Tuberous Sclerosis Complex (TSC) mouse model – Tsc1 Mouse Model (Tsc1 fl/fl-Camk2aCreERT2)
Evaluate the efficacy of novel therapeutics for TSC using the inducible, neuron-specific Tsc1 CamK2a-CreERT2 mouse model developed by the Elgersma labTsc1 mouse model key characteristics
Tsc1 mouse models are established preclinical tools for evaluating the efficacy of therapeutics for Tuberous Sclerosis Complex (TSC), a rare genetic disorder characterised by mTOR pathway dysregulation and multi-system tumour formation. Several Tsc1 mouse models are available for preclinical efficacy testing of novel TSC therapeutics, targeting different organ systems and disease manifestations — from renal and pulmonary pathology to the neurological phenotype, including epilepsy.
InnoSer offers preclinical research studies using a brain-specific, conditional, tamoxifen-inducible Tsc1fl/fl-Camk2a-CreERT2 (also referred to as the Tsc1-Cre+) mouse model, originally developed (Koene et al., 2019) and extensively characterized (Koene et al., 2021) by the lab of Prof. Ype Elgersma.
In this Tsc1 mouse model, conditional, tamoxifen-inducible homozygous Tsc1 deletion in forebrain excitatory neurons (CaMKIIα+) models the somatic bi-allelic mutations in TSC patients that are thought to be drivers for the epileptogenesis. Loss of bi-allelic Tsc1 results in mTORC1 hyperactivation, recapitulating the TSC1-mTORC1 signalling dysregulation that drives epileptogenesis. This provides a mechanistically relevant platform for evaluating interventions targeting this pathway.
Following the conditional deletion of Tsc1 in adolescent or adult mice, spontaneous seizures emerge within a well-defined time window. Moreover, the response to multiple anti-epileptic drugs (AEDs) mirrors the response seen in patients of TSC, with treatments that are most effective in the clinic also working best in the mouse model. In addition, like in TSC patients, most drugs can only suppress seizures in the Tsc1 mouse model to some extent (Koene et al., 2019), further highlighting the model’s translational relevance for novel drug development.
✓ The neuronal-specific, inducible Tsc1-Cre+ model (Koene et al., 2019; Koene et al., 2021) is exclusively offered at InnoSer in close collaboration with the lab of Prof. Dr. Ype Elgersma
✓ Tsc1 mice show robust, predictable seizure development ~ 8 days after Tsc1 deletion
✓ Following 12-18 days after Tsc1 deletion, mice die from SUDEP, enabling fast efficacy assessment
✓ The conditional, inducible Tsc1 deletion allows controlled disease onset at virtually any age – from juvenile to adult – enabling preventative and symptomatic study designs
✓ Key readouts include delay of epilepsy onset, delay of SUDEP, and epileptic frequency (monitored 24/7)
✓ Preclinical efficacy studies using the Tsc1 mouse model form a key part of our expertise in rare genetic neurological disorder models, including Fragile X syndrome, vanishing white matter (eIF2B), STXBP1 encephalopathy, Kabuki Syndrome, Phelan-McDermid syndrome, and Angelman syndrome
As a preclinical CRO with expertise in performing preclinical efficacy studies across multiple rare genetic disorders, InnoSer offers the scientific expertise, flexibility, and fast study start times to support your TSC drug development program. We support you in identifying new drug candidates, characterising their pharmacological properties, and conducting rigorous safety and efficacy studies — with direct access to the scientific team who has developed and validated the model you are working with.
Evaluate your target across epileptogenesis and seizure states in the Tsc1 mouse model
The Tsc1 mouse model combines inducible, neuron-specific disease onset with a time-resolved transcriptomic dataset — enabling you to assess whether your target is relevant in early epileptogenesis, established seizures, or both. From the lab of Prof. Ype Elgersma, PhDThe Elgersma lab generated a time-resolved RNA-seq dataset in the Tsc1 mouse model, capturing transcriptomic changes across two disease stages — early epileptogenesis and established seizures — including a rapamycin-treated arm. Transcriptomic profiling across disease stages reveals dynamic regulation of ion channels, synaptic signaling, and mTOR-related pathways (Koene et al., 2021).
Use this resource to assess the relevance of your targets of interest and identify opportunities for mechanism-driven therapeutic development.
Heatmap depicting the z scores of the 56 genes identified that are significantly up- or downregulated in Tsc1-Cre+ mice over time (for more details refer to Figure 8 of Koene et al., 2021)
Tsc1 mouse model validation datasets
Tsc1 mice develop tonic–clonic seizures in a narrow time window
Tsc1 deletion in female and male Tsc1-Cre+ mice aged 12-20 weeks old was induced via 4-day tamoxifen dosing protocol (i.p.). Brain activity was continuously monitored by using a wireless EEG device from the day of the first tamoxifen injection (A) EEG recordings show that all Tsc1-Cre+ mice develop epilepsy between 6 and 12 days after initiation of gene deletion. (B) Tsc1-Cre+ mice die from SUDEP (sudden unexpected death in epilepsy) 12–18 days after Tsc1 deletion.
Figures obtained with permission from the original publication (Koene et al., 2019)
Treatment with the mTOR inhibitor, Rapamycin, leads to amelioration of the epileptic phenotype of Tsc1 mouse model in a dose-dependent manner
Tsc1 deletion in female and male Tsc1-Cre+ mice aged 12-20 weeks old was induced via 4-day tamoxifen dosing protocol (i.p.). Mice were treated 4 days after gene deletion. (A) A delayed seizure onset is observed in mice treated with 3 mg/kg and 5 mg/kg rapamycin compared to Tsc1-Cre+ vehicle control mice and mice treated with 1 mg/kg rapamycin. (B) All mice treated with 3 mg/kg or 5 mg/kg rapamycin stayed alive as long the treatment lasted.
Figures obtained with permission from the original publication (Koene et al., 2019)
Pretreating Tsc1-Cre+ mice with standard-of-care AEDs does not prevent epileptogenesis, mirroring clinical outcomes in TSC population
Preventative treatment using vigabatrin (200 mg/kg), the commonly used AED to treat infantile spasms in TSC-infants, significantly delays (A) seizure onset and (B) lowers seizure frequency but does not prevent epileptogenesis in Tsc1-Cre+ mice. Tsc1 deletion in female and male Tsc1-Cre+ mice aged 12-20 weeks old was induced via 4-day tamoxifen dosing protocol (i.p.). Tsc1- Cre+ mice received daily drug injections starting on day 4 after gene deletion, with vehicle-treated mice serving as controls.
Figures obtained with permission from the original publication (Koene et al., 2019)
Key readouts in the Tsc1 mouse model
The People Behind Your Research
Prof. Dr. Ype Elgersma
External Consultant TSC
Prof. Dr. Ype Elgersma
Prof. Dr. Ype Elgersma is a Professor of Molecular Neuroscience, Chair of Research and Education, Dept. of Clinical Genetics, and Scientific Director at ENCORE Expertise Centre for Neurodevelopmental Disorders. Prof Elgersma acts as an advisor to InnoSer’s clients running preclinical efficacy Tuberous Sclerosis Complex (TSC) studies. His lab has developed and extensively characterized the Tsc1- cre+ mouse model, which has since been used in multiple preclinical intervention studies targeting TSC-related epilepsy.
Frequently Asked Questions
How does the Tsc1 Cre mouse model of TSC differ from other available mouse models?
The Tsc1-Cre+ model is a brain-specific, tamoxifen-inducible mouse model that allows controlled deletion of the Tsc1 gene specifically in forebrain excitatory neurons (CaMKIIα+). This results in spontaneous tonic-clonic seizures approximately 8 days after induction, closely recapitulating the epileptic phenotype seen in TSC patients.
Unlike constitutive knockout models, the conditional design allows precise control over the timing of Tsc1 gene deletion, enabling you to induce disease onset at different developmental stages, from juvenile to adult mouse. This enables you to perform both preventative studies to evaluate where your compound can prevent or delay seizure onset, or alternatively perform symptomatic treatment studies to assess the reduction of seizure burden and frequency in mice with established epilepsy.
Unlike astrocyte-targeted models, where Tsc1 deletion occurs in glial cells, or whole-brain Tsc1 knockouts affecting multiple cell types, the CaMKIIα-driven model selectively targets forebrain excitatory neurons. This neuron-specific deletion recapitulates the TSC1–mTORC1 signalling dysregulation that drives epileptogenesis, providing a mechanistically relevant platform for evaluating interventions aimed at this key pathway (Koene et al., 2019).
Importantly, brain-specific Tsc1 deletion circumvents the early lethality that was observed in earlier systemic or biallelic whole-body Tsc1 knockout mouse models (Abs et al., 2013), thereby enabling longitudinal studies and chronic treatment paradigms in adult animals.
Contact our expert team to discuss how this model can fit your specific preclinical study design.
Has disease modification been shown in the Tsc1 mouse model?
The Tsc1 mouse model has been validated by the lab of Prof. Ype Elgersma, demonstrating response to standard-of-care therapeutic interventions for TSC-associated epilepsy, namely rapamycin, the anti-epileptic drugs (AED) (i.e., vigabatrin, clobazam, tigabine, valproic acid, lamotrigine) and ketogenic diet (Koene et al., 2019).
Rapamycin (sirolimus) and its derivatives (rapalogs) are effective treatments for TSC by inhibiting the mTOR pathway, with reports showing reduction of tumor sizes, skin lesion treatment and management of epilepsy. The original publication has shown that treating Tsc1 mice with rapamycin delays seizure onset, as well as SUDEP as all mice treated with 3 mg/kg or 5 mg/kg rapamycin stayed alive as long as the treatment lasted (See figure 4 of Koene et al., 2019).
Pretreatment with multiple standard-of-care AEDs led to variable responses, mirroring the clinical reality that the majority of TSC patients do not respond to currently available anti-epileptic therapies, highlighting the model’s translational relevance for novel drug development. Accordingly, Vigabatrin, a first-line AED for infantile spasms used in TSC-associated epilepsy in humans, has significantly delayed seizure onset, and seizure frequency, albeit it did not prevent epileptogenesis in the Tsc1 mouse model. Furthermore, several commonly used AEDs (e.g., clobazam, tiagabine, valproic acid, lamotrigine) were tested prophylactically in the Tsc1 mouse model. None prevented epileptogenesis, and some had little or no effect on underlying mTORC1 signaling (Koene et al., 2019).
Lastly, ketogenic diets are frequently used in patients with drug-resistant epilepsy, including TSC, and have been reported to reduce seizure frequency in some cases (Ulamek-Koziol et al., 2019). In the Tsc1 mouse model, a ketogenic diet delayed seizure and extended survival compared to standard diet, albeit it did not significantly reduce seizure frequency (Koene et al., 2019), consistent with clinical evidence of seizure reduction in some patients.
At what age is Tsc1 deletion induced in the Tsc1 mouse model?
While Tsc1 deletion is commonly induced at 8-10 weeks of age, Tsc1 deletion can be performed at any age (from juvenile to adult mouse), allowing you to design preclinical studies that either test preventative strategies aimed at preventing epileptogenesis, as well as symptomatic interventions to reduce seizure burden in mice with an established epilepsy phenotype.
Reach out to our team to discuss how you can tailor your study design using the Tsc1 mouse model.
Is the Tsc1 mouse model suitable to evaluate multi-systemic therapies for Tuberous Sclerosis Complex (TSC), such as kidney involvement?
The Tsc1 model is a neuron-specific, inducible model whereby Tsc1 deletion is restricted to forebrain excitatory neurons (CaMKIIα+), meaning the model does not develop the renal, pulmonary, or dermatological manifestations seen in TSC patients. It has been developed specifically to model the epilepsy phenotype affecting 80-90% of TSC patients, and is characterized by spontaneous seizures and SUDEP. Therefore, the Tsc1 mouse model is relevant for programmes targeting TSC-related epilepsy and the mTORC1 signalling axis in the brain.
What types of therapies for Tuberous Sclerosis Complex (TSC) can be tested in the Tsc1 mouse model?
The Tsc1 mouse model supports evaluation of a broad range of therapeutic approaches targeting TSC-related epilepsy:
- mTOR pathway inhibitors for TSC: Mechanistically targeted mTOR pathway inhibitors, including rapamycin analogues and next-generation selective mTORC1 inhibitors, can be benchmarked against the model’s validated rapamycin response.
- Novel anti-epileptic drug (AED) compounds: the model’s responsivity to standard-of-care AEDs such as vigabartin mirrors clinical non-response rates in TSC patients and supports identification of novel compounds with superior efficacy.
- Novel ASO and oligonucleotide approaches for TSC: the model is compatible with ICV delivery and repeated dosing alongside continuous EEG monitoring via Neurologger implants, making it directly relevant for oligonucleotide programmes targeting the TSC1–mTORC1 pathway.
Is the Tsc1 mouse model relevant for companies developing mTOR pathway inhibitors beyond TSC?
The mTOR pathway is dysregulated across a broad range of diseases beyond TSC, including polycystic kidney disease, neurofibromatosis type 1, and certain cancers. The Tsc1-Cre+ model provides a well-validated, mechanistically grounded platform for benchmarking novel mTOR inhibitors against the established rapamycin response, making it directly relevant for programmes developing next-generation mTORC1 inhibitors, rapalogs, or dual mTORC1/mTORC2 inhibitors where TSC-related epilepsy is either the primary indication or a key proof-of-concept setting.
For companies targeting mTOR in the context of renal diseases, our ADPKD mouse model may also be a relevant complementary platform.
Contact our team to discuss how the Tsc1 model fits into your broader mTOR programme.
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