Introduction

Despite advances in anti-seizure medications (ASMs), approximately 30%–40% of people with epilepsy continue to experience uncontrolled seizures, highlighting a substantial unmet need for novel therapeutic strategies.¹

Gene therapy is emerging as a potential disease-modifying strategy, which aims to address the molecular and network-level drivers of epileptogenesis and chronic hyperexcitability. Two principal approaches are under investigation: (1) augmenting or activating genes with antiseizure or neuroprotective effects, and (2) silencing or downregulating genes and pathways that contribute to neuronal hyperexcitability.¹

In parallel, cell-based therapies are also being explored as circuit-restorative strategies to reduce seizure burden through transplantation of mesenchymal stem cells (MSC), bone marrow-derived mononuclear cells, neural stem cells, and MSC-derived exosomes.²

Gene therapy for monogenic epilepsies

Dravet syndrome (DS) is a developmental epileptic encephalopathy (DEE) caused by loss-of-function variants in the SCN1A gene, leading to impaired inhibitory interneuron activity and network hyperexcitability. ETX101 is an adeno-associated virus serotype 9 (AAV9)-based gene therapy designed to selectively increase SCN1A expression in GABAergic interneurons, correcting circuit dysfunction while minimizing off-target effects.³

Interim safety and preliminary efficacy results from the ongoing Phase I/II POLARIS program were presented at the 2025 American Epilepsy Society Annual Meeting. The program comprises three open-label, dose-escalation studies (ENDEAVOR; NCT05419492, WAYFINDER; NCT06112275, and EXPEDITION; NCT06283212) in children aged six months to seven years with SCN1A-positive DS receiving standard-of-care ASMs.⁴

As of June 1, 2025, 11 participants had received a single intracerebroventricular administration, with follow-up extending up to 58 weeks. No treatment-related serious adverse events (SEAs) or dose-limiting toxicities had been reported. Early data demonstrate dose-dependent reductions in seizure burden and rescue medication use, with a median 87% reduction in monthly countable seizure frequency at the highest dose (range 47–90%) during the evaluable post-dose period (Week 5–≥12). These preliminary findings support continued development of the first clinical investigation of a one-time, cell-type–selective gene regulation therapy for DS.⁴

In addition, AAV-mediated gene replacement is being explored for other ultra-rare monogenic DEEs, including SLC13A5 citrate transporter disorder. TSHA-105 is an AAV9-based gene therapy designed to express a fully functional SLC13A5 gene under the control of a synthetic promoter, with the goal of achieving stable, potentially life-long expression in non-dividing cells following a single lumbar intrathecal administration. The ongoing Phase I/II open-label study (NCT07102524) is evaluating the safety and efficacy of TSHA-105 in two individuals with genetically confirmed SLC13A5 citrate transporter disorder, representing a pivotal early clinical effort to translate gene replacement therapy into this severe, early-onset DEE.⁵

Gene therapy for focal epilepsies

Mesial temporal lobe epilepsy (MTLE) is the most common focal epilepsy, caused by recurrent seizures originating in the hippocampus. AMT-260 is an AAV9-based gene therapy that delivers engineered microRNAs to reduce aberrant GluK2 receptor expression in the epileptogenic hippocampus, targeting a key mechanism involved in seizure generation.⁶

AMT-260 is being evaluated in the ongoing GenTLE Phase I/IIa, multi-center, open-label trial (NCT06063850) in individuals with refractory MTLE. The study includes two dose cohorts of six patients each across multiple U.S. sites. A case study of the first participant treated showed a 92% reduction in seizure frequency, decreasing from an average of seven seizures per month pre-treatment to two seizures over the five-month period post-administration. No SEAs were reported, providing an encouraging early signal of safety and potential efficacy in this drug-resistant population.⁷

An alternative focal gene therapy strategy, which employs lentiviral-mediated delivery of an engineered potassium channel (EKC) to directly reduce neuronal hyperexcitability at the seizure focus, is currently being investigated. The ongoing Phase I/IIa, first-in-human, open-label trial (NCT04601974) is evaluating the safety of this approach in patients with refractory neocortical epilepsy who are already undergoing evaluation for surgical resection. The trial plans to enroll 10 participants, with an estimated primary completion in 2028.⁸

Cell-based and circuit restorative therapies

Cell-based and circuit-restorative approaches represent a new frontier in epilepsy treatment. Rather than targeting individual genes, these strategies aim to rebalance neuronal networks and are now advancing into early clinical studies.

NRTX-1001 is an allogeneic GABAergic interneuron product derived from human pluripotent stem cells, aiming to directly address the imbalance between excitation and inhibition that underlies MTLE.⁹ A first-in-human, open-label study (NCT05135091) investigated this agent in adult participants with drug-resistant unilateral MTLE. Participants received a one-time stereotactic hippocampal administration of NRTX-1001 with peri-procedural immunosuppression. Updated results presented at the 2025 American Academy of Neurology (AAN) Annual Meeting demonstrated that, among five patients in the low-dose cohort with at least 6 months follow-up, disabling seizure frequency was reduced by 82% during months 4–6 post-treatment. Four of five patients (80%) achieved ≥50% responder status. No treatment-related SEAs were reported, and preliminary assessments suggested potential improvements in selected memory measures.¹⁰

Building on these data, a separate Phase I/II multicenter, open-label trial in adults with drug-resistant bilateral MTLE (NCT06422923) has been initiated. This study will enroll 10 patients who will receive bilateral intracerebral administration of NRTX-1001, with follow-up for two years. The first patient has been dosed, with no significant surgical complications or adverse events reported to date.¹¹ Plans for the Phase III EPIC trial have also been announced, developed following discussions with the FDA under the Regenerative Medicine Advanced Therapy (RMAT) designation. Data from the Phase I/II and Phase III programs in both unilateral and bilateral MTLE are intended to support a future marketing application for NRTX-1001 in drug-resistant MTLE.¹¹

Other cell-based strategies are also under early clinical investigation in drug-resistant epilepsy including a single-center, non-randomized Phase I study (NCT06638970), which is evaluating the safety and clinical utility of human umbilical cord MSC-derived secretome injections and assessing the effects on seizure frequency and duration.¹² As well as this, an exploratory open-label trial (NCT05886205) is investigating induced pluripotent stem cell-derived exosomes (GD-iEXo-002) administered as nasal drops for refractory focal epilepsy, leveraging the low immunogenicity and blood-brain barrier permeability of exosomes to deliver bioactive factors with potential anti-inflammatory and neuroprotective effects.¹³ Together, these approaches reflect a broader effort to modulate activity at the circuit level, directly targeting neuronal networks to restore the balance between excitation and inhibition in drug-resistant epilepsy.

Future Directions

Gene and cell-based therapies for epilepsy have demonstrated significant promise in preclinical and early clinical studies, particularly for drug-resistant disease, but substantial challenges remain before they can become mainstream treatments. For gene therapy, key hurdles include achieving safe and efficient delivery across the blood-brain barrier, ensuring durable yet controllable gene expression, minimizing off-target effects, and managing immune responses to viral vectors.¹ Cell-based approaches face additional complexities, including ensuring long-term survival and functional integration of transplanted cells, avoiding tumorigenicity or cognitive adverse effects, and overcoming manufacturing, scalability, ethical, and regulatory barriers.¹ Addressing these challenges will be critical to translating the promise of these advanced therapies into safe, accessible, and durable treatment options for patients with epilepsy.

References