Overview of SYNGAP1 Treatments Under Development
Updated July 2021
This page borrows from the excellent Pathways to a Cure for SYNGAP1 article by Ashley Evans, SRF Co-Founder and SYNGAP1 mom. All information, content, and material provided in this document is for informational purposes only and is not intended to serve as a substitute for the consultation, diagnosis, and/or medical treatment of a qualified physician or healthcare provider.
Is there a Treatment for SYNGAP1?
When a loved one first gets diagnosed, it’s common to wonder if there is a treatment or cure for SYNGAP1. The answer is complex:
- There are treatments, drugs and medical procedures that can help address the symptoms of SYNGAP1 disorder.
- There are drugs that may improve the downstream effects of SYNGAP1 disorder.
- There are no treatments or drugs on the market that can address the underlying SynGAP protein deficiency (SYNGAP1 haploinsufficiency) caused by the genetic condition, but several are in development and are approaching the clinical trial phase.
- There are no treatments or drugs on the market that can repair the genetic error that causes SYNGAP1 disorder, but there are several gene therapy techniques that already exist and may be able to do so in the future.
This article summarizes what is currently known about these 4 categories and how SRF is helping accelerate or improve each for the SYNGAP1 community.
Addressing the Symptoms
SYNGAP1 disorder results in a spectrum of symptoms including intellectual disability, epilepsy, autism, hypotonia and many others. Some of these can be treated or improved by FDA approved medications.
There are a number of treatments available to treat epilepsy in general:
- Anti-epileptic drugs (AEDs): many broad and narrow spectrum anticonvulsants are available. In a significant portion of the SYNGAP1 population, one or several in combination are effective in reducing seizures. However, some SYNGAP1 patients have a drug-resistant form of epilepsy and do not benefit from AEDs.
- Cannabinoids: Although not tested in SYNGAP1 specifically, CBD has been shown to have antiepileptic efficacy in trials of other epilepsies. A number of SYNGAP1 patients use cannabinoids as an add-on therapy for seizure reduction.
- Special Diets: the ketogenic diet is now accepted as an approach for reducing seizures.
- Surgery: surgical procedures such as Vagus Nerve Stimulation (VNS) or Corpus Callosotomy may benefit carefully selected epilepsy patients with AED-resistant seizures.
An individualized approach that continuously requires multiple types of therapies is likely to be needed. Some combinations of the therapies below have been helpful in stimulating development.
- Cognitive development, sensory processing, autism: Speech Therapy, ABA or other behavioral therapy .
- Motor development: occupational and physical therapy.
- Alternative therapies: hippotherapy, aqua therapy, swimming, music therapy etc.
Sleep disruption is common in SYNGAP1. Over the counter supplements may help with falling or staying asleep. A safety bed may help with sleep hygiene. Consider a sleep study to determine if other factors such as sleep apnea are impacting sleep.
A psychiatrist and behaviorist should be part of a SYNGAP1 patient’s medical team and can advise on behaviors. Behavioral therapy is often beneficial and drugs may also be prescribed. Behavioral Intervention Plans are an important part of keeping the educational team trained and ready.
How is SRF Helping?
SRF is committed to educating the community and spreading awareness about the symptoms of SYNGAP1. SRF:
- Partners with Ciitizen on a SYNGAP1 Digital Natural History Study which will help caregivers collect medical records, participate in studies and help accelerate research, free of charge.
- Hosts a number of webinars with leading clinicians discussing various aspects of the disease and currently available treatments.
- As part of SynGAP Global Network, participates in the Syngap Global Family Support Facebook group, an invaluable resource where SYNGAP1 caregivers can share their experiences with symptoms and treatments.
- Hosts virtual family meetups twice a week to support SYNGAP1 caregivers, share stories and advice.
- Created Facebook micro-communities for caregivers to discuss specific situations (same genetic variant, grandparents, older patients, dads).
- Provides medical information sheets for clinicians who may not be familiar with SYNGAP1 Syndrome.
- Provides a facility for caregivers to record and rate their doctors so SRF can continue to expand and engage the clinician community.
Treating the Downstream Effects
SynGAP is a large and significant protein in the human body. It has many uses, not all of which are fully understood. SynGAP is particularly essential for the healthy formation and functioning of synapses in the brain. SYNGAP1 haploinsufficiency means cells have only about 50% of the SynGAP protein they need to function properly, resulting in the disease features such as learning difficulty, repetitive behaviors, hyperactivity, and more.
There may be drugs that can help treat some of these “downstream effects” resulting from insufficient SynGAP.
How is SRF Helping?
Statins are an example of repurposed medicines. Other existing compounds, herbal supplements, and repurposed FDA-approved drugs may have beneficial effects on pathways that were already impacted by SYNGAP1 disorder. This is particularly promising for older patients, as downstream treatment could mean a “rescue” of some symptoms even at later ages. SRF is:
- Working with researchers who are investigating compounds that target these downstream effects, and more results are coming.
- Funding the development of new models (cell lines) that can be used to test the efficacy of these compounds and for running High Throughput Screens (HTS) to identify promising repurposed drugs (more on HTS in Section III).
Correcting the SynGAP Protein Deficiency
It has been demonstrated in mice that restoring SynGAP production to normal levels, even in adult mice, results in an improvement of the phenotype. Restoration of SynGAP levels directly addresses one of the underlying causes of disease, it doesn’t just treat downstream effects.
Haploinsufficiency means there is one “working” copy of the SYNGAP1 gene which does not produce enough protein for typical function. Making the working copy work harder (or better), is one way of up-regulating (making more) SynGAP. There are several known techniques to up-regulate SynGAP production.
Note for missense variants: many of the techniques described in this section may result in up-regulation of both the working and broken copies of SYNGAP1. In the majority of cases, this does not appear to be a problem as the product of the broken copy is discarded by the body. However, some missense mutations may be dominant negative, meaning they have a detrimental effect on the working copy, or gain-of-function, meaning that they may cause a problem other than not enough SynGAP protein. Up-regulating a dominant negative or gain-of-function variant may cause problems, so every missense variant needs to be analyzed to ensure it is actually a loss-of-function variant that is safe to up-regulate.
Please refer to this analysis of current variants in Ciitizen which maps which variant may be amenable for which treatment category.
Antisense Oligonucleotides (ASO’s)
ASO’s are small fragments of RNA that can bind to a gene’s mRNA and modify its expression. For SYNGAP1, the end goal is to get the one functional copy of the gene to produce more “working” SynGAP protein. ASOs are precision drugs developed to target specific diseases.
ASO’s are already approved by regulators and available on the market for several diseases, most notably Spinal Muscular Atrophy (SMA). ASO’s targeting other haploinsufficiency disoders are already in pre-clinical trials or clinical trials, for example:
- Praxis Precision Medicines PRAX-222 (pre-clinical) for SCN2A
- Stoke Therapeutics’ MONARCH study (clinical phase 1/2A) for Dravet Syndrome
- GeneTX and Ultragenyx GTX-102 trial (phase 1/2) for Angelman Syndrome
ASO’s have been shown to up-regulate (increase production of) working SynGAP in several cellular studies, including:
- Stoke’s TANGO technology has positive results for SynGAP
- SRF Grant Recipient Dr. Richard Huganir’s lab demonstrated SynGAP increase after targeting a natural antisense transcript (Syngap1-AS) and received a SFARI grant to continue the work
ASO’s are a novel technology but one that is proven to work and is progressing for disorders similar to SYNGAP1. There is hope that an ASO targeting SYNGAP1 is not far off. However, ASO’s have some downsides:
- Like many drugs that need to enter the brain or the central nervous system, delivery is a challenge. ASO’s are currently delivered intrathecally (spinal tap), though there is on-going research to determine a safer way to deliver the treatment to the brain.
- ASO’s degrade inside the body and have to be re-administered regularly to maintain effectiveness. The approved ASO for SMA, for example, requires a maintenance dose every four months.
All genes in DNA are governed by regulatory elements. These elements are genomic regions that control the features of the gene. On genes that encode a protein, such as SYNGAP1, elements called promoters and enhancers instruct the gene how much protein to make. Identifying and “turning up” (like a volume switch) these elements could result in more SynGAP being generated.
Recent research has demonstrated that this approach could work for Dravet and other haploinsufficiency disorders. Pharmaceutical companies such as Encoded Therapeutics are already taking this approach forward to clinical trials.
This exciting area of research is particularly valuable for SynGAP because the size of the SYNGAP1 gene is too large for current gene replacement techniques (see section IV for more about gene replacement). SRF Grant recipient Dr. Elizabeth Heller at UPenn is currently researching regulatory elements of SYNGAP1 and treatment possibilities.
Premature Termination Codon (PTC) Read-through
Nonsense variants change DNA to cause encoding to stop prematurely (before the full-length functioning protein can be formed). The result is a truncated version of the protein that is degraded by a process called nonsense-mediated decay (NMD).
As nonsense variants cause a large number of human diseases, there is significant interest in “PTC read-through” technologies that can correct them. These range from small molecules (e.g. from PTC Therapeutics) to gene correction mechanisms such as tRNA which are being developed for Dravet by Tevard Biosciences and cystic fibrosis/primary ciliary dyskinesia by ReCode Therapeutics.
For SYNGAP1 patients with a nonsense mutation, these approaches may show promise as a way to repair the translation of the broken gene copy.
Small molecules are compounds that can reach and affect intracellular targets, what we commonly think of as drugs (or pills). Some of these compounds may have a positive effect on SYNGAP1 disorder by mitigating downstream effects (section II) or increasing the amount of SynGAP in the brain (section III).
Small molecules have a number of advantages over other treatments. For starters, compounds may already be FDA-approved for another purpose. If these drugs are proven to increase SynGAP production, they can go through a “re-purposing” process which is a significantly shorter path to clinical trials and eventual market availability. Furthermore, some compounds can be tailored to be small enough to enter the brain without an invasive delivery mechanism (just take a pill).
The challenge is finding a compound that will have the desired effect. Fortunately, modern analytical techniques now exist to accelerate the search. One technique combines in silico (computer model-based) and in vitro (test tube-based) screening. A computer model may be used to narrow down the list of all possible compounds to ones that make sense to screen given the target. Afterwards, a High Throughput Screen (HTS) is run using a biochemical or cell-based assay to detect compounds that affect the target.
There are examples of HTS successfully finding treatments for other disorders, which is why labs such as SRF Grant recipient Dr. Gavin Rumbaugh at Scripps, and Michael Courtney at Turku Bioscience are currently working on HTS for SynGAP up-regulation.
How is SRF Helping?
SRF is intensely focused on advancing and accelerating the treatments described in this section as they present the most realistic near-term therapies to address SYNGAP1 patients’ underlying condition, not just their symptoms. SRF is:
- Supporting research through several grants to advance development of all the described approaches in this section.
- Funding the development of new models (cell lines) that can accelerate testing and validation of these techniques.
- Investing in clinical trial readiness and biomarker development, so we have all the elements in place to get new treatments into patients as quickly as possible.
Repairing the Gene
SYNGAP1 disorder is caused by a typo in the DNA that stops expression of 50% of functional SynGAP protein. The most effective upstream treatment would bring this back up to 100% in every cell that typically has it, either by repairing the typo or modifying the function of the gene to produce more protein that works.
Gene Replacement Therapy (GRT)
GRT introduces a block of DNA that codes a gene into a set of target cells. This externally sourced gene (called a transgene) can replace a non-functional gene with a working one. This approach is already at the clinical trial stage for several neurological disorders by pharmaceutical companies such as Taysha Gene Therapies and Lysogene.
One significant challenge for SYNGAP1 is that it is very large (1,343 amino acids in the major isoform, where the average protein size is ~300 amino acids), which makes it difficult to package in the currently available delivery mechanisms (AAV, see Appendix). There are techniques in development to help overcome the size obstacle; for example, delivering a “mini-gene” that performs most or all of the function of the full gene. DNA may contain sections that are not particularly important to the final output of the gene, making it possible to trim them out and create a mini-gene. However, constructing a functional mini-gene requires significant analysis and expertise.
Base / Prime Editing
Base and prime editing are newly developed mechanisms to precisely modify DNA sequences to correct harmful variants. Built on the CRISPR/Cas9 gene editing system, these approaches avoid problematic DNA cutting. Instead of a cut, base editing enables precise single nucleotide edits on a single strand. Prime editing goes even further, enabling a correction of larger sequences of DNA.
At the time of writing, CRISPR gene editing technology is still bleeding edge. But the door is now open for a true “correction” of disease-causing genetic variants, not just for SYNGAP1, but for many genetic disorders.
How is SRF Helping?
Although SRF remains focused on the near-term therapies in Section III, discussions with researchers about next-generation gene therapies are on-going. SRF continues to seek grant opportunities to advance SYNGAP1 research in these areas.
About Adeno-Associated Virus (AAV)
Many of the therapies described in this document use AAV as a delivery mechanism. AAV9, in particular, can efficiently cross the Blood Brain Barrier (BBB) and infect brain cells such as neurons, making it a good choice for treating neurological disorders. AAV9 has a limited capacity, so it’s a challenge to fit in larger genes like SYNGAP1. However, other techniques such as targeting the regulatory elements, mini-genes or PTC read-through can be used with an AAV delivery system, as these strategies package smaller genes..
AAV’s have some distinct features:
- Unlike an ASO, it’s a “one shot” treatment. Once the virus infects the target cells, it will not lose effect until those cells divide. Neurons are not rapidly dividing cells, so the effects could remain for years. Some companies are investing in AAV re-dosing platforms which facilitates multiple AAV doses if needed
- AAV is a virus and could trigger an immune response, especially in older patients who may have developed anti-AAV antibodies through natural exposure.
- AAV has poor tissue targeting ability, leading to possible toxicity in other organs (e.g. the liver)
Although AAV technology remains a leading and very promising delivery method to the brain, it’s important to monitor these challenges and how they may impact potential treatments for SYNGAP1.