RNA targeting therapy for a prenatally enriched potassium channel associated with severe childhood epilepsy and premature death

Nature Communications · 2026-04-29

Abstract Dysfunction of the sodium-activated potassium channel K Na 1.1 (encoded by KCNT1) is associated with a severe neurodevelopmental condition characterized by frequent seizures (up to hundreds per day), treatment resistance, and increased mortality during childhood. Yet, recent progress with an RNA therapy targeting KCNT1 offers clinical promise 1 . We characterize the early developmental onset of K Na 1.1 channels in prenatal and neonatal brain tissue, establishing a timeline for pathophysiology and a window for therapeutic intervention. Using patch-clamp electrophysiology, we observe functional prenatal K Na 1.1 conductance that is developmentally regulated. In excitatory and inhibitory neurons derived from a child’s induced pluripotent stem cells with a KCNT1 pathogenic variant (p.R474H), we detect gain-of-function K + currents. We use an antisense oligonucleotide RNA therapy developed for two individuals with the p.R474H variant—which results in dramatic reductions in seizure occurrence and severity 1 —to profile cellular neurophysiology in patient-derived excitatory and inhibitory neurons. We observe a knockdown of p.R474H gain-of-function K + currents, resulting in a stimulation-dependent change in spiking output in patient-derived induced excitatory and inhibitory neurons. In mid-gestation primary human neurons, ASO knockdown suppresses current-evoked firing, suggesting a potential early therapeutic target before the onset of infantile encephalopathy.

Paying for precision: funding approaches for N-of-1 trials of individualized gene targeted therapies

Orphanet Journal of Rare Diseases · 2026-05-21

Individualized medicine has the potential to be a transformative approach to healthcare that tailors medical treatments to the unique makeup of each patient. This report explores the potential of individualized genetic medicines to meet the pressing need for effective treatments for individuals with rare genetic diseases, and funding models to support these treatments. Although recent successes have been achieved, significant administrative and financial challenges remain in implementing individualized treatment trials. This report investigates funding associated with such therapeutics. Funding challenges, key strategic operational factors, potential payor support, historic funding models, and ethical elements ultimately leading to financial support of patient treatment are considered. By addressing these questions, this report aims to provide an overview of the complex issues surrounding individualized medicine, offering insights into balancing its promises with practical and ethical considerations as the field and associated funding models continue to evolve.

Antisense oligonucleotide-mediated knockdown therapy in two infants with severe KCNT1 epileptic encephalopathy

Nature Medicine · 2026-04-01

KCNT1-related epileptic encephalopathy, including epilepsy of infancy with migrating focal seizures, is a severe neurodevelopmental disorder associated with refractory seizures, profound neurologic impairment and premature death. It is caused by de novo genetic variants in KCNT1 that alter the function of Slack, an evolutionarily conserved sodium-gated potassium channel that modulates neuronal firing patterns and excitability. Pathogenic KCNT1 variants lead to overactive Slack channels, boosting total neuronal potassium currents by up to 40%, driving cortical hyperexcitability and causing seizures. Here we investigate antisense oligonucleotide-mediated KCNT1 knockdown as a therapeutic strategy for patients with epilepsy of infancy with migrating focal seizures. Intrathecal delivery of an experimental, non-allele-specific, KCNT1-targeting antisense oligonucleotide by lumbar puncture in two 2-year-old females with KCNT1 p.R474H, a severe, recurrent pathogenic variant, led to a significant reduction in seizure frequency and intensity. However, investigational treatment was also associated with the development of ventricular enlargement or hydrocephalus in both patients, prompting in one case the redirection of goals of care, pointing to a potential monitorable toxicity of some intrathecal antisense oligonucleotides.

Understanding perspectives of safety-net NICU neonatologists disclosing genomic sequencing results: a mixed methods approach

Journal of Perinatology · 2026-05-05

OBJECTIVE: Examine neonatologists' perspectives on disclosing rapid genomic sequencing (rGS) results, including the barriers and facilitators they perceive. STUDY DESIGN: Neonatologists from 10 NICUs participating in the Virtual Genome Center (VIGOR) study were surveyed after each rGS disclosure and interviewed regarding their experience after 2 or more disclosures. Quantitative results were compared by result type, and qualitative results were iteratively coded for themes. RESULTS: 93% of neonatologists felt comfortable disclosing rGS results regardless of result type. Neonatologists utilized multiple resources to prepare for disclosures, including the VIGOR Clinical Interpretive Report, medical literature, and local genetics experts. They preferred to have a geneticist present during disclosure when possible. Neonatologists were motivated to participate in disclosures to help families and leverage existing trust. CONCLUSION: Neonatologists are important to the rGS disclosure experience, but a joint effort with genetics experts may be the ideal model to successfully expand access. TRIAL REGISTRATION NUMBER: NCT05205356/clinicaltrials.gov .

Words about Words

Modern Language Quarterly · 2025-01-28 · 1 citations

P581: Customized “clinical interpretive reports” of genomic sequencing results for non-genetics providers in safety-net neonatal intensive care units: Development and implementation

Genetics in Medicine Open · 2025-01-01

Rapid genomic sequencing (rGS) has high diagnostic and clinical utility in Neonatal Intensive Care Units (NICUs). However, safety-net NICUs that disproportionately serve marginalized populations face barriers that limit access to rGS, including limited genetics expertise, high cost, and complicated logistics. The Virtual Genome Center (VIGOR) study is an implementation study that aims to address these barriers by providing rGS in safety-net NICUs using an innovative virtual delivery model. In the VIGOR study, neonatal providers with often limited genetics expertise who work in safety-net NICUs disclose rGS results to families.

Individualized therapy development for rare diseases: individualized at every step of the way

Therapeutic Advances in Rare Disease · 2025-10-01

Patient-Oriented Priorities for Pediatric Erythromelalgia: A Priority-Setting Process

Children · 2025-11-02

Background/Objectives: Erythromelalgia is a rare condition characterized by burning pain, redness, and warmth primarily in the extremities, usually worsened by heat and alleviated by cold. The objective of this study was to identify the top 10 priorities in pediatric erythromelalgia from multiple perspectives, including clinicians, people with lived experience of childhood-onset erythromelalgia, and their family members. Methods: A modified James Lind Alliance Priority-Setting Process was conducted. The top priorities were identified through four phases: (1) an international online survey to gather priorities, (2) data processing, (3) an interim prioritization online survey, and (4) a virtual workshop to set the final priorities. Results: In phase 1, 185 potential priorities were submitted by 74 respondents (53% patients, 24% family members, and 23% clinicians) that were developed into 68 unique research questions (phase 2). In phase 3, of the 68 questions, 50 were rated for importance by 58 participants (38% patients, 36% family members, and 26% clinicians), reducing the list to 25 questions. In phase 4, the top 10 was reached through consensus by 12 participants (33% patients, 25% family members, and 42% clinicians) across Canada, South Africa, the United States of America, and the United Kingdom. Conclusions: The final priorities focused on the treatment of erythromelalgia, understanding underlying mechanisms, the association of erythromelalgia with various body systems, and generating awareness. This list is the first international patient-centered research agenda for childhood-onset erythromelalgia and a call to action from key partners to improve future research and care.