Sandy is a volunteer with SRF and aunt to 5-year-old Syngapian Myla. Though not a scientist by trade, like many others in the “Rare Community,” she’s trying to learn as much as she can and appreciates a conference like this, which educates and informs researchers, clinicians and laypeople alike.
Over 70 participants from nine countries met online on Dec. 3, 2021 to listen to seven industry leaders in the rare disease community discuss advances in both scientific research and collaboration efforts happening around genetic neurodevelopmental disorders.
The event, the Third Annual Synapse Roundtable, was an expansion of the first two years of the Syngap Research Fund’s SynGAP Roundtable. SRF’s managing director Mike Graglia says, “We get more done when we work together. That is why we expanded our annual research roundtable to focus on collaboration with two other rare disease groups we respect: STXBP1 Foundation and Cure SHANK.” The meeting was cohosted by all three groups and moderated by Mike Graglia; Charlene Son Rigby, president, STXBP1 Foundation; and Geraldine Bliss, president, CureSHANK.
As with the first annual roundtable, this one was held just before the annual meeting of the American Epilepsy Society, and many of the speakers were in Chicago for that convention, some even presenting their research there.
We heard from seven speakers, each of whom work on at least two of the three genes represented. My layperson’s summary is below. I can’t promise to do justice to the science (although I will try!). For that, I suggest you watch the full Roundtable recording. But I can very confidently highlight the common thread throughout the presentations: We really are stronger together. We can go further, faster if we collaborate and share resources. Our speakers are leaders in that.
Cures happen faster when unique disorders find strength in collaboration
The Consortium for Outcomes Measures and Biomarkers for Neurodevelopmental Disorders (COMBINEDBrain) is devoted to fast-tracking cures for severe, rare genetic neurodevelopmental disorders (NDD). Dr. Bichell emphasized the importance of bringing patients and patient-led foundations to the table with clinicians, researchers and pharmaceutical firms in order to develop treatments.
COMBINEDBrain puts patients in the center of the work they do. They want to know what matters to patients and families. What is it like to be living with a disease, and what kinds of outcomes matter in the long run? That’s what cures will look like. While animal models are an important part of drug development (testing, measuring), a patient-centric approach puts emphasis on natural history studies and disease burden as part of disease model phenotyping, biomarker identification and outcomes measurements.
COMBINEDBrain has opened up their biorepository to all neurodevelopmental disorders. As Dr. Bichell says, “You’re special, but not that special.” Together, we can be more efficient and effective.
Sensorimotor integration in gut and brain of zebrafish, SYNGAP1 and SHANK3 models
Dr. Dallman’s lab uses zebrafish to help understand how changes in genes affect behavior. They are looking at GI symptoms within the autism spectrum disorder (ASD) because little is known about them and they’re of big concern. Zebrafish models can be used to test the hypothesis that reduced gut motility is common to ASD-linked GI distress.
Why zebrafish? The fish are nearly transparent, so researchers can easily watch digestion in action and can quantify the behavior. They’ve been looking at wild type, SHANK3 and SYNGAP1 models to see differences in motility patterns. “Whole gut transit” takes longer in fish with both disorders than it does in the wild type.
Leaving the lab and moving into the home, Dr. Dallman told us of clinical studies underway to help better understand GI symptoms in NDDs. In one study, subjects eat a muffin with blue dye and then wait to see how long before there is “blue poop.” They’ve also developed an app to track GI symptoms. The hope is that these measures and insights can help inform treatment and develop strategies to treat GI symptoms in ASD, a very worthy goal.
Clinical trial readiness endpoints and outcomes
Dr. Kolevzon works on Phelan-McDermid syndrome (SHANK3 haploinsufficiency) as part of the Developmental Synaptopathies Consortium (DSC). DSC has continued refining the phenotypes of the NDDs they study through a longitudinal study of four-plus years. He emphasized the importance of quantifying phenotypes in preparation for identifying measures for clinical trials. Understanding the natural history will also help identify targets for therapeutic interventions and help develop clinical best practices.
One of the challenges for clinical trial readiness is finding the right tools to measure change over time. Some of the scales measured by existing tools aren’t useful in the NDD population. Dr. Kolevzon’s team is excited about a new sensory measurement tool they’ve developed, the Sensory Assessment for Neurodevelopmental Disorders (SAND), capturing visual, tactile and auditory sensitivities. The tool has potential uses in both research and clinical settings.
The goal is that when there are therapeutics ready to test in trials, they’ll be ready with the right kinds of measures.
Sleep and other potential biomarkers for SHANK3 and SYNGAP1
Why study sleep? Dr. Smith-Hicks outlined the many important roles sleep plays in our lives. It’s critical for many physiological functions, key for neurogenesis and plasticity. Sleep disturbances are a common feature in many NDDs (present in 50-95%). Disrupted sleep has an adverse effect on the quality of life to both patient and caregiver. It worsens problem behavior and cognition.
Animal models have shown that SYNGAP1 and SHANK3 play important roles in sleep. A three-site study was done to evaluate sleep difficulties. The screening tool used was the Children’s Sleep Habits Questionnaire (CSHQ), which can parse sleep features into eight subscales, such as bedtime resistance, sleep onset delay, duration, anxiety and more. The CSHQ showed more sleep difficulties in SYNGAP1 patients. Some measures they scored higher in were bedtime resistance and daytime sleepiness.
Tracking patient sleep profiles via the CSHQ could be a useful tool when thinking about measuring treatments and their effects on sleep.
Simons Searchlight Registry Insights
Dr. Chung discussed the Simons Searchlight program, which exists to help understand genetic NDDs. Its mission is to shed light on these conditions by collecting high quality natural history data and building strong partnerships between researchers, industry and families.
Detailed medical and behavioral histories are collected, along with genetic test results and biospecimens. Data is made available to families and also qualified researchers. Having such a registry allows for connections between researchers and potential participants from around the world. The rich data in the registry can hopefully be useful in clinical trial readiness.
In addition, even now clinical care can benefit from the resources of the program. Genetic references guides for individual genes, such as those written up in the Gene Reviews publication, are readily available to clinicians.
One very useful piece of the program is called Research Match, a way to advertise IRB-approved research studies to the community. This is an opportunity for participants to be involved in research being done on their gene(s) and a way for researchers to be matched to potential subjects. Another resource Searchlight has is a bank of iPSC lines for a number of conditions available to researchers.
Data sharing is at the core of the Simons Foundation. Data and samples are available for qualified researchers. And even more exciting to hear, especially for the SRF community, is that Simons is partnering with Ciitizen, finding ways to connect patient-reported data with medical record data, starting with SYNGAP1 and STXBP1 patients.
Ciitizen Registry Updates on SYNGAP1 and STXBP1
Ms. Brimble explained that Ciitizen is a patient-mediated data platform that allows users to collect and store their medical records. Through a combination of artificial intelligence and human reviewers, the platform transforms unstructured records into digital and relevant datasets such as genetic findings, clinical diagnoses, medication, side effects, etc. The data can be shared as a user chooses.
At its core, it’s a digital natural history study (NHS). Such studies are critical to understanding how disease affects patients and evolves over time. De-identified data can be made available to academic researchers with proper IRB documentation and a signed agreement at no cost, and to pharmaceutical companies for a licensing fee.
There are currently sets of complete records for both SYNGAP1 (105) and STXBP1 (70) patients in Ciitizen. (Ed. note: There are additional in-progress records in the database too.) Ms. Brimball shared some of the data collected as a way of encouraging collaboration and further use of it. She helped us appreciate the challenges with creating a full set of records. She called the process of collecting and processing hundreds of documents in various formats from multiple institutions “ruthless.”
But once this is done, it is possible to look at diseases side by side and start to tease apart differences, similarities, therapies, and other properties of each (e.g., age at diagnosis, age of symptom onset, medications, and much more).
As for collaboration, Ciitizen is also working to connect patient data with other platforms (including Simons Searchlight). They really want to see the data used as part of an effort to accelerate clinical programs.
Antisense oligonucleotide therapies for STXBP1 and SYNGAP1 disorders
Dr. Prosser’s lab is tackling the haploinsufficiency at the core of many genetic disorders. His lab is studying both STXBP1 and SYNGAP1; they are looking for ways to increase the amount of productive RNA in the working copy of the gene. They are focusing on antisense oligonucleotide (ASO) therapies to do so.
ASOs have had some success already (Hep C, amyloidosis, cardiovascular disease), and the work in Dr. Prosser’s lab around RNA manipulation has already shown some promise in STXBP1 and SYNGAP1. Specifically, they are looking at increasing gene expression to increase protein expression.
Testing to date has been done via cell line screening. Will it work in patients? That’s why iPSCs (induced pluripotent stem cells) are so important. ASOs can be tested on patient neurons generated from these cells. Dr. Prosser’s lab has generated iPSCs on both diseases; they’re now testing ASOs to find ones that restore the most amount of proteins.
There are many exciting efforts in research labs and industry that are working to further the goal of finding treatments and cures for NDDs that affect our family members and loved ones. And it’s encouraging to know that these dedicated scientists and related industry leaders are working collaboratively and working on related diseases, leading to economies of scale. This gives me hope that breakthroughs are coming soon.