This article has been circulated to the full SRF Scientific Advisory Board and a number have given comments.
When I was (briefly) a graduate student, I made a rule: if I could not explain what I was doing to my (infinitely patient, loving, but non-expert in my field of study) mom, then either I wasn’t trying hard enough to communicate, or it wasn’t worth doing.
I didn’t ever get a PhD. Or an MD. Or any form of science degree: I was a freshman in high school when I last took a biology class.
I am a parent — an informed, hopeful parent — who founded SRF with my husband Mike last year, an organization that is laser-focused on identifying treatments targeting the root cause of the debilitating neuro-developmental condition that is SynGAP.
So what is the basis for our hope? Since our son Tony was diagnosed as one of ~430 known patients with SynGAP last year, my husband and I spent countless hours talking to neurologists, researchers, biotech professionals, and other rare disease advocates, trying to understand whether there could be — in the timeframe that matters — research on SynGAP that could lead to a cure for his disease.
The scientists were very patient with us. And as we reflected on everything they shared, we concluded that there was indeed good reason to hope that advances in research could help our child.
We concluded further that there were key gaps between the work being done in the ordinary course in academic research labs (important research, but targeted toward advancing knowledge & science generally, not infused with the urgency that drives us) and the work that could help this generation of children (our children). We knew we had an opportunity to do something — everything we could do — to develop therapies for SynGAP patients.
What will we do with our organization? We are focused on understanding the current landscape of SynGAP research, identifying key gaps in knowledge, and fillings those gaps so that we can establish pathways to treatments.
We need those pathways because, as the incredible Dr. David Fajgenbaum (read his book) recognized, and as I would have explained it to my mom: “Doctors don’t cure disease. Drugs do.”
What kinds of drugs could help our kids?
Right now, two approaches seem most compelling (small molecule and ASO — more on these below), but there are other approaches (esp AAV-mediated gene therapies) that we need to explore as well.
Then, to start, what is the root cause of SynGAP that we are trying to attack?
Ninth grade biology redux: typically developing people have 23 pairs of chromosomes — one copy of each is inherited from mom & dad. Chromosomes are extremely long strands with repeating series of four different nucleotides (3 billion base pairs in total), which are bound together in the ‘double helix’ called DNA. We can think of these nucleotides as the letters or building blocks of our genetic code. Almost every cell in our body contains these chromosomes, which act as a blueprint for our bodies, personalities, capabilities etc. The DNA distributes that blueprint by making instructions (RNA) that gets translated into proteins — the proteins that are needed to grow, walk, speak, roll our tongues, etc. etc.
What they didn’t teach me in ninth grade biology (or I don’t remember): When the average person’s DNA is created, ~100 of these 3 billion base pairs undergo de novo (new) mutations — for no particular reason, an incorrect nucleotide gets inserted into the DNA sequence. The significant majority of the time, these de novo mutations have zero impact (~99% of DNA is “non-coding,” i.e., is just part of a long strand that doesn’t get translated by the RNA into proteins, and many other mutations are harmless). Our children’s de novo mutations in the SYNGAP1 gene, however, have devastating consequences.
Why is a SYNGAP1 mutation so bad? Because the SYNGAP1 gene is responsible for creating SynGAP protein. SynGAP is one of the key proteins that enables learning and memory — it is critical to enabling neural plasticity. Our children have one “good” copy of the SYNGAP1 gene and therefore generally have a smaller amount of the SynGAP protein (we presume ~50% but that is a critical research topic — more on that below).
In scientific terms then: SYNGAP1 is a single gene, de novo (not inherited) loss-of-function mutation that causes haploinsufficiency (one gene doesn’t work properly). The problem we have is that our kids have less of the protein than they need.
And that last part is a good thing.
Why? Because, in principle, if we could find ways to make more SynGAP protein, then our kids may be able to have typical neural plasticity, which could give them a better shot at being able to learn, remember, and develop in a more typical way, and also not suffer from seizures. (Importantly, research shows that synaptic function can be “rescued”: i.e., if you increase the protein levels in adolescent mice, who have Syngap1 mutations at birth, they stop seizing and show other signs of improved behavior.
How would we make more SynGAP protein? There are three main theoretical approaches, the first two of which are exciting possibilities for the relative near term: small molecules (pills that work to increase the amount of SynGAP protein expression), ASOs (small strands of nucleotides that interact with the RNA from the gene that is good at making the protein, and causes it to make more), and gene therapy (viral vectors that go in and fix the underlying issue in the DNA).
Why hasn’t it been done yet? Lots of reasons. The SYNGAP1 gene was only found to create problems in humans ~10 years ago. The SynGAP protein is expressed in the brain, so any treatment would need to pass the blood-brain barrier. And, of course, this is an ultra-rare disease, one of a rapidly growing, long list of mutations. The number of researchers / scientists / biotechs with the skills to work on these problems is growing a lot more slowly.
What has been done so far? For SynGAP to be attractive to biotechs, the syndrome needs to be as well-understood as possible. We are fortunate in that several academic labs (Jacques Michaud, Rick Huganir, Gavin Rumbaugh, Jimmy Holder, Marcelo Coba, Helen Bateup, others) have built models (iPSC lines, organoids, and mice) of the disease. These models are valuable because they represent important functions of SynGAP: iPSC lines (induced pluripotent stem cell lines) are models of patient neurons, which are derived from patient blood samples; organoids are more complex models of multiple cell types from the brain; and mice can be bred to have a specific SynGAP mutation from a patient known to have the disease, or to have a classic “knock-out” of the gene, resulting in 50% expression of SynGAP protein.
By creating these models, these labs have helped us to understand some of the functions of SynGAP in the brain. These models (which are — generally speaking — available in the public domain) also create a mechanism for us to study what treatments may be effective.
What needs to be done next? We need to (1) build better models, (2) build screens to identify which small molecules are most relevant, (3) pursue “ASO” approaches, which would increase the amount of protein in the brain, and (4) prepare for success: identify biomarkers and build a biobank so that researchers will know when they have been successful and can test their potential drugs against patient samples, as well as work towards a natural history study, which can help accelerate the timing of clinical trials once a treatment approach is found.
If we are going to build a drug that increases the amount of SynGAP protein, we need to understand as well as we can: what it is that the SynGAP protein does, what helps or hinders its expression, how much of the protein our kids express, etc.
Right now, we know some of the functions of the SynGAP protein, but we don’t know all of them. We don’t know how much SynGAP protein our children produce (does the “good” SYNGAP1 gene produce the same amount it normally would, or does the error on the “bad” gene either get in the way or allow it to produce more)? Is any of this correlated to the different mutations that our children have and the way they present the disease? (i.e., some of our children are wheelchair-bound, while some can run; a few can speak while most are functionally non-verbal; many have intractable seizures throughout their lives while a few have never had an abnormal EEG). How much good SynGAP protein is needed to improve associated symptoms?
HTS are one of the exciting places where advances in technology make rapid progress possible: historically, testing whether a certain drug would work for a certain problem required feeding the drug into tiny pipette after tiny pipette and measuring the results, one by one. HTS today rely on complex tools that allow the investigators to test tens-of-thousands of potential compounds in rapid succession.
The promise of a HTS is that this rapid testing mechanism will allow researchers to identify molecules that were originally identified as treatments for other conditions, but which also increase SynGAP expression (so-called “repurposing” of existing chemicals). If found, we would be able to rapidly treat our children with compounds already known to be safe.
What has been done so far?
A — “N of 1” studies have indicated that repurposed pills can reduce symptoms of SynGAP: Statins, the well-known cholesterol drugs, appear to have had an impact on cognitive functioning, behavior and seizures for a few SynGAP patients, when administered on a compassionate use basis.
This is interesting at a basic level because it indicates that a pill, designed for another purpose entirely, may affect the cognition and behavior of a SynGAP patient. But it is potentially quite interesting because of research that shows that, while SynGAP models typically show unusually high levels of “Ras signaling” (a pathway within the cells), models treated with lovastatin have their Ras signaling reduced to more normal levels — which is to say, that the underlying neurobiology that we know is related to the SynGAP protein, is affected by a statin. Which could mean that the amount (or efficacy) of the SynGAP protein itself is affected, which, if true, would imply that it is possible to address the problem our children have at its root cause.
(You can read more in this paper and this paper, and for parents, if this sounds interesting, you can talk to your doctor about gaining access to lovastatin for your child as an N of 1 trial, recognizing that the potential benefits here are not yet fully understood.)
Further research is underway at James Clement’s lab in India as well as at Gerhard Kluger and Till Hartlieb’s clinic in Vogtareuth, Germany, to find out more about whether statins do in fact regulate levels of SynGAP protein and if the success with single patients can be replicated in a larger population.
B— An HTS screen is underway at Scripps Research: Dr. Rumbaugh at Scripps Research has a grant from the NIH to perform HTS in neurons with only one “good” copy of Syngap1. The idea here is to find a drug-like substance that makes this “good” copy work even better to compensate for the copy that is broken by de novo variants. Scripps is a great place to perform HTS because it owns one of the largest drug libraries in the world, including the largest drug repurposing library, call ReFRAME. The models that Dr. Holder and others have built will allow Dr. Rumbaugh to test if drug candidates identified in HTS are effective in models made from SYNGAP1 patients.
What needs to be done next? SRF is currently evaluating building out so-called biochemical assays (vs. the phenotypic or cell-based assays that Dr. Rumbaugh’s screen relies on), which can be a simpler and more adaptable approach to HTS. However, the drawback to these “simpler” assays is that they are less directly related to the cause of SYNGAP1 disorders (i.e. the failure of brain cells to make enough SynGAP protein).
We are also evaluating supporting the build-out of other model types that can be used for HTS and exploring additional drug libraries.
If one of the SYNGAP1 genes does not express SynGAP protein (or expresses an insufficient amount), but the other does, there is a theoretical possibility to increase the expression of the SynGAP protein from the “good” SYNGAP1 gene — which could simulate a “normal” environment. Antisense oligonucleotides (ASOs) are a mechanism to do just that.
What are ASOs? Back to that ninth grade biology discussion: proteins get made when DNA copies itself, producing mRNA (messenger RNA). The mRNA will then produce a certain quantity of the relevant protein — exactly how much is determined by the “instructions” on the underlying mRNA.
Enter ASOs: an ASO is a small piece of single-stranded DNA that, in our case, would find the part of the mRNA regulating the protein expression. Instead of that part of the mRNA acting to reduce protein production, that part of the mRNA will meets its ASO counterpart and both will dissolve. The good SYNGAP1 gene would then act without a regulator, and produce more SynGAP protein than it normally would.
In other words, ASOs for haploinsufficiencies like SynGAP would “stop the stop” — to use some highly imperfect analogies, be the method by which a local train turns into an express train, or be a way to drink water directly from a jug rather than through a straw.
Is that really possible? Yes. ASOs are a novel modality for sure, but they have been proven to be effective in Spinal Muscular Atrophy and Batten’s Disease, are currently being trialed in Dravet Syndrome, and are a topic of early biotech interest for other haploinsufficiencies, including SynGAP.
ASOs are also not an easy modality to dose: for the ASO to operate, it needs to go to the place where the protein is doing its work (i.e., the brain), which is to say, ASO treatments are expected to be conducted via spinal tap. Further, ASOs typically degrade every few months, so a patient being treated by an ASO would need to undergo that spinal tap a few times a year.
That said, the ASO approach could theoretically address all of the symptoms of SynGAP by addressing the root cause of the problem of SynGAP, i.e., insufficent protein expression.
So what are we doing about it? SRF’s grant to Dr. Huganir’s lab and our Australian colleagues’ grant to the Florey Institute were focused on supporting development of ASOs.
Also, the work we are doing around improving the number and types of SynGAP models will be supportive of ASO work, as it is (clearly) critical for us to understand the specifics of how much SynGAP our children express.
What is next?
We need to do more modeling of the protein type. That is, we need to better understand which “isoforms” of SynGAP (the 20 different forms of SynGAP) are typically expressed, and in which ratios, so that we can make sure that the upregulated protein mimics the typical expression. Dr. Huganir’s continued ASO work focuses on that area, and as mentioned, this area of drug development is one of high interest for biotechs.
WHEN our focused research teams identify drug target candidates (small molecule, ASO, or otherwise), they will need to make sure that the drugs they find are actually impacting the amount of SynGAP protein in humans. In order to do this, we will need to identify so-called “biomarkers” of the protein — other things that are always there when the appropriate amount of SynGAP protein is in the body. We are currently fundraising for a grant in this area.
And, when these research teams identify these drugs, they will want to test them against as many mutation types as possible before trying them in humans. So, we will work on building a “stem cell repository” — we will work with families and researchers to draw patients’ blood, differentiate that blood into stem cells, and ask for those stem cells to be stored in a location that all SynGAP researchers can access. This approach will reduce the barriers to progress for academics and smaller biotechs, making it easier for those focused on other diseases to choose SynGAP as their next target.
Finally, and importantly, we will support and leverage existing work related to a “natural history study.” A natural history study is a well-organized and structured look at the clinical symptoms of the disease, as it presents in our patients over time. A well-designed natural history study can accelerate the choices researchers make in designing clinical trials, and in some cases can ultimately serve as the control arm of a clinical trial for rare disease, which reduces the timeframe to treatment.
So, there you have it. The basis for my (informed, impatient) hope. The basis on which we founded SRF: that to find a cure for SynGAP will be hard, but not impossible. Because SynGAP, for its dizzying range of symptoms, is, at its genetic core, a simple disease: a typo on a gene that causes less protein to be produced.
The dedicated researchers and scientists have made great progress in the last ten years. But there is much more to do and, by working together, I do believe that we can go far. And, for the sake of our kids, we must.