is currently raising funds to support advanced research on the SynGAP protein, learn more and/or support it at this link.

A lot of the research has been delayed due to Covid-19 and at least 6 months were “lost”. However, all of this research is promising and there is a great deal of research around the world in addition to that of Dr. Rumbaugh. We should not expect to have a solution tomorrow but progress is fast and visible.

An important piece of information (confirmed again by Dr. Rumbaugh) is the fact that the treatment could have a beneficial effect on both children and adults. Initially, research tended to show that the early years of brain development were the only “windows of opportunity for change”, however there is now evidence in mice that the restoration of the SYNGAP1 protein would work in adults too.

If a treatment is found, we may not be able to expect a miracle solution – but we can realistically strive for a decrease in epilepsy, reduce behavioral problems and increase understanding and communication skills. So let’s cross our fingers and support all of the researchers who are working on these projects!