Post authored by: Jeffrey Cottrell, PhD; Perry Spratt, PhD; Morgan Weberg, BS

Link to Publication

Dear SCN2A Community, 

A recent research study published in Nature Medicine from physicians at Rady Children’s Hospital, Rush Medical Center, and the n-Lorem Foundation presented clinical trial results on the use of an allele-selective antisense oligonucleotide (ASO) for two different individuals diagnosed with an SCN2A-Related Disorder (SRD). 

The FamilieSCN2A Foundation understands that news like this raises hope and that families may have questions and want to know next steps. We are dedicated to providing our community with scientifically accurate and up-to-date information. 

What the study found

In this clinical study, physicians developed allele-specific ASOs for two individuals: patient one diagnosed with a heterozygous SCN2A gain-of-function pathogenic variant (c.5645G>A, p.Arg1882Gln) and patient two with a heterozygous pathogenic mixed-function SCN2A variant (c.2558>A, p.Arg853Gln). The physicians designed the ASOs to specifically reduce the levels of the protein with the disease-causing variant.

To evaluate the therapeutic impact of the ASOs, physicians assessed primary, secondary, and additional outcome measures. The primary measure focused on seizure control improvements, including seizure counts and reduction in antiseizure medication (ASM) use. The secondary measures evaluated enhancements in neurodevelopmental skills and communication. Other outcomes included gastrointestinal symptom severity, adaptive behavior functioning, and two parent/caregiver rating scales: one assessing irritability, hyperactivity, lethargy/withdrawal, and speech, and the other evaluating abnormal muscle tone effects such as spasticity, floppiness, and dyskinesia.

Patient one showed an increase in seizure-free days from 57.8% before ASO treatment to 66.5% afterward, with an estimated 26% reduction in seizure frequency following ASO initiation, though this was not statistically significant. Additionally, this patient was successfully weaned off phenytoin, a birth-dependent ASM. Improvements were also observed in growth measures using the Bayley Scales of Infant and Toddler Development Fourth Edition (BSID-4) and in communication abilities reported by observers (ORCA).

Patient two experienced a rise in seizure-free days from 0% pre-treatment to 46% post-treatment, along with a statistically significant 90% reduction in seizure counts after starting the ASO. This patient also exhibited meaningful improvements in communication, along with reductions in maladaptive behaviors and irritability, as measured by the Vineland-3 Adaptive Behavior Scale.

Neither patient encountered treatment-related adverse events or serious adverse events, with no abnormal biochemical, hematological, ECG, or EEG findings.

Considering all results, this study provides a proof of concept supporting the use of antisense oligonucleotides to directly modify the genetic expression of pathogenic SCN2A variants and may contribute to improvements in disease burden. 

A note on allele-specific and non-allele-specific ASOs:

Every individual contains two copies of a gene. One copy of the gene is on one allele, and the other copy is on another allele. Most pathogenic variants in the SCN2A gene occur on only one allele. Considering the increase of ASOs for treatment of rare genetic disorders, it is important to understand how these target SCN2A gene expression: 

• The ASO developed by Praxis, Elsunersun, is currently recruiting for a Phase III Study: the EMBRAVE3 Study. This ASO targets BOTH copies of the SCN2A gene, even if only one of the copies contains the pathogenic variant, defining it as a non-allele-specific ASO. 

• The ASOs presented in Nature Medicine were designed for two individuals diagnosed with a pathogenic variant in the SCN2A gene to reduce activity of just the copy of the gene that has the disorder-causing variant, defining them as allele-specific ASOs. 

• The ASO developed for patient one targets the specific gain-of-function variant R1882Q itself, and-by doing so, reduces the expression of the variant copy.

• In contrast, the ASO developed for patient two targets what’s called a common single nucleotide polymorphism (SNP) that is near the disorder-causing variant, near the same copy of the SCN2A gene that contains the disorder-causing variant. Because this SNP is so near the disease-causing variant and on the same copy of the gene, the ASO reduces expression of the variant copy.

What are common SNPs?

• Each individual has in their DNA thousands of individual genetic variants – changes of single letters. They typically do little to alter DNA activity, and if anything, provide some of the tiny differences that make people individual. They are inherited and can be quite common, so in some cases, say half of individuals have specific common SNPs. The SCN2A gene has a number of these common SNPs that do not alter the function of the gene and do not cause an SRD. However, because these SNPs can be on the same copy of the gene as the disorder-causing SCN2A variant, an ASO can be developed that targets that bad copy of SCN2A – not through the specific disorder-causing variant but through this common SNP that happens to be near that copy of the gene. This means 1) that this specific ASO could be used to knock down any bad copy of SCN2A that has this SNP near it, so the specific disorder-causing variant doesn’t matter and 2) not every child with an R853Q variant will be able to be treated with this ASO. They would have to have this common SNP in the same copy of the gene. 

Why these results matter and current gap in knowledge:

This study is excellent evidence that allele-specific ASOs can provide at least some significant improvements in symptoms. This is a landmark advance in the field. 

The process by which n-Lorem developed these treatments was originally designed for N of 1 clinical trials and is therefore not straightforward to scale to larger populations of individuals with pathogenic SCN2A variants. 

That said, other organizations are also capitalizing on this proof of concept and developing similar approaches to ensure regulatory compliance and accessibility that will be scalable and available to larger populations diagnosed with an SRD, if successful. ASOs are being developed for gain-of-function SCN2A pathogenic variants. As of now, these ASOs in development are in the preclinical phase and are currently being tested in animal and cellular models. In addition, the Aligning Research to Impact Autism (ARIA) is an innovative program partnering with academic institutions across the United States to accelerate the development and availability of genetically-based therapies for six rare genetic disorders, including SCN2A. The program will conduct a nationwide baseline clinical trial to establish the basis for the development of ASOs. Recruitment for this trial is anticipated to begin in the fall, and updates will be communicated accordingly.

Future n-Lorem treatments:

The process for n-Lorem accepting new patients for ASO therapies has not changed based on these results. Families are required to provide a copy of their genetic report along with a list of signs and symptoms of the disease when completing a patient application. For families living outside of the United States, they can also fill out a patient application if they would like the n-Lorem Foundation to retain their information for future communications if an opportunity opens up in their country of residence. For families interested in exploring further, we encourage you to visit the n-Lorem website and contact the study team directly at info@nlorem.org. 

Next steps for individuals and families: 

The FamilieSCN2A Foundation understands that topics like genetic therapies, clinical trials, and experimental treatments can be sensitive for some families, especially regarding eligibility, enrollment, and other qualifications. We want to emphasize that there is hope, not only for those currently affected by an SCN2A-Related Disorder but also for those who may be diagnosed in the future. We encourage families to consult with their medical team about their loved one’s care management before making any changes to treatment, participating in a clinical trial, or accessing investigational therapies.

We strongly encourage families to: 

• Sign up for our newsletter to stay up to date 
• Join the SCN2A Dragonfly Patient Registry to provide critical information for drug development
• Visit our website to learn about research and clinical trial opportunities, see key publications, and view our glossary to help understand research vocabulary
• Share questions in our SCN2A Global Support Network 
• Refer your medical team to our clinician information page and SCN2A Learning Portal
• Participate in the upcoming EL-PFDD meeting with the FDA on October 23, 2026

Final words: 

We ensure that families who may be eligible for treatment receive the most current and reliable information to make informed decisions with their medical team. We are committed to fostering engagement and collaboration with industry partners, academic and research institutions, and non-profit initiatives that aim to develop therapeutics for rare genetic disorders, including SCN2A. With increasing momentum in SCN2A research from drug developers, industry partners, and basic science researchers, we are optimistic that a treatment for every individual living with an SRD will become available someday. We will continue to closely monitor the research and keep the community informed at every step of the journey toward treatments for SCN2A-related disorders.  

Thank you for being a part of this mighty community. 

With gratitude, 

FamilieSCN2A Foundation Team

Leah Myers – Executive Director

Jeff Cottrell – Chief Scientific Officer

Amanda Gale – Director of Programs & Operations 

Angie Weaver – Director of Philanthropy & Development 

Melody Kisor – Director of Advocacy & Education 

Morgan Weberg – Research Coordinator