This blog was written by CURE SYNGAP1 Chief Scientific Officer Kathryn Helde, PhD, SYNGAP1 Mom to Joey.
Additional information can be found in this companion piece: Preparing for SYNGAP1 Clinical Trials: What Families Need to Know. Also see CURE SYNGAP1 Episode 202 – It is time to get ready for clinical trials, this is how. #S10e202.
Three categories of new and emerging medicines for SYNGAP1-Related Disorders (SRD) are in clinical trials or will be soon. We present a description of each type of medicine – commonly called ASOs, AAVs, and small molecules – so families can get acquainted with upcoming clinical trial opportunities. We offer this primer, comparison, and glossary for educational purposes; this document is subject to improvements and corrections and is the opinion of Kathryn Helde, PhD, Chief Scientific Officer at CURE SYNGAP1. When Clinical Trials are recruiting, there will be ample medicine-specific and trial-specific information from the sponsor. Always consult with your doctor for further information and for any decisions on medications.
- Small Molecule: like most drugs we take, a chemical in a pill or other form
- Two new drugs and four repurposed drugs are currently in Clinical Trials
- ASO: a medicine that binds to SYNGAP1 RNA to increase SYNGAP1 protein
- Multiple types of SYNGAP1 ASOs are in development
- CAMP4 expects to be in global Phase 1/2 later in 2026
- AAV: a delivery method to introduce DNA to tissues and cells
- Several AAV-based gene replacement strategies are in the pipeline
- Plus several other therapeutic strategies that deliver DNA via AAV
Practical differences between these three therapeutic modalities are shown in the chart below. The Key Examples row includes links for a layperson in addition to links for an audience with a college-level biology education. If you don’t like one link, click on another!
| Common name: | Small Molecule | ASO | AAV |
| Full name: | Small Molecule Drugs | Antisense Oligonucleotide | Adeno-Associated Virus |
| Type of Medicine for SYNGAP1-Related DIsorders: | Small Molecule Drugs | RNA-based medicine that targets the SYNGAP1 gene RNA | Viral delivery of DNA-based medicine |
| Mechanism for SYNGAP1-Related Disorders: | Most in this category bind to one or more protein targets to make a symptom better. Some small molecule drugs may even increase SYNGAP1 function directly. | ASOs bind to SYNGAP1 RNA to increase SYNGAP1 function. Mechanisms include increasing expression of the gene, increasing the time the RNA is active, switching the ratio of different versions of the gene, and more. | AAV gene replacement delivers SYNGAP1 DNA to make up for a missing or broken SYNGAP1 gene. Future AAV-based drugs may use CRISPR to edit or increase expression of SYNGAP1, or other therapeutic strategies. |
| Complexities: | Multiple targets for small molecules (side effects); basket trials for multiple similar disorders. | Many strategies to choose from; many possible sequence targets. | Isoform choice and gene length; choice of AAV type; possible systemic immunosuppression at time of dose. |
| How long the medicine lasts in the body: | Short-lived: Requires daily or frequent administration. | Transient: Requires repeat dosing. May include one or more “loading” doses followed by “maintenance” doses (e.g., every few months). | Long-term: Potentially “one-and-done” (lasts years/decades). |
| How the medicine is given to the patient: | Typically oral delivery (pills/liquid), (or transdermal, nasal or suppository). Small Molecule drugs move around the body quickly. The least invasive, can be dosed at home. | Often intrathecal Spinal tap: In a clinic, using a needle to put the ASO into the fluid around the spinal cord, to reach the brain quickly and without going through the liver. | Single IV infusion In a clinic, often with immunosuppression, a needle delivers the AAV Intravenously; the medicine must cross out of the vasculature into the brain. |
| Regions and Tissues Targeted: | Broad tissue reach: often crosses the blood-brain barrier easily. Different for different drugs, but often broad reach. | High precision: Affects the SYNGAP1 gene and not others. Tissue expression TBD. | Custom expression. Tx limited by the size of the gene (payload). Tissue expression TBD. |
| Key Example: | miglustat (Zavesca) for Niemann-Pick Type C. | Nusinersen (Spinraza) for Spinal Muscular Atrophy | Zolgensma for Spinal Muscular Atrophy |
| Drugs for single or basket DEEs: | DEEs Bexicaserin P3 DEEs Releutragine P3 DEEs Ravicti | Angleman GTX-102 P3 Angelman ION582 P3 Dravet STK-001 P1/2aOLE | Rett TSHA-102 P1/2 Dravet ETX101 P1/2 |
| video recordings for SRD therapeutics | #120 v, w, x #121 o, p | CAMP4; #121 q #120 q, r | Allen Institute |
Notes: P1/2=Phases 1/2 combined; P3=Phase 3; OLE=Open Label Extension; see ClinicalTrials.gov for more drug and trial info;
1. Small Molecule Drugs
These are traditional chemical compounds that are small enough to enter cells and interact with proteins. Improvements in drugs for SRD are already showing early promise. Improved sleep, reduced seizure burden, reduced irritability, improved gut function, improved cognition, improved communication are all possible improvements to be found with new and better small molecule drugs. Decrease in medication burden will also be an important improvement.
- Strengths: These are the most “patient-friendly” in terms of delivery—usually a pill or liquid taken at home. They can also be designed to cross the blood-brain barrier more effectively than some biologics. They wash out (so they can be stopped due to side effects or other issues).
- Weaknesses: They rarely treat the “root” genetic cause. Instead, they often manage secondary effects, for example by cleaning up collateral damage caused by the disease. They wash out (so they must be dosed continuously).
2. Antisense Oligonucleotides (ASO)
ASOs are short, synthetic strands of nucleotides designed to seek and bind to specific RNA. ASOs closely mimic RNA in shape, information, and binding, yet evade degradation. Depending on the strategy employed, ASOs can act like “transcriptional accelerators,” “brakes,” “molecular erasers” or “patch kits.” For SRD, the CAMP4 medicine CMP-002 upregulates the SYNGAP1 gene by reducing the function of an RNA that limits SYNGAP1 expression.
- Strengths: There are multiple strategies for making an ASO against a gene, and there are at least four strategies in development for SRD. The drug lasts in the body for months, but not forever, so it can be stopped if needed because of a side effect or adverse event.
- Weaknesses: Since ASOs wear off (over months), lifelong redosing is predicted. Current best practices for delivery include invasive procedures like lumbar punctures to deliver the drug directly to the central nervous system. IV delivery may become routine in the future, but is not currently the standard.
3. AAV-Based Gene Therapy
AAVs use a hollowed-out, viral capsid to “shuttle” a DNA-based medicine into the body’s tissues and cells. For SRD, gene replacement is farther along than other other DNA-based strategies such as CRISPR base editing, CRISPR activation, or tRNA suppressor therapeutics.
- Strengths: It targets the root cause at the DNA level. In non-dividing cells (like neurons), the therapeutic DNA can persist for a very long time, offering the hope of a permanent cure with a single dose.
- Weaknesses: After one dose, the body is likely to develop an immune response to the AAV “shuttle” so only one dose is possible. There are “cargo” size limits; the SYNGAP1 gene is just over the generally accepted limit for size, so one of four different options is needed:
- Reduce the gene size (“Mini-Gene”) this strategy is the most popular
- Use two different AAVs and have them combine in the body
- Try it “too long” and deal with reduced efficiency of packaging (Allen Institute did this for a mouse model of SRD, but it is unlikely to become an approved drug).
- Find or alter an AAV to hold a larger DNA cargo.
For additional information on future clinical trials, see Preparing for SYNGAP1 Clinical Trials: What Families Need to Know
Glossary
| Abbreviation | Name | Description |
| AAV | Adeno-Associated Virus | (As in AAV Gene Therapy): This is like a “delivery truck.” Scientists use a tiny, harmless virus shell to carry a DNA medicine, such as a healthy, working copy of a gene, directly into cells in your body. The goal is a treatment that could last a lifetime. |
| Access | Access means a drug is available and affordable. Approval by the FDA means a drug is safe and effective, but Access is what actually puts the medicine into a patient’s hands by making it affordable through health insurance coverage. | |
| Administration | Route of Delivery | The way a patient takes the medicine, such as swallowing a pill, getting an IV, or having a shot in the back (Intrathecal delivery, or IT). |
| AE | Adverse Event | Any health problem or unfavorable change that happens to a participant during a clinical trial, regardless of whether it was actually caused by the treatment being tested. AEs are reported with a severity score to show intensity. |
| ASO | Antisense Oligonucleotide | Think of this as a “patch kit” for your body’s instructions. It is a tiny, man-made string that seeks and binds to your RNA (the intermediate between a gene’s DNA and protein) to fix how a gene’s instructions are read. ASOs don’t last forever, so the medicine requires a new dose every few months through a shot in the back. |
| CT | Clinical Trials | A special testing period and heavily regulated process where doctors and scientists study new medicines in people to make sure they are safe and actually work before they are sold to everyone. |
| CTR | Clinical Trial Readiness | Steps needed to make clinical trials happen and be successful. A few examples: understanding the Natural History of the disorder, understanding what is meaningful to patients and their families, having clinical measures that are validated for the disorder, and more. |
| DNA | (long term storage of instructions) | The “instruction manual” found in every cell of your body that tells your body how to grow and stay healthy. |
| Drug | Small molecule drug | These are traditional medicines, like a pill or liquid you swallow at home. They are small enough to enter cells and help manage symptoms like seizures or sleep issues, but they usually don’t fix the root cause of the genetic disorder. |
| Durability | How long a medicine lasts in the body before another dose is needed. Based on the combination of how long the drug stays in the body before it washes out, and how long the effect of the drug lasts after the drug is gone. | |
| Effectiveness | Measures of effectiveness answer the questions “Does it work?” Effectiveness is a measure of whether a drug works in real world settings, where patients may have a diversity of symptoms and adherence and supervision are less strict than in a clinical trial setting. | |
| Efficacy | Efficacy answers the question “Can it work?” under “ideal” circumstances. Efficacy in a clinical trial measures how well a treatment works under ideal and controlled circumstances. Patients are chosen under defined criteria to get the best measures of improvement; adherence and supervision are closely monitored. | |
| Gene | A unit of genetic instructions, including the DNA , RNA, and protein made from a gene. | A gene is stored and passed down as DNA. To be used, that gene is made into an intermediate called RNA, where a lot of regulation can happen (amount and different forms). The RNA is used to make the final machine: the SYNGAP1 protein, which is a small molecular machine with multiple jobs (like a swiss army knife: one tool, lots of options for functions.) While people typically refer to the DNA form, all the forms can be considered products of the same gene. |
| Genome | “the human genome” is found in the nucleus, in chromosomes made of tightly packed DNA | All the instructions to make a person are stored in DNA and called the genome. The human genome is made up of ~22,000 genes plus a lot of other DNA that helps the information be stable long term, inherited, and available when needed. |
| HEOR | Health Economics and Outcomes Research | HEOR tells insurance companies (payers) why they should pay for treatments. Health Economics measures the cost of care under various treatment regimes, and Outcomes Research measures the quality of life on different treatment regimes. |
| IT delivery | Intrathecal delivery | (also can be referred to as a Lumbar Puncture or a Spinal Tap): A way to give medicine by using a needle to inject medicine into the fluid around the spinal cord. This delivery placement helps the medicine reach the surface of the brain quickly. |
| Isoform | One of several different (but highly related) gene products from one gene. The SYNGAP1 gene has multiple RNA isoforms that use alternate stretches of DNA (exons) to make proteins with different modules on the ends. | |
| PD | Pharmacodynamics What does the drug do to the body? | The study of a drug’s power and effects—the specific biological changes (like increased sleep or decreased irritability) that happen because the drug is present. |
| PK | Pharmacokinetics What does the body do to the drug? | How does a drug last and get removed from the body of the patient? What is the time it takes from dosing to peak drug concentration in target tissues, and what is the time it takes to remove half the drug from target tissues? |
| p. | Protein final gene product | A tool (Swiss Army Knife) or machine inside your cells. The SYNGAP1 protein is made from the SYNGAP1 RNA, which is made from the SYNGAP1 gene (DNA). |
| P1 | Phase 1 | Phase 1 in a clinical trial answers the question “Is it safe?” How does the drug get broken down and leave the body? (PK). What does the drug do to the body? (what changes for the patient– PD) and by measuring adverse events with treatment. |
| P1/2 | Phase 1/2 | A combined Phase 1/2 looks at safety, dosage, and preliminary efficacy in one streamlined trial. P1/2 is often used for disorders with a small patient population like rare diseases. |
| P2 | Phase 2 | Phase 2 in a clinical trial determines dosage of a treatment along with continued safety and preliminary efficacy. If the drug “seems to work” then Phase 3 can start. |
| P3 | Phase 3 | Phase 3 in a clinical trial is meant to show whether a drug is truly better than what we currently have. It is much larger than Phases 1 and 2 (more patients). P3 looks at how well the drug works (efficacy) compared to either a placebo or data for untreated individuals (e.g. Natural History Study data). |
| OLE | Open Label Extension | After a protocol in a trial, there may be an OLE period where any current participant is offered drug treatment (whether they were on placebo or not). This can be the only way to be on drug before a trial ends and regulators decide whether the drug is approved. Note it is not a sure thing to be in a trial; each trial has inclusion and exclusion criteria, and each trial has a limited number of spots for patients. |
| P4 | Phase 4 “Post-Marketing Surveillance” | After a drug is approved, Phase 4 includes gathering long term safety data, expanding access to a wider population of patients than meet strict earlier trial criteria, and comparisons to and combinations with other drugs. Phase 4 lasts as long as the drug is on the market. |
| Payer | Insurance | Insurance companies may resist paying for expensive therapeutics, so we want to show the Health Economics and Outcomes Research of SRD. (HEOR, Access) |
| Protein | Dietary Protein | When eating you may consider the amount of protein, carbs, and fats in your foods. This is unrelated to how the SYNGAP1 protein causes SRD. Eating extra protein cannot make up for the lack of SYNGAP1 protein. When we eat protein, we are mostly eating the ‘bulk’ parts of plants and animals, like muscles (steak) or nuts and seeds from plants. While these foods also contain thousands of tiny protein machines that run the cells, we get most of our nutrition from the larger structural and storage proteins. |
| RNA | (short term copies of single page of instructions) | A messenger in your body that carries instructions from your DNA to help build things your body needs. SYNGAP1 RNA is made from the SYNGAP1 gene (DNA), and the RNA is used to make SYNGAP1 protein. Multiple forms (“isoforms”) of the RNA exist, and they create different versions of the SYNGAP1 protein. |
| Sponsor | The sponsor is the organization or person that takes overall responsibility for starting, managing, and often paying for a clinical trial – typically the pharmaceutical company where the medicine is developed and will be sold. | |
| SRD | SYNGAP1-Related Disorders Also known as: SYNGAP1-Related ID SYNGAP1-DEE SYNGAP1-NSID AID5, and others | In SRD, the body doesn’t have enough SYNGAP1 protein, which is needed in the brain for learning and elsewhere for other types of health. In order to know you have SRD, genetic testing shows a change in the SYNGAP1 gene that causes disease. |
| Tx | Therapeutics | Therapeutics are medicines and treatments. Many types and categories exist. |
To request additions to the Glossary above, please email cso@cureSYNGAP1.org.
| Biology concepts central to gene-based therapeutics are described simply below: |
| DNA Deoxyribonucleic acid | DNA is like a Master Cookbook The permanent instructions inherited from parents; long term storage whether or not in use. | The “original recipe” for the SYNGAP1 protein, kept safely in the cell’s library (the nucleus). |
| SRD therapeutics that use or target DNA include: *AAV-based gene replacement *base editing *CRISPRa (“a” is for gene activation) |
| RNA Ribonucleic acid | RNA is like Index Cards Portable, short-term copies of the instructions that will be used to create the final product (proteins). | A handwritten copy of the recipe. Cells can make different versions (isoforms) to change the final result. |
| SRD therapeutics that target RNA include ASOs that upregulate SYNGAP1 gene function by: *interfering with an RNA that dampens SYNGAP1 gene expression *extending the life of SYNGAP1 RNA *increasing the amount of the critical isoform and decreasing other forms |
| Protein | Protein is the Final Dish The actual “tool” that goes to work – it acts like a Swiss Army Knife with many jobs. | The finished SYNGAP1 protein, which acts as a “traffic controller” in the brain to manage nerve signals. |
| SRD therapeutics that target proteins (SYNGAP1 protein or other proteins) are often small molecules. |