in this month’s update, we invite you to explore recent developments in rare neurodevelopmental disorders associated with epilepsy and seizure phenotypes. We highlight emerging therapeutic approaches, discuss the importance of selecting translationally relevant preclinical models, and share how InnoSer is expanding its capabilities to support research in this rapidly evolving field.

Rare disease drug development is gaining momentum as advances in genetics and diagnostics continue to improve our understanding of disease mechanisms and uncover new therapeutic opportunities. Translating these discoveries into effective therapies requires preclinical models that faithfully reflect human disease biology. At InnoSer, we provide access to validated rare disease models that help accelerate preclinical research and support informed drug development decisions.

Below we spotlight three rare neurodevelopmental disorders, tuberous sclerosis complex (TSC), Rett syndrome, and STXBP1 syndrome, that illustrate this evolution in therapeutic development. While all three can present with overlapping clinical features, including epilepsy, developmental delay, and intellectual disability, they arise from distinct genetic and molecular mechanisms.

Understanding those differences is critical for selecting the right preclinical model and evaluating next-generation therapeutic strategies designed to target the underlying disease mechanism

Now offering: A validated TSC seizure model

Tuberous sclerosis complex (TSC) is driven by loss-of-function variants in TSC1/TSC2 that dysregulate the mTOR pathway. The disease is highly heterogeneous, with patients presenting a broad spectrum of neurological and systemic manifestations, including epilepsy, intellectual disability, autism spectrum disorder, and lesions affecting multiple organs. Despite mTOR inhibitors such as everolimus, refractory epilepsy still affects up to two-thirds of patients (Curatolo et al., 2018; Furber et al., 2025).

In collaboration with Prof. Ype Elgersma’s laboratory, where the model was originally developed, InnoSer exclusively offers access to the Tsc1fl/fl-Camk2a-CreERT2 mouse model as part of our expanding neurodevelopmental disorder and epilepsy portfolio, alongside the Mecp2 and STXBP1 syndrome models.

MODEL HIGHLIGHTS:

• Predictable spontaneous seizure development, enabling assessment of seizure onset, frequency, and survival
• Demonstrated responsiveness to vigabatrin, mTOR-targeting therapies, and ketogenic diet interventions
• Applicability for the evaluation of gene therapy approaches, including AAV-mediated gene replacement strategies

New validation: Spike-Wave Discharges (SWDs) in the Mecp2 Model of Rett syndrome

Rett syndrome is caused primarily by loss-of-function mutations in MECP2, leading to intellectual disability, motor dysfunction, and epilepsy after a period of apparently normal development in children. The disorder primarily affects females, who are typically heterozygous for the mutation — carrying one mutant and one functional copy of the gene. The 2023 FDA approval of trofinetide treats downstream symptoms, but doesn’t restore MECP2 function itself — leaving gene-level correction a promising opportunity for therapeutic intervention (FDA., 2023; Samanta et al., 2026).

Translating advanced genetic therapeutic strategies into effective treatments requires preclinical models that faithfully reproduce the disease biology, including readouts that translate to the clinic. The Mecp2 model exhibits spontaneous spike-wave discharges (SWDs), giving a direct, quantifiable readout of the network dysfunction underlying Rett syndrome’s epilepsy phenotype. This makes it relevant both to companies developing MECP2 mutation-specific interventions and to platform companies developing anti-epileptic therapies for developmental and epileptic encephalopathies (DEEs) more broadly.

MODEL HIGHLIGHTS:

• Confirmation of characteristic spike-wave discharges associated with Rett syndrome-related network dysfunction
• Pharmacological responsiveness to lamotrigine and levetiracetam, two antiepileptic therapies used to treat Rett syndrome patients
• Robust longitudinal EEG assessment, with SWDs consistently detectable from 15 to at least 27 weeks of age, providing a broad treatment window for therapeutic evaluation

In collaboration with the STXBP1 Foundation: A Newly validated patient-variant model of STXBP1

STXBP1 syndrome is caused by pathogenic variants in the STXBP1 gene (or Munc18-1), driving early-onset epilepsy, developmental delay, and movement abnormalities that often persist despite anti-seizure treatment.

Understanding of the disease biology has advanced and therapeutic development has expanded beyond symptomatic management to include approaches designed to address the underlying molecular defect. Gene replacement, antisense oligonucleotide (ASO) therapies, readthrough compounds, and genome-editing strategies are all being explored. This has increased the need for preclinical models that reflect the specific disease mechanism targeted by each therapeutic approach (Ruano-Rodríguez et al., 2025; Goss et al., 2024).

InnoSer supports the development of next-generation STXBP1-targeted therapeutics by offering a platform for complementary preclinical models. In addition to the established Stxbp1+/− haploinsufficiency model, InnoSer recently participated in the validation of the novel Stxbp1_R122X patient-variant model, developed through a collaboration led by the STXBP1 Foundation. Together, these models enable the evaluation of both gene restoration and mutation-specific therapeutic approaches.

MODEL HIGHLIGHTS:

• Stxbp1+/− haploinsufficiency model: suitable for therapies aimed at restoring or increasing STXBP1 expression, including gene replacement and ASO-based approaches
• Stxbp1_R122X patient-variant model: supports evaluation of variant-targeted strategies, including stop-codon readthrough, mutation-specific ASOs, base editing, and NMD inhibition
• Both models are characterized using wireless EEG, video monitoring, and accelerometer recordings in freely moving animals

The evolving landscape of rare neurological disease research

TSC, Rett syndrome, and STXBP1 syndrome present a broadly similar clinical picture, but reflect three distinct disease mechanisms, and each still has a clear unmet need: refractory epilepsy in TSC despite mTOR inhibition, symptom-focused rather than MECP2-restoring treatment in Rett syndrome, and a haploinsufficiency model that, on its own, cannot inform variant-specific therapies in STXBP1 syndrome. Matching a preclinical model to the specific mechanism, and to the specific gap in current treatment, is what allows the next generation of therapies in each disease to be evaluated in the correct biological context.

As therapeutic approaches become increasingly precise, the requirements for preclinical models continue to evolve alongside them. We continue to expand and characterize our rare disease portfolio to support drug developers working across a broad range of mechanisms, from pathway modulation and symptom management to gene replacement, RNA editing, and other disease-modifying strategies.

Ready to elevate your preclinical research? Let’s work together to ensure your novel therapies achieve optimal clinical outcomes.  

Working on a rare neurological disease program such as TSC, Rett syndrome, and STXBP1 syndrome?

Our team is happy to discuss how model selection, study design, and endpoint strategy can be aligned with the therapeutic mechanism under investigation.