Last year I attended the Syngap Conference organized by the SynGAP Research Fund the day before the American Epilepsy Society (AES) meeting. It was fantastic, but I did not write a separate summary for it, only a mention as part of my AES summary. But then this year I attended again the Syngap Conference, again the day before AES 2023 started, and I believe it deserves a separate summary. So here it goes: these are my main learnings from the 2023 Syngap Conference about the SYNGAP research and therapeutic field.

1 – COOL AND SCARY NEW BIOLOGY

There was a lot about the biology of the SYNGAP1 gene and the SynGAP protein at the conference. The main learnings that stayed with me are two:

Did you know that SynGAP seems to control cytoskeleton (the cell skeleton) and in particular the primary cilia? This is like a special part of the neuron that looks like a short tail. This is interesting because I work very much in CDKL5 deficiency disorder (another neurodevelopmental syndrome with epilepsy) and CDKL5 is also doing the same things!! This whole “cilia connection” is very cool and also very puzzling. I don’t know what to do with this information, but it seems that proteins that evolved to control the cell skeleton and that special primary cilia might have also evolved to control synaptic remodeling and that is why we get neurodevelopmental syndromes with epilepsy when they are mutated. Helen Willsey from UCSF was such a great speaker! One of the highlights of the conference.

That was the cool new biology. The scary new biology is that we learnt that syngapians spend in REM sleep only half of the time that other people do. REM sleep is when we dream… so having SYNGAP steals the dreams of the kids, and this is very sad. The good news is that REM sleep could be a biomarker for these kids.

2 – HELP OUR KIDS NOW: DRUG REPURPOSING

There were several talks about drug repurposing, which means seeing if there could be already something sitting at the pharmacy shelf (perhaps even in the supplement shelves) that could help syngapians today. Repurposing is the search for faster treatments while investing in the long term disease-modifying treatments.

We learnt about a research program by Rarebase using patient-derived neurons to characterize some potential drugs that may help increase the mRNA of SYNGAP1 (remember that there is one good copy of the gene that we can use to get more protein), and one in fruit flies missing SYNGAP1. The mutant flies have small eyes looking disorganized, which serves a read out to look for drugs and supplements that could fix their problem and therefore compensate for lack of SYNGAP1. The researcher, Clement Chow, explained that they are finding many drugs that come up as positive and that have similar action, like many anti-inflammatory drugs, so the results are looking promising. And we also heard from Zach Grinspan who has been running a repurposing trial in SLC6A1 and STXBP1 with a drug called phenylbutyrate that will also be tested in SYNGAP. This talk opened a very interesting debate about this type of repurposing trial. For example: do we need a consensus to pick the winner compounds? How are we going to test the potential repurposing drugs if they are already available for example at CVS? Should we go through 6 months of paperwork just to have ethical approval and spend much money on trials or go ahead and try it individually? And how would we learn from those N-of-1 family-run studies?

Prof Ingrid Scheffer, who is one of the most famous doctors in the rare epilepsy space, insisted that the only way to know if something works (and is safe) is to run randomized controlled trials, and that the burden should be in the companies that own those drugs, not on the patient groups. This was a great debate!

3 – THERAPIES TOMORROW: HIGHWAY TO CURES

To cure a disease like SYNGAP we know very well what we need to do: help neurons make more SynGAP. I moderated this session with the message that “we have all of the ingredients that we need to fix SYNGAP”: we know the cause, we have one good copy of the gene to use, the disease is not degenerative, the animal models are good, and the animal models indicate that the disease is likely reversible. We are also talking about a relatively large rare disease, with a very strong patient community working on solving the right problems, and there are already several companies working on treatments.

We had a presentation from Praxis and one from Stoke, both working on ASOs to boost SynGAP production using the good gene copy. In both cases, these companies have more advanced ASO programs for other epilepsy syndromes so we will get to use those learnings for SYNGAP. And we also had a presentation from Tevard, a company working on a gene therapy to help neurons skip premature stop-codons caused my non-sense mutations. Tevard is planning to run clinical trials with this gene therapy in a selection of genetic epilepsy syndromes including SYNGAP, and they are ready to start safety studies in non-human primates next year to then progress to clinical trials.

I also know that there are more therapies being developed to target the cause of the disease, and some of those companies where present in the room although they didn’t give a talk, so therapies are coming.

And to prepare the field for those therapies the community is running A LOT of clinical studies to know the natural history of the disease and possible outcome measures (scales) to use for trials. A LOT. This included a disease concept model, the Ciitizen study, and an excellent endpoint-enabling study at CHOP that is designed the same way that companies design their observational studies, this is top quality. Also a lot on biomarkers. What I wonder is how to integrate all these data. What is clear is that with so much work this is not a road to trials, but a highway to trials, in particular the trials for disease-targeted treatments (the cures).

4 – THE KEY CHALLENGE OF MISSENSE CAN’T WAIT

The disease that we often call SYNGAP for short happens when one of the two copies of the SYNGAP1 gene is mutated, and this mutation sometimes breaks the future protein (non-sense, frame-shift, truncation, deletions) but sometimes the mutation makes a protein that has one wrong letter. This is not trivial, and read this section until the end to know the mind-blowing implications. This means that many SYNGAP patients have a mutated protein instead of a missing protein. What if we can fix those? Maybe they just need a bit of help with folding. What if they stay around and don’t let the good proteins work? Then we need a strategy to remove them. This is why there are several programs trying to understand what happens to those mutated proteins, which are often unique to each patient with a missense mutation. This includes in silico modeling and also in vitro real experiments.

But the biggest implication is perhaps not for treatment, but for diagnostics. We learnt from Gemma Carvill that genetic labs often don’t know how to interpret these changes of letter, so patients receive a genetic report for “VUS” or Variant of Unknown Significance. With a VUS you cannot be diagnosed, because maybe the gene is totally fine (we all have some different letters here and there in our DNA that are harmless). In SYNGAP1 gene sequencing for patients with epilepsy, the large majority are VUS, like 80% or so, so they don’t get a diagnosis. The other 20% is split between benign (trivial) mutations, and pathogenic which are the real SYNGAP. But then Gemma and her colleagues train a computational model to predict if a missense is bad or trivial, they found out that about 22% of the VUS are likely pathogenic mutations. What this means is that if we could solve the meaning of the missense mutations, the diagnosed patient population with SYNGAP could multiply by 3 or so. This has mind-blowing implications, not only to grow the patient population but to then help those new patients access better treatments and clinical trials and a community of families like theirs.

No wonder this is such an important priority for the SynGAP Research Fund!

5 – ALL FOR ONE

A real team

I am used to seeing patient groups focused on one country or territory, even when they call themselves international. This is understandable. I am a Spanish scientist, so I often collaborate with the groups in Europe (proximity and shared regulatory framework) and in Latin America (shared language and culture). And what I love about the SynGAP Research Fund is that it integrates all those worlds. You could even see that in the logos in all the conference materials:

SynGAP Research Fund
SynGAP Research Fund EU
Fondo de Investigación de SynGAP

And you could also see it around the room, because this group is very international. We had Mike and Aaron and Hans and Sidney and Lauren and others from the US, and Vicky and Martha and Carlos Caparrós and others from Latin America, and Katrien and Virginie and likely others from Europe. This is a true international team and this is exceptional and wornderful.

Get treatment for everyone

A message that was heard multiple times during the scientific program was the concern for all families living with a syngapian:

The focus on repurposing was: how can we get these treatments to everyone?
The focus on missense was: how can we find all those missing families so they are not left in the dark?
The joint work of the different territories US/EU/LATAM is also about getting to everyone.
Mike Ganglia closed the scientific conference with the words “what are all the people out there doing with their non-diagnosed syngapians?! We owe it to those parents”

A unique community

Clement Chow (the fruit fly scientist) explained that “Mike found us on Twitter, where all beautiful relationships start”, referring to Mike Graglia. And now Clement is working on finding repurposing candidates for SYNGAP!

My own path to get to know this community was similar. I was invited to give a talk in San Diego in 2018, and a SYNGAP dad reached out to me also through Twitter and asked me if I would like to meet his son with SYNGAP and his family while I was in town. That was Aaron, Jaxon’s dad, and it is a very good strategy to get scientists to get interested in a rare disease.

These two stories are an example of the proactivity of the SRF and the SYNGAP patient community, and other quotes that I wrote down during the 2023 conference also communicate this same message:

Tom Frazier, who is developing web-based measures of behavior and cognition: “This community volunteers for studies more than any other”.

Clement Chow: “[…]the strength of foundations leading the therapeutic discovery for rare diseases right now, and this foundational machine is best oiled than any other foundation that I have worked with, you should be proud of it”.

Then the following day was the Families Day with I believe more than 40 families attending and even using the opportunity to collect clinical data for some of the research studies. This community is exceptional and ready to partner and drive research forward.

* * * * * *

I hope you enjoyed this summary. If you are a SYNGAP family member, try to join us next year in Los Angeles right before AES 2024, there is also a second day focused on families after the scientific day. And if you are a scientist or clinician, please also come to LA one day early. This disease has all of the ingredients that we need to fix it, and a unique community behind it. Please join.

PS: my summary from AES 2023 is HERE