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Dr. Andres Jimenez-Gomez is currently the director of the Neurodevelopmental Disabilities Program at Joe DiMaggio Children’s Hospital, with training and expertise in neurodevelopmental disabilities (board certified 2021), child neurology (board certified 2019), and pediatrics and global health. His clinical practice spans the lifelong care of individuals with different neurodevelopmental disorders. “My particular interests and research lie in neurogenetic conditions and mind-body integration, as well as care and education in developmental conditions and disability in LMICs.”
This summary is intended as an ample overview of what was discussed during Day 1 of the SYNGAP1 Conference 2023, hosted by SynGAP Research Fund, as seen from a medical/scientific perspective. I hope to inform families and community members from a more simplified, grosso modo perspective. It is not intended to serve as an exhaustive and all-encompassing summary; conferences themselves will be available online for further detail, including complete videos of presentations and slideshows. Nonetheless, this summary intends to bring forth the fundamental aspects of most importance to families and caregivers. I have included personal commentary in italics for individual consideration.
[Editor’s note: In addition to this blog, Dr. Ana Mingorance shared her own comments in her blog, “What I learnt at the SYNGAP Conference 2023“. Both are incredible accounts of Science Day in Orlando and well worth reading.]
Session 1: “New Findings”
This session combined perspectives from the clinic (Prof. Ingrid Scheffer) and the labs in regard to treatment avenues (Prof. Janos Zempleni) and a basic understanding of SYNGAP1 (Dr. Helen Willsey).
New insights in the DEEs, including SYNGAP1, by Prof. Ingrid Scheffer Clinically, a salient point to remember is that, beyond SYNGAP1, 1 in 591 children have a developmental and epileptic encephalopathy (DEE), the overarching term grouping different conditions under which SYNGAP1 is classified. This signals an opportunity to Foster collaborations- whilst individually, each condition remains “rare,” unified conditions offer the possibility for collaborations in visibility, research, etc. The total is larger than the sum of our parts.
Keep in mind, however, that not all DEEs have a similar presentation. Some evident, severe risks in certain conditions (e.g., sudden death-SUDEP- in Dravet) are not shared by SYNGAP1; nonetheless, an emerging idea is that in many DEEs, the concerns over seizures become secondary as time passes, and caregiver concerns and needs tend to gravitate towards development/cognition and behavior. Here, there is a big void in research, only just starting to become of interest and often tending towards the anglosaxon “behaviorist” management focus which is far from perfect. An opportunity to research sociocultural differences and management strategies emerges.
-Gene delivery by milk exosomes restores Syngap expression in mouse brains, by Prof. Janos Zempleni: First, there are a growing number of possible interventions that, despite being preliminary and preclinical, are promising from a perspective of their development, as well as their possible applicability and administration. One example offered is that of milk exosomes, a possible vehicle to bring therapies directly into the brain after a nasal spray administration. This is in very early stages, but it is interesting to see other mechanisms of administration that may be able to be developed in a broader and more financially sustainable manner; it is encouraging to see something such as nasal administration as a potentially effective vehicle. Years before this may become standard do remain, however.
-SYNGAP1 beyond the Synapse, by Dr. Helen Willsey: Second, SYNGAP1 is not only synapsis, and one important aspect observed- in a frog model! – is that of Syngap1 expression in cell cilia, which are small brushes on the surface of many cells in our body that may serve to “brush” things along (such as helping with gut transit or in coughing up mucus), or even for cell-to-cell communication. This matters because we know SYNGAP1 is not only seizures and development; other symptoms may have different mechanisms- and possibly other treatments (for example, gut symptoms). It is also important because we need to know the potential effects of any treatment of SYNGAP1 that are not isolated to the brain.
Session 2: “Drug Repurposing”
This session was a bit more controversial. There is a large interest in finding and repurposing many existing medications/molecules, in a way, to “shorten” the time to an effective treatment. However, finding the right molecules and testing them is a challenge.
The first two presentations by Dr. Chris Moxham (Rarebase PBC) and Dr. Clement Chow (University of Utah) fundamentally show us different ways to identify possible medication/molecular candidates that may impact Syngap1 function. These strategies vary in their effectiveness and cost. On one end, complex systems generating iPSC (“stem cell”) models in the lab to test molecules and utilize AI to see their effect directly; on the other, fruit fly (Drosophila) breeding as a cheap avenue to screen different drugs/molecules and possibly different, very specific effects as markers of improvement (in this case, looking at the size of the fly’s eye!). Each of these has its own pros and cons. Fundamentally, one should understand this is a “screening” strategy, which is to say, understanding if the molecules have any impact on Syngpa1 functioning. The size of said impact and how it may translate to benefit in human patients is not elucidated. But this helps focus research on specific existing orphaned medications.
Dr. Zach Grinspan (Weill Cornell Medicine) presented an example of one such drug repurposing with 4-phenylbutyrate (4PB), a medication utilized in certain inborn errors of metabolism. This was employed in a group of patients with STXBP1 y SLC6A1 (another two DEEs). 4PB’s safety profile is understood; however, its mechanism of action is not. It was observed it may improve seizures for SLC6A1 patients but not in STXBP1. Part of the controversy is in its unknown mechanism of action, as well as its elevated cost absent proper randomized control trial testing (the standard approach for scientific evidence and drug development). This was the important argument brought by Dr. Scheffer, who stated that the elevated cost ($800k per year per patient) required more judicious testing. Another contrasting argument from the industry becomes: who will fund this research for medications that are existing and commercialized if it is not going to produce a (financial) benefit for the industry per se? This is an ethical dilemma. It is worth remembering, however, that now interesting molecules such as fenfluramine (Fitempla) were also abandoned/orphan medications, now sparking great interest in DEE epilepsy care. I see potential in some of these medication repurposing efforts in working with certain symptoms as a palliative measure but not as a cure.
Session 3: “Understanding SYNGAP1”
This session was a combination of certain prior presented information on study models (e.g., Dr. Marcelo Coba’s discussion on iPSC models for SYNGAP1) and other novel aspects of the non-synaptic function of Syngap1 (Dr. Marcella Birtele), as well as certain computational analyses of the functioning of the Syngap protein (Drs. Michael Courtney and Pekka Postila). While some of these talks were very interesting and thought-provoking, the clinical relevance at present is limited. This would not necessarily impact what we offer in our clinical care in the short term and- in my opinion- is less relevant to families at present.
Perhaps the most clinically applicable and potentially practice-changing talk was by Dr. Gemma Carvill (Northwestern University) regarding the computational analysis of variants of uncertain significance (VUS) that are missense in Syngap 1. The focus is to generate a model that can estimate whether a VUS is indeed the cause of a patient’s condition/symptoms (“pathogenic/likely pathogenic”). There is an ever-growing list of VUS in Syngap1 and other genes that, clinically, we struggle to respond to. This model is thus interesting because it would allow more accurate prediction and response. In part, I think the number of VUS has largely increased because, when labs need to “read” our genes, they also need to have good knowledge of the symptoms a person presents with. If physicians are not bringing forth complete information, labs (GeneDx, Invitae) may detect “a change” but cannot make a full interpretation of the finding if it doesn’t know the symptoms. Therefore, models where we can take more complete information from other patients or models, and in which we can observe possible changes to protein’s ability to function, may be very helpful, especially if it is used “automatically” either from the lab or from the physician’s office. With this in mind, it is still in the clinician’s hands to significantly reduce the VUS avalanche by offering complete and rigorous information. The model presented in itself is also similar to other collaborative models for candidate genes, such as the Undiagnosed Diseases Network (UDN), but in this case, it focused on VUSs in DEEs.
Session 4: “Therapeutic Strategies”
This was an excellent session with an excellent overview of the novel advancements from different pharma labs (Praxis, Stoke, Tevard) of ways by which one can increase the functioning of the Syngap1 protein along different steps in the protein’s production in the cell.
A very basic overview of protein production in the cell:
-Antisense oligonucleotides (ASO), are basically a small piece of RNA sequence that binds to the messenger RNA (mRNA), to impact its ability to produce protein. It can increase or decrease it. Examples are TANGO-ASO (TANGO being the technology employed to create ASOs in Stoke) and Praxis (Prax-090)
-Suppressor transfer RNA (tRNA) seek to “suppress” the point where a mistake (mutation) may be in the mRNA sequence to allow the translation process to continue unaffected and fully produce protein.
In all cases, these very promising technologies are a display of great scientific/technological progress. It is possible that we may have clinical trials for Syngap in the near future: PRAX-090 would seem to be closing in. Nonetheless, remember that this process still takes time from approval for human trials, to defined mechanisms of administration (how will we get ASOs or Sup-tRNA into the brain?), etc.
Session 5: “Clinical Trial Readiness”
This session was predominantly a discussion of the progress of phenotyping (complete clinical description of the condition) and natural history (evolution of the condition over time), mainly carried out in Boston (group of Drs. Sahin and Poduri) and Philadelphia (Dr. Helbig’s group). The discussion was centered around different mechanisms and combinations of data collection, processing through computational analyses, and employment of AI to identify patterns in the long-term evolution of SYNGAP1 symptomatology (and in other DEEs). A very important point from all 3 presenting groups- Boston, Cornell, Philly- was observing the “meaningful” symptoms from a family perspective, often leaning towards behavior, development, emotional well-being, GI, sleep, and others.
This session visibilizes the great importance of families and their participation in research. Identifying the clinical aspects and important symptoms means we have better “endpoints” and “goal posts” for when treatments are made available, whether these are palliative (symptoms-based) or curative (repairing Syngap1). Again why family inclusion in studies aiming to determine “natural history” and “deep phenotyping” is key. Given the urgency and financial limitations, in other places such as LatAm, an approach may be longitudinal studies with a cross-sectional overview to identify symptoms in different patients at different ages to somewhat better understand the evolution of the condition and additional endpoints.
Session 6: “CTR/Quantitative Measures”
(I preface by recognizing I had to step away from this session. However, I had the fortune of talking directly with Dr. Frazier previously about his research, sitting in on several presentations on Orca for Angelman syndrome during FAST/FAST-ABOM, and chatting post-hoc with Dr. Alfredo Gonzalez-Sulser. I also relied on Marta Dahiya’s wonderful summary).
This session sought to understand additional “endpoints better” and “biomarkers” that regulators (FDA, EMA, others), researchers, and industry may be interested in, to seek better objective data on the possible efficacy of treatment. Several different measures developed are discussed, some being more clinically based (observing behaviors), others reliant on paraclinical studies (EEG tracing)
A measure of eye tracking for social/behavioral traits (Dr. Tom Frazier) can be done remotely and is founded on a series of behavioral/adaptive/cognitive/communication questionnaires. This seeks to understand the behavioral profile (subjective, or as seen by families) and combine it with objective data (video tracking) to establish baseline traits and possible impact of medications.
A second measure studies communication in individuals with severe communication impairments who would struggle to perform in traditional measures. Orca has become a very exhaustive and inclusive tool that measures alternative communication strategies patients often develop- verbal, nonverbal, behavioral, etc. This also serves as a possible marker of treatment effect.
EEG, in turn, focuses much deeper than what is routinely observed in the clinic. Here, we are looking at specific patterns typical to Syngap1 and other DEEs during wakefulness and sleep for baseline and, as possible, very objective biomarkers for treatment efficacy. Here, the search is for patterns- more than specific changes- supported by the use of AI models.
This is a very promising field, in which families would have a great ability to participate. Tools such as Orca are already in use and have even been translated into other languages. Using these as part of clinical care whenever possible may be of interest. Similarly, we could consider how to advance and even utilize dr Frazier’s tool in other cultural contexts. Notwithstanding, this all will need training.
I hope this summary/commentary is of help to all,