RARE DISEASE
Tuberous sclerosis complex
Tuberous sclerosis complex
Tuberous sclerosis complex
Synonyms: Bourneville syndrome, Tuberous sclerosis
Synonyms: Bourneville syndrome, Tuberous sclerosis
Synonyms: Bourneville syndrome, Tuberous sclerosis
Drug discovery
19
drugs
With orphan designations
Overview
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder caused by TSC1 or TSC2 gene mutations, leading to mTOR pathway dysregulation and multi-organ hamartomas. Clinical features include epilepsy, TSC-associated neuropsychiatric disorders (TAND), renal angiomyolipomas, cardiac rhabdomyomas, and dermatologic manifestations. Diagnosis involves genetic testing and clinical criteria, with surveillance for systemic complications [1][2][18].
Burden
Economic burden: Annual healthcare costs exceed €11,000 per patient with epilepsy, driven by medications, hospitalizations, and specialist care [4][9][14].
Morbidity/mortality: Neurologic sequelae (90% epilepsy, 40–50% intellectual disability) and renal complications are leading causes of morbidity; mortality linked to seizures, renal failure, or SEGAs [1][4][14].
Quality of life: TAND affects ~85% of patients, contributing to educational/career disruptions and caregiver strain [1][14].
Therapies
mTOR inhibitors (sirolimus, everolimus): Reduce tumor growth, manage refractory epilepsy, and improve pulmonary/renal outcomes [8][10][13].
Epilepsy management: Antiseizure medications (e.g., vigabatrin for infantile spasms), surgical resection of epileptogenic foci, and early seizure control to mitigate cognitive deficits [3][8][13].
Multidisciplinary care: Dermatologic interventions (e.g., mTOR inhibitor creams), renal surveillance, and neurodevelopmental support [6][13][16].
Categories: rare circulatory system diseases, rare developmental anomalies during embryogenesis, rare genetic diseases, rare neoplastic diseases, rare neurological diseases, rare renal diseases, rare skin diseases, rare transplant-related disorders
Research Papers
2,502 drug discovery papers about Tuberous sclerosis complex, with 2 first-in-class and 29 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2,502 drug discovery papers about Tuberous sclerosis complex, with 2 first-in-class and 29 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-06 | [Extremely severe pulmonary lymphangioleiomyomatosis with combined brain, liver, kidney, and lung involvement: a case report].
We reported a case of extremely severe tuberous sclerosis complex-associated lymphangioleiomyomatosis (TSC-LAM) involving the brain, liver, kidneys, and lungs that was successfully treated with sirolimus, with a complete 17-year follow-up. The patient was diagnosed in 2008 and experienced rapid progression; by 2012, the patient had developed respiratory failure, severe anemia, renal insufficiency, and extreme abdominal distension. After 3 days of treatment with sirolimus, the aforementioned symptoms improved significantly, and respiratory failure resovled. Over the following 7 years of regular maintenance therapy, lung function declined only slightly each year, and the 6-minute walking test(6MWT) showed no decline. However, after sirolimus was discontinued from January 2020 to April 2021, the patient's lung function and 6MWT declined rapidly, with concurrent development of pneumothorax. Although sirolimus was subsequently resumed and remained effective, with no recurrence of pneumothorax or chylothorax, parameters such as lung function and 6MWT still did not recover significantly. This case suggests that TSC-LAM requires long-term maintenance therapy with sirolimus. Abrupt discontinuation of treatment may lead to rapid clinical deterioration.
2026-07-29 | A systematic review of highly purified cannabidiol in developmental and epileptic encephalopathies and complex treatment-resistant epilepsies: Nonseizure outcomes.
A plant-derived, highly purified cannabidiol (CBD) oral solution (Epidiolex® [US]/Epidyolex® [EU]) is approved for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC). Improvements in nonseizure outcomes including cognition and behavior have been reported in patients with epilepsy administered CBD. This systematic literature review (SLR) evaluated studies reporting changes in nonseizure outcomes after CBD initiation in patients with developmental and epileptic encephalopathies (DEEs) and complex treatment-resistant epilepsies (TREs) other than LGS, DS, and TSC. An SLR was conducted in March 2024 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Embase, Medline, and Cochrane Central Register of Controlled Trials libraries were searched for studies on TREs, CBD, nonseizure outcomes, and adverse events (AEs). Results were narratively summarized. Thirty-two studies comprising 1343 patients were included. Thirty-one studies reported improvement in nonseizure outcomes in ≥ 1 patient, including neuropsychiatric function (n = 9/9 studies), cognitive function (n = 9/9), use of concomitant antiseizure medications (n = 7/8), communication (n = 7/7), behavior (n = 7/7), motor function (n = 6/6), healthcare utilization (n = 5/5), quality of life (n = 5/5), global change (n = 4/4), sleep (n = 2/2), and development (n = 2/2). Reported AEs were consistent with the known safety profile of CBD and most commonly gastrointestinal, including diarrhea (17-34%), vomiting (5-50%), and decreased appetite (7-20%). This SLR mainly identified observational studies with moderate to high bias risk. The available evidence suggests CBD may improve various nonseizure outcomes in patients with DEEs and complex TREs, while underscoring the need for rigorous confirmatory studies.
2026-07-19 | Progress report on new epilepsy treatments: A summary of the Eighteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVIII). I. Treatments in preclinical and early clinical development.
Over the last 34 years, the Eilat Conference on New Antiepileptic Drugs and Devices has provided an interactive forum for stakeholders to discuss investigational and recently licensed treatments for seizures and epilepsy. The Eighteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVIII) took place in Madrid, Spain, on May 3-6, 2026. This article provides summaries of eight treatments in preclinical and early clinical development that were presented at EILAT XVIII. These include AUT00206, a positive allosteric modulator of Kv3.1 and Kv3.2 voltage-gated potassium channels in development for the treatment of rare epilepsy syndromes as well as neurodevelopmental and neuropsychiatric disorders; ION283, an antisense oligonucleotide designed to suppress the expression of glycogen synthase 1, under investigation for the treatment of Lafora disease; MSCA-7136, a selective allosteric RAS/mitogen-activated protein kinase-extracellular signal regulated kinase (MEK) inhibitor being developed for the treatment of focal seizures associated with mesial temporal lobe epilepsy and seizures associated with tuberous sclerosis complex; OV329, a selective inhibitor of γ-aminobutyric acid (GABA) aminotransferase, in development for the treatment of drug-resistant focal seizures; PTI5803 (probenecid), an uricosuric agent and a blocker of pannexin 1 channels, repurposed as a treatment for seizures associated with focal cortical dysplasia; simufilam, a filamin A modulator under investigation for the treatment of tuberous sclerosis complex-related epilepsy; SN-2000, a selective allosteric phosphodiesterase 4B inhibitor, in development for the treatment of focal seizures; and sodium selenate, a promoter of the dephosphorylation of pathological hyperphosphorylated tau in the brain, under investigation as a disease-modifying agent in mesial temporal lobe epilepsy. Treatments in more advanced clinical development are discussed in an accompanying article.
2026-07-12 | Co-Creation of the EpiCom Clinical Trial: Bringing the Tuberous Sclerosis Complex Patient Community, Healthcare Professionals, and the Pharmaceutical Industry Together.
Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) affect most patients with TSC and encompass a range of psychiatric, intellectual, neuropsychological, and behavioral manifestations of the disease. Epilepsy Comorbidities (EpiCom), an ongoing, phase 3b/4, open-label study, is assessing the effects of adjunctive therapy with a plant-derived, highly purified pharmaceutical formulation of cannabidiol (Epidiolex® [US]/Epidyolex® [EU], 100 mg/mL oral solution) on TAND, including behavioral outcomes, in participants with TSC-associated seizures. EpiCom was designed in collaboration with the TSC community including patients, caregivers, and healthcare professionals (HCPs), to incorporate stakeholder perspectives into study design and execution. To describe how collaboration among patient advocacy groups (PAGs), HCPs, and the clinical trial sponsor helped optimize the co-creation and execution of the EpiCom study. HCPs and PAG advisors, including caregivers of individuals with TSC, were identified across the USA and Europe and invited to participate in an advisory board meeting to discuss the challenges faced by the TSC community. Surveys collected PAG and HCP input on topics, including study objectives, outcome assessments, study design, eligibility criteria, and recruitment. PAG and HCP advisory board meetings were then conducted to capture patient/caregiver and HCP perspectives on the EpiCom study design, including the objectives, feasibility, resources needed for successful execution, and strategies to engage the patient community throughout the study. A joint PAG-HCP Steering Committee comprising 5 PAG representatives and 15 HCPs from the USA, Canada, and Europe was formed to guide study objectives and PAG engagement, and to provide study oversight. Advisory board meetings (9 PAG advisors; 14 HCPs) provided insight into the needs of the TSC community and ways to enhance collaboration with patients and caregivers. Feedback from the advisory boards and steering committee meetings refined the EpiCom study objectives and informed recruitment strategies, study duration, patient- and HCP-friendly study design considerations, preferred data collection methods, and communication plans. These insights supported the development of a decentralized clinical trial framework aimed at reducing participant burden and barriers. PAG input guided the decision to broaden study eligibility criteria by removing seizure severity and intelligence quotient requirements and include remote assessments to facilitate capturing data in everyday settings. HCP input guided inclusion of clinical outcome measures, including the use of the novel TAND Self-Report Quantified Checklist to assess behavioral changes. Proactively involving PAGs, caregivers, and HCPs enabled the co-creation of a study that explicitly addresses outcomes important to the broader TSC community. This patient- and caregiver-informed approach of EpiCom also highlights the need for stronger collaboration between industry and PAGs in clinical trials, including the opportunities and challenges of trial implementation. NCT05864846 (May 9, 2023).
2026-07-09 | Seizure-induced apnea causes sudden death independent of cortical spike wave discharge in mouse models of Tuberous Sclerosis Complex.
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of seizure-related mortality for people with epilepsy (PWE). Current evidence suggests that many cases of SUDEP are due to seizures that produce respiratory arrest, aka seizure-induced apnea. Patients with tuberous sclerosis complex (TSC) are at a significant risk of SUDEP, and mouse models of TSC have early mortality. Previous reports in TSC mouse models demonstrate that although Vigabatrin suppresses seizures, it does not improve survival. In other mouse models, our team has demonstrated that seizure-induced apnea occurs during tonic seizures, and that cortical spike-wave discharge (SWD) is not necessary to produce apnea during exogenously stimulated seizures. We hypothesized that seizure-induced apnea drives fatality independent of SWD in the spontaneous seizures of TSC mouse models, and this is why Vigabatrin treatment is ineffective. Two TSC mouse models were continuously monitored with electroencephalography, electrocardiography, plethysmography, and video recording to detect spontaneous seizures and SUDEP events. A subset of mice received daily Vigabatrin. Both TSC mouse models exhibited two spontaneous seizure types: clonic seizures with SWD and tonic seizures without SWD. All seizure-related fatalities were due to seizure-induced apnea. Across 21 SUDEP events, 20 occurred immediately after tonic seizures. Vigabatrin nearly eliminated clonic seizures but did not prevent tonic seizures and the concurrent apnea. In addition, Vigabatrin-treated mice exhibited cardiac signals that declined hours before SUDEP. These findings underscore the need for SUDEP-specific interventions beyond seizure suppression.
proteins
2026-05-04 | Evidence for FOXL2 Association with the Tsc1 Regulatory Region in Mice.
Ovarian reserve and reproductive life are closely linked concepts in female reproductive biology. The ovarian reserve consists of primordial follicles and refers to the number and quality of oocytes (eggs) remaining in the ovaries at any given time. Follicular dynamics shape a woman's reproductive lifespan, ultimately leading to menopause. Elucidating the underlying genetic and molecular pathways of follicle maturation and depletion is thus crucial for understanding menopausal onset and progression, both in normal and pathophysiological contexts, such as primary ovarian insufficiency, defined as menopause before the age of 40. A key factor in ovarian differentiation and fertility maintenance is FOXL2, a forkhead family transcription factor that plays a crucial role in follicle formation and development, ovarian maintenance, and sex determination. By employing a ChIP-Seq approach in mice, we identified a previously unreported binding of FOXL2 to a Tsc1 regulatory region. Our data, along with a thorough literature review, support the hypothesis that FOXL2-mediated activation of Tsc1 in granulosa cells can help maintain primordial follicles in a dormant state by suppressing mTORC1 signalling. Understanding the mechanisms behind ovarian reserve may lay the foundation for developing novel fertility preservation strategies, improving fertility treatment protocols and promoting in vitro activation of cryopreserved ovarian tissue to support folliculogenesis.
2025-07-11 | Modulation of infiltrating CD206+ macrophages restricts progression of pulmonary lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a low-grade neoplasm caused by the proliferation of tuberous sclerosis complex (TSC) 1- or TSC2-deficient LAM cells, resulting in progressive cystic lung disease. The currently approved treatment for LAM delays disease progression but the disease recurs if treatment is discontinued. Therefore, new therapeutic targets and/or strategies are necessary for a cure. Immunosuppressive M2-like macrophages are involved in the progression of various cancers, but their role in the pathophysiology of LAM and as a putative therapeutic target is unknown. To identify the different immune cell populations involved in LAM, we generated a single-cell transcriptomic map of pulmonary LAM. Interactions between macrophages and LAM cells were studied using the Visium spatial transcriptomic platform and immunofluorescence staining on human pulmonary LAM specimens. Direct co-culture models were used to characterise the influence of TSC2-deficient cells on macrophage differentiation. The efficacy of targeting M2-like macrophages was assessed in preclinical mouse models of TSC2-deficient subcutaneous tumours treated with RP-182, a synthetic peptide which reprogrammes macrophages towards an antitumour M1-like phenotype. Single-cell RNA-sequencing analysis revealed that the majority of macrophages in pulmonary LAM display immunosuppressive markers, including CD206/MRC1 and CD163. Spatial transcriptomic and immunofluorescence analyses showed that M2 macrophages are in close proximity to LAM cells and that LAM cells that are in close proximity to macrophages highly express macrophage-homing factor chemokine ligand CXCL12. In vitro, co-culture of human and mouse macrophages with TSC2-deficient cells resulted in the upregulation of M2-marker-expressing macrophages. Targeting M2 macrophages via treatment with the CD206 modulator RP-182 impaired the growth of TSC2-deficient tumours in vivo. LAM cells recruit and polarise macrophages towards an M2 phenotype. M2-like CD206high macrophages may represent a potential therapeutic target in LAM.
2025-06-25 | Cell-cell communication dysregulation in tuberous sclerosis complex cortical tubers and focal cortical dysplasia
Malformations of cortical development are manifestations of mTORopathies, including tubers in context of Tuberous Sclerosis Complex (TSC) cortical tubers and Focal Cortical Dysplasia (FCD), and are associated with epilepsy, often accompanied by comorbidities such as autism spectrum disorder (ASD). This study aims to investigate the cell-type-specific transcriptional alterations and disrupted intercellular communication networks in mTORopathies, focusing on their implications for cortical network dysfunction. Using single-cell RNA sequencing, we identified 33 transcriptionally distinct cell clusters across control and pathological samples, including neuronal, glial, and endothelial populations. Our analysis revealed disease-specific changes, such as the loss of certain glutamatergic and microglial clusters in cortical tubers (TSC), MTOR_FCD and DEPDC5_FCD, and the presence of a unique endothelial cluster in pathological samples. Pathway enrichment analysis highlighted the critical role of synaptic signaling, axonogenesis, and neuroimmune regulation in these disorders. Additionally, cell-cell communication network analysis demonstrated disrupted interactions between neuron-astrocyte, astrocyte-OPC, and microglia-neuron across mTORopathies. We found that the neurexins-neuroligins (NRXN-NLGN) signaling pathway, crucial for synapse formation and stability, was altered in both glutamatergic and GABAergic neurons, reflecting dysregulated synaptic plasticity and impaired neuron-glia communication. These findings provide novel insights into the molecular underpinnings of mTORopathies and suggest potential therapeutic targets to restore cellular communication and synaptic function in these disorders.
2025-02-12 | Ezrin defines TSC complex activation at endosomal compartments through EGFR-AKT signaling.
Endosomes have emerged as major signaling hubs where different internalized ligand-receptor complexes are integrated and the outcome of signaling pathways are organized to regulate the strength and specificity of signal transduction events. Ezrin, a major membrane-actin linker that assembles and coordinates macromolecular signaling complexes at membranes, has emerged recently as an important regulator of lysosomal function. Here, we report that endosomal-localized EGFR/Ezrin complex interacts with and triggers the inhibition of the Tuberous Sclerosis Complex (TSC complex) in response to EGF stimuli. This is regulated through activation of the AKT signaling pathway. Loss of Ezrin was not sufficient to repress TSC complex by EGF and culminated in translocation of TSC complex to lysosomes triggering suppression of mTORC1 signaling. Overexpression of constitutively active EZRINT567D is sufficient to relocalize TSC complex to the endosomes and reactivate mTORC1. Our findings identify EZRIN as a critical regulator of autophagy via TSC complex in response to EGF stimuli and establish the central role of early endosomal signaling in the regulation of mTORC1. Consistently, Medaka fish deficient for Ezrin exhibit defective endo-lysosomal pathway, attributable to the compromised EGFR/AKT signaling, ultimately leading to retinal degeneration. Our data identify a pivotal mechanism of endo-lysosomal signaling involving Ezrin and its associated EGFR/TSC complex, which are essential for retinal function.
2025-01-23 | Brain-related sexual dimorphism in tuberous sclerosis complex: an overlooked matter.
Biological sex strongly impacts tuberous sclerosis complex (TSC) symptoms like epilepsy and autism. However, the mechanisms driving this influence remain largely unknown. Here, we discuss how sex-specific changes in brain synapses and neural networks may drive these differences, offering insights that could be crucial for developing targeted therapies for TSC.
gene therapies
2026-07-24 | Case Report: Induction of labor and postpartum management for fetal cardiac rhabdomyoma: a genetic etiology-based analysis of three cases.
Fetal cardiac rhabdomyoma (CR) is a rare primary cardiac tumor often linked to tuberous sclerosis complex (TSC) caused by TSC1/TSC2 mutations, yet its genetic heterogeneity and individualized perinatal management remain incompletely defined. This case series reports three primigravid women with fetuses diagnosed with CR at different gestational ages, who received induced labor via various regimens. Genetic testing identified a paternally inherited TSC2 mutation in one case, a de novo TSC1 mutation in another, while genetic analysis was declined in the third. Distinct differences exist in recurrence risk, long-term neurological prognosis and corresponding clinical decision-making between de novo TSC1 variants and paternally inherited TSC2 mutations, which fully reflects prominent genetic heterogeneity among TSC-related fetal CR. This study demonstrates the clinical and genetic heterogeneity of fetal CR, and highlights that ultrasound evaluation, TSC1/TSC2 genetic testing, and multidisciplinary care are crucial for guiding induction timing, perinatal management, and genetic counseling to improve perinatal outcomes.
2026-03-09 | Neurogenetic tumor syndromes: The current landscape of workup and treatment.
Experts and generalists from numerous clinical disciplines are likely to encounter and be involved in the care of patients with neurogenetic tumor syndromes. Considerations for genetic testing are discussed. Specific conditions including neurofibromatosis type 1, neurofibromatosis type 2-related schwannomatosis, von Hippel-Lindau disease, tuberous sclerosis, Lynch syndrome, Turcot syndrome, Li-Fraumeni syndrome, and others are reviewed. A variety of targeted therapies which have received regulatory approval for these disorders are described and promising future directions for therapeutics are highlighted.
2025-12-08 | Cerebellar tubers in tuberous sclerosis complex: MRI characteristics and longitudinal evolution in a pediatric and young adult cohort
Abstract Background Tuberous sclerosis complex (TSC) is a multisystem genetic disorder characterized by the development of benign tumors across multiple organ systems. While supratentorial cerebral manifestations are well documented, infratentorial involvement, particularly cerebellar tubers, remains less explored. This study aimed to evaluate the prevalence, imaging characteristics, and longitudinal changes of cerebellar tubers in patients with TSC. Methods A retrospective analysis was conducted on 61 pediatric and young adult patients diagnosed with TSC who underwent brain MRI between 2005 and 2023. MR imaging included standard sequences such as T1WI, T2WI, FLAIR, DWI, ADC mapping, SWI, and post-contrast T1WI. All scans were independently reviewed by three experienced neuroradiologists (each one with 15 years of experience); they were blinded to clinical data. Results Cerebellar tubers were identified in 29 out of 61 patients (47.5%), totaling 50 lesions. The most common morphology was wedge-shaped (96%). Signal intensity varied across sequences: T1 hypointense (92%), T2 hyperintense (86%), and FLAIR mixed patterns (variable). Enhancement after contrast administration was observed in 6% of tubers (striated pattern), and calcifications were present in 14%. Retraction deformities adjacent to tubers were noted in 48% of cases. Patients with cerebellar tubers had significantly more cerebral tubers than those without (mean: 29 vs 22; p < 0.001). Follow-up MRI in 13 patients (mean follow-up: 5.3 years) showed stability in 84.6%, slight regression in 7.7%, and progression in 7.7%. Conclusions Cerebellar tubers are relatively common in TSC and exhibit distinct morphological and signal characteristics. These lesions demonstrate dynamic behavior over time, correlating with supratentorial abnormalities and potentially influencing neurobehavioral outcomes. Awareness of these features can aid in early diagnosis and long-term monitoring.
2025-12-03 | Renal epithelioid angiomyolipoma: A multi-institutional, international cohort study with emphasis on clinicopathologic prognostic indicators.
Renal angiomyolipoma (AML) is a benign perivascular epithelioid cell neoplasm that is often associated with tuberous sclerosis complex (TSC). Epithelioid AML (eAML), a very rare and potentially malignant variant, can be challenging to radiologically differentiate from benign AML and other renal tumors. Adverse histological features have previously been associated to poorer oncological outcomes. This study aimed to characterize this rare disease entity and validate previously reported adverse prognostic factors. This multicenter, retrospective cohort study analyzed 76 patients diagnosed with eAML between 2001 and 2024 across 15 participating centers. Inclusion criteria were histological diagnosis of eAML with negative cytokeratin markers and positive melanocytic markers. Patients were stratified according to previously described adverse pathological features. A total of 76 patients were studied. Most were female (70%), with a median age of 48 years and, 19 patients had TSC. Median tumor size was 45 mm, with a rate of atypical epithelioid cells >70% in 26 (34.2%) patients. According to the Nese's and Brimo's classifications, 4% and 14% of patients were at high risk, respectively. During a median follow- up of 30-months, 5 (6.7 %) patients developed metastases, and 4 (5.3 %) died. At univariable analysis, the number of adverse pathological risk factors, according to both classifications, was significantly associated with worse metastasis free survival (MFS) and cancer specific survival (CSS). Due to the low number of events, a multivariable analysis was not carried out. eAML is extremely rare, and primarily affects middle-aged women. This cohort validated previously described pathological risk factors for worse prognosis, suggesting that patients with multiple adverse features may require more intensive follow-up.
2025-09-22 | Progress in genetic mechanisms and precise treatment of neurocutaneous syndrome-related epilepsy.
Neurocutaneous syndromes are a group of genetic disorders involving the nervous and cutaneous systems, including Tuberous Sclerosis Complex (TSC), neurofibromatosis type 1 (NF1), and Sturge-Weber syndrome (SWS), and others. The incidence of epilepsy, a core clinical manifestation, is significantly higher than in the general population. The purpose of this narrative review is to provide an updated overview of the genetic mechanisms and recent advances in precise treatment for neurocutaneous syndrome-related epilepsy. We conducted a comprehensive search of the PubMed, Scopus, EMBASE, and Web of Science databases using all MeSH terms related to 'Neurocutaneous Syndromes', 'Epilepsy/genetics', 'Signal Transduction', and 'Precision Medicine'. Selected papers underwent review and risk of bias (RoB) assessment to evaluate core questions. Somatic or germline mutations dysregulate key signaling pathways (e.g., mTOR, Ras-MAPK, PI3K-AKT), inducing malformations of cortical development (MCD) and neuronal-glial dysfunction that collectively form epileptogenic networks. This constitutes the primary pathogenic mechanism underlying neurocutaneous syndrome-related epilepsy. Precise treatment strategies based on molecular mechanisms have achieved breakthroughs: mTOR inhibitors significantly reduce seizure frequency in TSC patients, and cannabidiol (CBD) demonstrates broad-spectrum antiepileptic efficacy in TSC and Dravet syndrome. Advances in surgical techniques, such as multimodal imaging-guided resection, improve outcomes in refractory epilepsy. However, clinical translation faces challenges including technical limitations in detecting mosaic mutations, insufficient specificity of targeted drugs, and interdisciplinary collaboration gaps. Future directions require integrating multi-omics technologies, developing novel gene therapies (e.g., CRISPR-based approaches), and establishing multicenter databases linking genotype-phenotype-treatment responses to advance personalized precision medicine.
oligonucleotides
2024-10-16 | Subependymal Giant Cell Astrocytoma: The Molecular Landscape and Treatment Advances.
Subependymal giant cell astrocytoma (SEGA) is most often found in patients with TSC (Tuberous Sclerosis Complex). Although it has been classified as a benign tumor, it may create a serious medical problem leading to grave consequences, including young patient demise. Surgery and chemotherapy belong to the gold standard of treatment. A broader pharmacological approach involves the ever-growing number of rapalogs and ATP-competitive inhibitors, as well as compounds targeting other kinases, such as dual PI3K/mTOR inhibitors and CK2 kinase inhibitors. Novel approaches may utilize noncoding RNA-based therapeutics and are extensively investigated to this end. The purpose of our review was to characterize SEGA and discuss the latest trends in the diagnosis and therapy of this disease.
2024-08-23 | miR-25-5p in exosomes derived from UVB-induced fibroblasts regulates melanogenesis via TSC2-dominated cellular organelle dysfunction.
Few reports have confirmed whether exosomes derived from fibroblasts can regulate the process of melanogenesis. We wondered whether exosomes derived from fibroblasts could have a potent regulatory effect on melanogenesis and explored the underlying mechanisms. This study aimed to find the role of fibroblasts in melanocytes and revealed the related mechanisms. RT-qPCR, Western blot analysis were conducted to measure the RNA and protein expression level of various related genes. miRNA sequencing, mass spectrum analysis and subsequent bioinformatics analysis were employed to find the underlying targets. Zebrafish were employed to measure the melanin synthesis related process in vivo. Furthermore, electron microscopy, ROS measurement and dual-luciferase reporter assay were adopted to investigate the relationship between these processes. We found that exosomes derived from human primary dermal fibroblasts were internalized by human primary melanocytes and MNT1 cells and that the melanin content and the expression of melanin synthesis-related proteins TYR and MITF was inhibited by exosomes derived from UVB-induced human primary dermal fibroblasts. The miRNA expression profile in secreted exosomes changed significantly, with miR-25-5p identified as capable of regulating TSC2 expression via the CDS region. The miR-25-5p-TSC2 axis could affect the melanin content through subsequent cellular organelle dysfunction, such as mitochondrial dysfunction, endoplasmic reticulum stress and dysregulation of lysosomal cysteine proteases. We unveiled a novel regulatory role of fibroblasts in melanocytes, facilitated by the secretion of exosomes. miR-25-5p within exosomes plays a pivotal role in regulating melanogenesis via TSC2-induced cellular organelle dysfunction.
2023-04-03 | MicroRNA Expression Profile in TSC Cell Lines and the Impact of mTOR Inhibitor.
The aim of this study was to assess the potential implication of microRNA on tuberous sclerosis (TSC) pathogenesis by performing microRNA profiling on cell lines silencing TSC1 or TSC2 genes using qPCR panels, before and after incubation with rapamycin. Significant differences in expression were observed between samples before and after rapamycin treatment in nineteen miRNAs in TSC1, five miRNAs in TSC2 and seven miRNAs in controls. Of miRNAs dysregulated before rapamycin treatment, three normalized after treatment in the TSC1 group (miR-21-3p, miR-433-3p, let-7g-3p) and one normalized in the TSC2 group (miR-1224-3p). Of the miRNAs dysregulated before rapamycin treatment in the TSC1 and TSC2 groups, two did not normalize after treatment (miR-33a-3p, miR-29a-3p). The results of the possible targets indicated that there are four common genes with seed regions susceptible to regulation by those miRNAs: ZBTB20, PHACTR2, PLXNC1 and ATP1B4. Our data show no changes in mRNA expression of these targets after rapamycin treatment. In conclusion, results of our study indicate the involvement of miRNA dysregulation in the pathogenesis of TSC. Some of the miRNA might be used as markers of treatment efficacy and autonomic miRNA as a target for future therapy.
2022-10-27 | Extracellular vesicles derived from endometrial epithelial cells deliver exogenous miR-92b-3p to affect the function of embryonic trophoblast cells via targeting TSC1 and DKK3.
Extracellular vesicles (EVs) could mediate embryo-maternal communication to affect embryo implantation by delivering biology information, including microRNA (miRNA), protein, lipid. Our previous research shows that miR-92b-3p was differentially expressed in EVs of uterine flushing fluids during the embryo implantation period. However, the role of miR-92b-3p from EVs in embryo implantation remains elusive. EVs were isolated from porcine endometrial epithelial cells (EECs) by ultracentrifugation. MiR-92b-3p mimics and EVs were used to regulate the expression of miR-92b-3p in porcine trophoblast cells (PTr2 cells). Cell proliferation, migration and adhesion analyses were used to observe the phenotype. RT-qPCR, western blot and dual-luciferase reporter assay were used to assess the targets of miR-92b-3p. In this study, EVs derived from porcine EECs were identified and could be taken up by PTr2 cells. We found that the EVs derived from EECs transfected with miR-92b-3p mimic (EVs-miR-92b-3p) significantly promoted the proliferation, migration and adhesion of PTr2 cells. We verified that Tuberous sclerosis complex subunit (TSC1) and Dickkopf 3 (DKK3) were the target genes of miR-92b-3p. Moreover, our study showed that miR-92b-3p plays a vital role in PTr2 cells via targeting TSC1 and DKK3. Furthermore, the 3'UTR vectors of TSC1 and DKK3 can rescue the effect of miR-92b-3p on PTr2 cells. Taken together, this study reveals a novel mechanism that EVs derived from porcine EECs treated with miR-92b-3p crosstalk with trophoblasts by targeting TSC1 and DKK3, leading to an enhanced ability for implantation.
2022-04-12 | Peripheral Serum Exosomes Isolated from Patients with Acute Myocardial Infarction Promote Endothelial Cell Angiogenesis via the miR-126-3p/TSC1/mTORC1/HIF-1α Pathway.
Angiogenesis is required for improving myocardial function and is a key factor in long-term prognosis after an acute myocardial infarction (AMI). Although exosomes are known to play a crucial role in angiogenesis, the role of peripheral exosomes in angiogenic signal transduction in patients with AMI remains unclear. Here, we explored the effect of exosomes extracted from the peripheral serum of AMI patients on angiogenesis and elucidated the downstream pathways. Serum exosomes were obtained from patients with AMI (AMI-Exo) and healthy individuals (Con-Exo). The exosomes were cocultured with human umbilical vein endothelial cells (HUVECs) in vitro, with aortic rings ex vivo, and were used to treat mouse hind-limb ischemia and mouse AMI model in vivo. AMI-Exo raised HUVEC proliferation, tube formation, and migration, and enhanced microvessel sprouting from aortic rings compared to Con-Exo, both in vitro and ex vivo. Quantitative reverse transcription-polymerase chain reaction revealed that the abundance of miR-126-3p, a crucial regulator of angiogenesis, was increased in AMI-Exo. The inhibition of miR-126-3p decreased the benefits of AMI-Exo treatment, and miR-126-3p upregulation enhanced the benefits of Con-Exo treatment in HUVECs, aortic rings, the mouse hind-limb ischemia model, and the mouse AMI model. Knockdown and overexpression analyses revealed that miR-126-3p regulated angiogenesis in HUVECs by directly targeting tuberous sclerosis complex 1 (TSC1). Moreover, we found that miR-126-3p could inhibit TSC1 expression, which further activated mTORC1 signaling and increased HIF-1α and VEGFA expression, ultimately promoting angiogenesis. Collectively, our results provide a novel understanding of the function of exosomes in angiogenesis post AMI. We demonstrated that exosomes from the peripheral serum of AMI patients promote angiogenesis via the miR-126-3p/TSC1/mTORC1/HIF-1α signaling pathway.
other
2026-05-31 | Long-term outcomes of selective arterial embolization in giant renal angiomyolipoma: A retrospective single-center study.
To evaluate the long-term outcomes of selective trans-arterial embolization (SAE) in patients with giant (⩾10 cm in size) renal angiomyolipomas (AMLs) at our tertiary referral center. This retrospective, single-center study included 44 patients who underwent SAE for AMLs of ⩾10 cm size between July 2018 and June 2024. Collected data included demographics, tumor characteristics, clinical symptoms, type of intervention, tumor size before and after embolization, and renal function. Outcomes assessed were tumor size reduction, preservation of renal function, reintervention rates during follow-up and complications following SAE. The study included 46 tumors in 44 patients. Mean patient age was 40.4 years (range: 23-60), with 86.3% being females. Mean follow-up duration was 25.2 months (range: 6-70 months). Eleven patients (25%) were associated with TSC, and all were offered Everolimus postoperatively. The mean tumor size decreased significantly from 13.2 ± 3.12 cm pre-embolization to 10.3 ± 2.45 cm post-embolization (p = 0.003). Renal function remained stable during follow-up, with no significant changes in serum creatinine (p = 0.6) and eGFR (p = 0.8). The overall success rate was 84.7%, with 13.6% experiencing re-intervention. Complications included post-embolization syndrome (43.1%) and allergic reactions (6.8%), while one patient required nephrectomy due to a perinephric abscess. Selective Trans-arterial Embolization is a safe and effective treatment for giant renal AMLs, resulting in significant tumor size reduction, symptom relief, and preservation of renal function. It offers a minimally invasive alternative to traditional surgical approaches, particularly for patients with high surgical risk or those requiring nephron-sparing procedure.
2026-05-01 | A case report of transcatheter arterial embolization for extra-renal retroperitoneal angiomyolipoma associated with tuberous sclerosis complex.
An 83-year-old male who underwent left nephrectomy about 40 years ago presented with a fatty mass in the retroperitoneum on CT images. The patient was diagnosed with extra-renal retroperitoneal angiomyolipoma (AML) through CT-guided retroperitoneal biopsy. Based on additional tests, the patient was also diagnosed with tuberous sclerosis complex (TSC). Given the substantial size (over 4 cm) of the tumor and the presence of an aneurysm, transcatheter arterial embolization (TAE) was performed to prevent rupture. Transcatheter embolization of the left testicular artery, left inferior phrenic artery, and left first lumbar artery did not result in any major complications. In addition, the tumor size had significantly reduced 12 months after TAE, and no aneurysm was detected. Extra-renal retroperitoneal AMLs associated with TSC are extremely rare, and may involve more feeding arteries than renal AMLs. Given the challenges in performing emergency TAE for ruptured extra-renal retroperitoneal AMLs, it is preferable to prevent rupture using this approach.
2025-11-19 | Focal postnatal deletion of Tsc2 causes epilepsy.
Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in either the TSC1 or TSC2 genes. These mutations prevent the TSC1/TSC2 protein complex from forming, resulting in hyperactivation of the mechanistic target of rapamycin (mTOR) cell growth and protein synthesis pathway. Epilepsy is one of the most common neurological symptoms in TSC patients, often associated with focal cortical lesions. However, it is not fully established whether such focal abnormalities are sufficient on their own to generate seizures and associated behavioral deficits. Here, we created a novel mouse model to test the hypothesis that a focal, postnatal deletion of Tsc2 from cortical neurons is sufficient to induce an epileptogenic network and produce behavioral changes relevant to TSC. Tsc2 was deleted from neurons in a focal area of the frontal cortex in Tsc2 fl/fl (fTSC2 KO) mice following neonatal bilateral AAV9-CaMKII-Cre-mCherry injections on postnatal day 2. One group of adult fTSC2 KO and Tsc2 wt/wt (control) mice was implanted with cortical electrodes for combined video-EEG monitoring. A separate group of control and fTSC2 KO mice, injected with a lower viral titer, underwent video recording and behavioral exploration analysis in a novel environment. Tissue was collected for histology. All adult fTSC2 KO mice implanted with cortical electrodes had seizures, whereas no control mice did. Histological analyses showed that virally infected cells in fTSC2 KO mice had enlarged somas and increased mTOR activation (pS6 expression). These fTSC2 KO mice also had decreased parvalbumin and somatostatin interneuron densities in the surrounding cortex. fTSC2 KO mice displayed increased anxiety-like behaviors, spending significantly less time in the center of the novel environment compared to controls. A focal, postnatal deletion of Tsc2 from cortical neurons is sufficient to cause both epilepsy and behavioral deficits in mice. This model recapitulates key phenotypes of TSC, including abnormal cell growth, reduced inhibitory cell density, and increased microglia activation. This fTSC2 KO model is advantageous for delineating the cortical changes that support epilepsy and behavioral deficits in TSC, and for investigating possible targets for therapeutic intervention.
2025-10-10 | mTOR dysregulation induces IL-6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a rare disease of women in which TSC2 deficient 'LAM cells' with dysregulated mTOR signalling and recruited fibroblasts form nodules causing lung cysts and respiratory failure. We examine if mTOR dysregulation can induce senescence and impair the response to lung injury in LAM. The senescence markers p21, p16 and the SenMayo gene set are increased in LAM lungs and colocalise with alveolar type 2 cells. LAM models induce mTOR dependent senescence in alveolar type 2 cell organoids in vitro and in vivo. IL-6 produced by LAM cells, induces p16 and p21 in alveolar type 2 cells, inhibits epithelial wound resolution and is related to lung function in LAM patients. Rapamycin and the IL-6 receptor antagonist Tocilizumab reduce alveolar type 2 cell organoid p21 accumulation and Tocilizumab enhances epithelial wound repair. Targeting IL-6 signalling in parallel with mTOR inhibition, may reduce lung damage in LAM.
2025-09-19 | High-throughput bioprinting to produce micropatterned neuroepithelial tissues and model TSC2-deficient brain malformations.
In vitro human pluripotent stem cell (hPSC)-derived models have been crucial in advancing our understanding of the mechanisms underlying neurodevelopment, though knowledge of the earliest stages of brain formation is lacking. Micropatterning of cell populations as they transition from pluripotency through the process of neurulation can produce self-assembled neuroepithelial tissues (NETs) with precise spatiotemporal control, enhancing the fidelity of hPSC models to the early developing human brain and their use in phenotypic assessments. Here, we introduce an accessible, customizable, and scalable method to produce self-assembled NETs using bioprinting to rapidly deposit reproducibly sized extracellular matrix droplets. Matrix addition to the media provides a scaffold that promotes 3D tissue folding, reflecting neural tube development. We demonstrate that these scaffolded NETs (scNETs) exhibit key architectural and biological features of the human brain during normal and abnormal development-notably, hyperproliferation and structural malformations induced by TSC2 deficiency-and provide a robust drug screening tool.
small molecules
2026-08-06 | [Extremely severe pulmonary lymphangioleiomyomatosis with combined brain, liver, kidney, and lung involvement: a case report].
We reported a case of extremely severe tuberous sclerosis complex-associated lymphangioleiomyomatosis (TSC-LAM) involving the brain, liver, kidneys, and lungs that was successfully treated with sirolimus, with a complete 17-year follow-up. The patient was diagnosed in 2008 and experienced rapid progression; by 2012, the patient had developed respiratory failure, severe anemia, renal insufficiency, and extreme abdominal distension. After 3 days of treatment with sirolimus, the aforementioned symptoms improved significantly, and respiratory failure resovled. Over the following 7 years of regular maintenance therapy, lung function declined only slightly each year, and the 6-minute walking test(6MWT) showed no decline. However, after sirolimus was discontinued from January 2020 to April 2021, the patient's lung function and 6MWT declined rapidly, with concurrent development of pneumothorax. Although sirolimus was subsequently resumed and remained effective, with no recurrence of pneumothorax or chylothorax, parameters such as lung function and 6MWT still did not recover significantly. This case suggests that TSC-LAM requires long-term maintenance therapy with sirolimus. Abrupt discontinuation of treatment may lead to rapid clinical deterioration.
2026-07-29 | A systematic review of highly purified cannabidiol in developmental and epileptic encephalopathies and complex treatment-resistant epilepsies: Nonseizure outcomes.
A plant-derived, highly purified cannabidiol (CBD) oral solution (Epidiolex® [US]/Epidyolex® [EU]) is approved for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), or tuberous sclerosis complex (TSC). Improvements in nonseizure outcomes including cognition and behavior have been reported in patients with epilepsy administered CBD. This systematic literature review (SLR) evaluated studies reporting changes in nonseizure outcomes after CBD initiation in patients with developmental and epileptic encephalopathies (DEEs) and complex treatment-resistant epilepsies (TREs) other than LGS, DS, and TSC. An SLR was conducted in March 2024 according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Embase, Medline, and Cochrane Central Register of Controlled Trials libraries were searched for studies on TREs, CBD, nonseizure outcomes, and adverse events (AEs). Results were narratively summarized. Thirty-two studies comprising 1343 patients were included. Thirty-one studies reported improvement in nonseizure outcomes in ≥ 1 patient, including neuropsychiatric function (n = 9/9 studies), cognitive function (n = 9/9), use of concomitant antiseizure medications (n = 7/8), communication (n = 7/7), behavior (n = 7/7), motor function (n = 6/6), healthcare utilization (n = 5/5), quality of life (n = 5/5), global change (n = 4/4), sleep (n = 2/2), and development (n = 2/2). Reported AEs were consistent with the known safety profile of CBD and most commonly gastrointestinal, including diarrhea (17-34%), vomiting (5-50%), and decreased appetite (7-20%). This SLR mainly identified observational studies with moderate to high bias risk. The available evidence suggests CBD may improve various nonseizure outcomes in patients with DEEs and complex TREs, while underscoring the need for rigorous confirmatory studies.
2026-07-19 | Progress report on new epilepsy treatments: A summary of the Eighteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVIII). I. Treatments in preclinical and early clinical development.
Over the last 34 years, the Eilat Conference on New Antiepileptic Drugs and Devices has provided an interactive forum for stakeholders to discuss investigational and recently licensed treatments for seizures and epilepsy. The Eighteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XVIII) took place in Madrid, Spain, on May 3-6, 2026. This article provides summaries of eight treatments in preclinical and early clinical development that were presented at EILAT XVIII. These include AUT00206, a positive allosteric modulator of Kv3.1 and Kv3.2 voltage-gated potassium channels in development for the treatment of rare epilepsy syndromes as well as neurodevelopmental and neuropsychiatric disorders; ION283, an antisense oligonucleotide designed to suppress the expression of glycogen synthase 1, under investigation for the treatment of Lafora disease; MSCA-7136, a selective allosteric RAS/mitogen-activated protein kinase-extracellular signal regulated kinase (MEK) inhibitor being developed for the treatment of focal seizures associated with mesial temporal lobe epilepsy and seizures associated with tuberous sclerosis complex; OV329, a selective inhibitor of γ-aminobutyric acid (GABA) aminotransferase, in development for the treatment of drug-resistant focal seizures; PTI5803 (probenecid), an uricosuric agent and a blocker of pannexin 1 channels, repurposed as a treatment for seizures associated with focal cortical dysplasia; simufilam, a filamin A modulator under investigation for the treatment of tuberous sclerosis complex-related epilepsy; SN-2000, a selective allosteric phosphodiesterase 4B inhibitor, in development for the treatment of focal seizures; and sodium selenate, a promoter of the dephosphorylation of pathological hyperphosphorylated tau in the brain, under investigation as a disease-modifying agent in mesial temporal lobe epilepsy. Treatments in more advanced clinical development are discussed in an accompanying article.
2026-07-12 | Co-Creation of the EpiCom Clinical Trial: Bringing the Tuberous Sclerosis Complex Patient Community, Healthcare Professionals, and the Pharmaceutical Industry Together.
Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) affect most patients with TSC and encompass a range of psychiatric, intellectual, neuropsychological, and behavioral manifestations of the disease. Epilepsy Comorbidities (EpiCom), an ongoing, phase 3b/4, open-label study, is assessing the effects of adjunctive therapy with a plant-derived, highly purified pharmaceutical formulation of cannabidiol (Epidiolex® [US]/Epidyolex® [EU], 100 mg/mL oral solution) on TAND, including behavioral outcomes, in participants with TSC-associated seizures. EpiCom was designed in collaboration with the TSC community including patients, caregivers, and healthcare professionals (HCPs), to incorporate stakeholder perspectives into study design and execution. To describe how collaboration among patient advocacy groups (PAGs), HCPs, and the clinical trial sponsor helped optimize the co-creation and execution of the EpiCom study. HCPs and PAG advisors, including caregivers of individuals with TSC, were identified across the USA and Europe and invited to participate in an advisory board meeting to discuss the challenges faced by the TSC community. Surveys collected PAG and HCP input on topics, including study objectives, outcome assessments, study design, eligibility criteria, and recruitment. PAG and HCP advisory board meetings were then conducted to capture patient/caregiver and HCP perspectives on the EpiCom study design, including the objectives, feasibility, resources needed for successful execution, and strategies to engage the patient community throughout the study. A joint PAG-HCP Steering Committee comprising 5 PAG representatives and 15 HCPs from the USA, Canada, and Europe was formed to guide study objectives and PAG engagement, and to provide study oversight. Advisory board meetings (9 PAG advisors; 14 HCPs) provided insight into the needs of the TSC community and ways to enhance collaboration with patients and caregivers. Feedback from the advisory boards and steering committee meetings refined the EpiCom study objectives and informed recruitment strategies, study duration, patient- and HCP-friendly study design considerations, preferred data collection methods, and communication plans. These insights supported the development of a decentralized clinical trial framework aimed at reducing participant burden and barriers. PAG input guided the decision to broaden study eligibility criteria by removing seizure severity and intelligence quotient requirements and include remote assessments to facilitate capturing data in everyday settings. HCP input guided inclusion of clinical outcome measures, including the use of the novel TAND Self-Report Quantified Checklist to assess behavioral changes. Proactively involving PAGs, caregivers, and HCPs enabled the co-creation of a study that explicitly addresses outcomes important to the broader TSC community. This patient- and caregiver-informed approach of EpiCom also highlights the need for stronger collaboration between industry and PAGs in clinical trials, including the opportunities and challenges of trial implementation. NCT05864846 (May 9, 2023).
2026-07-09 | Seizure-induced apnea causes sudden death independent of cortical spike wave discharge in mouse models of Tuberous Sclerosis Complex.
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of seizure-related mortality for people with epilepsy (PWE). Current evidence suggests that many cases of SUDEP are due to seizures that produce respiratory arrest, aka seizure-induced apnea. Patients with tuberous sclerosis complex (TSC) are at a significant risk of SUDEP, and mouse models of TSC have early mortality. Previous reports in TSC mouse models demonstrate that although Vigabatrin suppresses seizures, it does not improve survival. In other mouse models, our team has demonstrated that seizure-induced apnea occurs during tonic seizures, and that cortical spike-wave discharge (SWD) is not necessary to produce apnea during exogenously stimulated seizures. We hypothesized that seizure-induced apnea drives fatality independent of SWD in the spontaneous seizures of TSC mouse models, and this is why Vigabatrin treatment is ineffective. Two TSC mouse models were continuously monitored with electroencephalography, electrocardiography, plethysmography, and video recording to detect spontaneous seizures and SUDEP events. A subset of mice received daily Vigabatrin. Both TSC mouse models exhibited two spontaneous seizure types: clonic seizures with SWD and tonic seizures without SWD. All seizure-related fatalities were due to seizure-induced apnea. Across 21 SUDEP events, 20 occurred immediately after tonic seizures. Vigabatrin nearly eliminated clonic seizures but did not prevent tonic seizures and the concurrent apnea. In addition, Vigabatrin-treated mice exhibited cardiac signals that declined hours before SUDEP. These findings underscore the need for SUDEP-specific interventions beyond seizure suppression.
proteins
2026-05-04 | Evidence for FOXL2 Association with the Tsc1 Regulatory Region in Mice.
Ovarian reserve and reproductive life are closely linked concepts in female reproductive biology. The ovarian reserve consists of primordial follicles and refers to the number and quality of oocytes (eggs) remaining in the ovaries at any given time. Follicular dynamics shape a woman's reproductive lifespan, ultimately leading to menopause. Elucidating the underlying genetic and molecular pathways of follicle maturation and depletion is thus crucial for understanding menopausal onset and progression, both in normal and pathophysiological contexts, such as primary ovarian insufficiency, defined as menopause before the age of 40. A key factor in ovarian differentiation and fertility maintenance is FOXL2, a forkhead family transcription factor that plays a crucial role in follicle formation and development, ovarian maintenance, and sex determination. By employing a ChIP-Seq approach in mice, we identified a previously unreported binding of FOXL2 to a Tsc1 regulatory region. Our data, along with a thorough literature review, support the hypothesis that FOXL2-mediated activation of Tsc1 in granulosa cells can help maintain primordial follicles in a dormant state by suppressing mTORC1 signalling. Understanding the mechanisms behind ovarian reserve may lay the foundation for developing novel fertility preservation strategies, improving fertility treatment protocols and promoting in vitro activation of cryopreserved ovarian tissue to support folliculogenesis.
2025-07-11 | Modulation of infiltrating CD206+ macrophages restricts progression of pulmonary lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a low-grade neoplasm caused by the proliferation of tuberous sclerosis complex (TSC) 1- or TSC2-deficient LAM cells, resulting in progressive cystic lung disease. The currently approved treatment for LAM delays disease progression but the disease recurs if treatment is discontinued. Therefore, new therapeutic targets and/or strategies are necessary for a cure. Immunosuppressive M2-like macrophages are involved in the progression of various cancers, but their role in the pathophysiology of LAM and as a putative therapeutic target is unknown. To identify the different immune cell populations involved in LAM, we generated a single-cell transcriptomic map of pulmonary LAM. Interactions between macrophages and LAM cells were studied using the Visium spatial transcriptomic platform and immunofluorescence staining on human pulmonary LAM specimens. Direct co-culture models were used to characterise the influence of TSC2-deficient cells on macrophage differentiation. The efficacy of targeting M2-like macrophages was assessed in preclinical mouse models of TSC2-deficient subcutaneous tumours treated with RP-182, a synthetic peptide which reprogrammes macrophages towards an antitumour M1-like phenotype. Single-cell RNA-sequencing analysis revealed that the majority of macrophages in pulmonary LAM display immunosuppressive markers, including CD206/MRC1 and CD163. Spatial transcriptomic and immunofluorescence analyses showed that M2 macrophages are in close proximity to LAM cells and that LAM cells that are in close proximity to macrophages highly express macrophage-homing factor chemokine ligand CXCL12. In vitro, co-culture of human and mouse macrophages with TSC2-deficient cells resulted in the upregulation of M2-marker-expressing macrophages. Targeting M2 macrophages via treatment with the CD206 modulator RP-182 impaired the growth of TSC2-deficient tumours in vivo. LAM cells recruit and polarise macrophages towards an M2 phenotype. M2-like CD206high macrophages may represent a potential therapeutic target in LAM.
2025-06-25 | Cell-cell communication dysregulation in tuberous sclerosis complex cortical tubers and focal cortical dysplasia
Malformations of cortical development are manifestations of mTORopathies, including tubers in context of Tuberous Sclerosis Complex (TSC) cortical tubers and Focal Cortical Dysplasia (FCD), and are associated with epilepsy, often accompanied by comorbidities such as autism spectrum disorder (ASD). This study aims to investigate the cell-type-specific transcriptional alterations and disrupted intercellular communication networks in mTORopathies, focusing on their implications for cortical network dysfunction. Using single-cell RNA sequencing, we identified 33 transcriptionally distinct cell clusters across control and pathological samples, including neuronal, glial, and endothelial populations. Our analysis revealed disease-specific changes, such as the loss of certain glutamatergic and microglial clusters in cortical tubers (TSC), MTOR_FCD and DEPDC5_FCD, and the presence of a unique endothelial cluster in pathological samples. Pathway enrichment analysis highlighted the critical role of synaptic signaling, axonogenesis, and neuroimmune regulation in these disorders. Additionally, cell-cell communication network analysis demonstrated disrupted interactions between neuron-astrocyte, astrocyte-OPC, and microglia-neuron across mTORopathies. We found that the neurexins-neuroligins (NRXN-NLGN) signaling pathway, crucial for synapse formation and stability, was altered in both glutamatergic and GABAergic neurons, reflecting dysregulated synaptic plasticity and impaired neuron-glia communication. These findings provide novel insights into the molecular underpinnings of mTORopathies and suggest potential therapeutic targets to restore cellular communication and synaptic function in these disorders.
2025-02-12 | Ezrin defines TSC complex activation at endosomal compartments through EGFR-AKT signaling.
Endosomes have emerged as major signaling hubs where different internalized ligand-receptor complexes are integrated and the outcome of signaling pathways are organized to regulate the strength and specificity of signal transduction events. Ezrin, a major membrane-actin linker that assembles and coordinates macromolecular signaling complexes at membranes, has emerged recently as an important regulator of lysosomal function. Here, we report that endosomal-localized EGFR/Ezrin complex interacts with and triggers the inhibition of the Tuberous Sclerosis Complex (TSC complex) in response to EGF stimuli. This is regulated through activation of the AKT signaling pathway. Loss of Ezrin was not sufficient to repress TSC complex by EGF and culminated in translocation of TSC complex to lysosomes triggering suppression of mTORC1 signaling. Overexpression of constitutively active EZRINT567D is sufficient to relocalize TSC complex to the endosomes and reactivate mTORC1. Our findings identify EZRIN as a critical regulator of autophagy via TSC complex in response to EGF stimuli and establish the central role of early endosomal signaling in the regulation of mTORC1. Consistently, Medaka fish deficient for Ezrin exhibit defective endo-lysosomal pathway, attributable to the compromised EGFR/AKT signaling, ultimately leading to retinal degeneration. Our data identify a pivotal mechanism of endo-lysosomal signaling involving Ezrin and its associated EGFR/TSC complex, which are essential for retinal function.
2025-01-23 | Brain-related sexual dimorphism in tuberous sclerosis complex: an overlooked matter.
Biological sex strongly impacts tuberous sclerosis complex (TSC) symptoms like epilepsy and autism. However, the mechanisms driving this influence remain largely unknown. Here, we discuss how sex-specific changes in brain synapses and neural networks may drive these differences, offering insights that could be crucial for developing targeted therapies for TSC.
gene therapies
2026-07-24 | Case Report: Induction of labor and postpartum management for fetal cardiac rhabdomyoma: a genetic etiology-based analysis of three cases.
Fetal cardiac rhabdomyoma (CR) is a rare primary cardiac tumor often linked to tuberous sclerosis complex (TSC) caused by TSC1/TSC2 mutations, yet its genetic heterogeneity and individualized perinatal management remain incompletely defined. This case series reports three primigravid women with fetuses diagnosed with CR at different gestational ages, who received induced labor via various regimens. Genetic testing identified a paternally inherited TSC2 mutation in one case, a de novo TSC1 mutation in another, while genetic analysis was declined in the third. Distinct differences exist in recurrence risk, long-term neurological prognosis and corresponding clinical decision-making between de novo TSC1 variants and paternally inherited TSC2 mutations, which fully reflects prominent genetic heterogeneity among TSC-related fetal CR. This study demonstrates the clinical and genetic heterogeneity of fetal CR, and highlights that ultrasound evaluation, TSC1/TSC2 genetic testing, and multidisciplinary care are crucial for guiding induction timing, perinatal management, and genetic counseling to improve perinatal outcomes.
2026-03-09 | Neurogenetic tumor syndromes: The current landscape of workup and treatment.
Experts and generalists from numerous clinical disciplines are likely to encounter and be involved in the care of patients with neurogenetic tumor syndromes. Considerations for genetic testing are discussed. Specific conditions including neurofibromatosis type 1, neurofibromatosis type 2-related schwannomatosis, von Hippel-Lindau disease, tuberous sclerosis, Lynch syndrome, Turcot syndrome, Li-Fraumeni syndrome, and others are reviewed. A variety of targeted therapies which have received regulatory approval for these disorders are described and promising future directions for therapeutics are highlighted.
2025-12-08 | Cerebellar tubers in tuberous sclerosis complex: MRI characteristics and longitudinal evolution in a pediatric and young adult cohort
Abstract Background Tuberous sclerosis complex (TSC) is a multisystem genetic disorder characterized by the development of benign tumors across multiple organ systems. While supratentorial cerebral manifestations are well documented, infratentorial involvement, particularly cerebellar tubers, remains less explored. This study aimed to evaluate the prevalence, imaging characteristics, and longitudinal changes of cerebellar tubers in patients with TSC. Methods A retrospective analysis was conducted on 61 pediatric and young adult patients diagnosed with TSC who underwent brain MRI between 2005 and 2023. MR imaging included standard sequences such as T1WI, T2WI, FLAIR, DWI, ADC mapping, SWI, and post-contrast T1WI. All scans were independently reviewed by three experienced neuroradiologists (each one with 15 years of experience); they were blinded to clinical data. Results Cerebellar tubers were identified in 29 out of 61 patients (47.5%), totaling 50 lesions. The most common morphology was wedge-shaped (96%). Signal intensity varied across sequences: T1 hypointense (92%), T2 hyperintense (86%), and FLAIR mixed patterns (variable). Enhancement after contrast administration was observed in 6% of tubers (striated pattern), and calcifications were present in 14%. Retraction deformities adjacent to tubers were noted in 48% of cases. Patients with cerebellar tubers had significantly more cerebral tubers than those without (mean: 29 vs 22; p < 0.001). Follow-up MRI in 13 patients (mean follow-up: 5.3 years) showed stability in 84.6%, slight regression in 7.7%, and progression in 7.7%. Conclusions Cerebellar tubers are relatively common in TSC and exhibit distinct morphological and signal characteristics. These lesions demonstrate dynamic behavior over time, correlating with supratentorial abnormalities and potentially influencing neurobehavioral outcomes. Awareness of these features can aid in early diagnosis and long-term monitoring.
2025-12-03 | Renal epithelioid angiomyolipoma: A multi-institutional, international cohort study with emphasis on clinicopathologic prognostic indicators.
Renal angiomyolipoma (AML) is a benign perivascular epithelioid cell neoplasm that is often associated with tuberous sclerosis complex (TSC). Epithelioid AML (eAML), a very rare and potentially malignant variant, can be challenging to radiologically differentiate from benign AML and other renal tumors. Adverse histological features have previously been associated to poorer oncological outcomes. This study aimed to characterize this rare disease entity and validate previously reported adverse prognostic factors. This multicenter, retrospective cohort study analyzed 76 patients diagnosed with eAML between 2001 and 2024 across 15 participating centers. Inclusion criteria were histological diagnosis of eAML with negative cytokeratin markers and positive melanocytic markers. Patients were stratified according to previously described adverse pathological features. A total of 76 patients were studied. Most were female (70%), with a median age of 48 years and, 19 patients had TSC. Median tumor size was 45 mm, with a rate of atypical epithelioid cells >70% in 26 (34.2%) patients. According to the Nese's and Brimo's classifications, 4% and 14% of patients were at high risk, respectively. During a median follow- up of 30-months, 5 (6.7 %) patients developed metastases, and 4 (5.3 %) died. At univariable analysis, the number of adverse pathological risk factors, according to both classifications, was significantly associated with worse metastasis free survival (MFS) and cancer specific survival (CSS). Due to the low number of events, a multivariable analysis was not carried out. eAML is extremely rare, and primarily affects middle-aged women. This cohort validated previously described pathological risk factors for worse prognosis, suggesting that patients with multiple adverse features may require more intensive follow-up.
2025-09-22 | Progress in genetic mechanisms and precise treatment of neurocutaneous syndrome-related epilepsy.
Neurocutaneous syndromes are a group of genetic disorders involving the nervous and cutaneous systems, including Tuberous Sclerosis Complex (TSC), neurofibromatosis type 1 (NF1), and Sturge-Weber syndrome (SWS), and others. The incidence of epilepsy, a core clinical manifestation, is significantly higher than in the general population. The purpose of this narrative review is to provide an updated overview of the genetic mechanisms and recent advances in precise treatment for neurocutaneous syndrome-related epilepsy. We conducted a comprehensive search of the PubMed, Scopus, EMBASE, and Web of Science databases using all MeSH terms related to 'Neurocutaneous Syndromes', 'Epilepsy/genetics', 'Signal Transduction', and 'Precision Medicine'. Selected papers underwent review and risk of bias (RoB) assessment to evaluate core questions. Somatic or germline mutations dysregulate key signaling pathways (e.g., mTOR, Ras-MAPK, PI3K-AKT), inducing malformations of cortical development (MCD) and neuronal-glial dysfunction that collectively form epileptogenic networks. This constitutes the primary pathogenic mechanism underlying neurocutaneous syndrome-related epilepsy. Precise treatment strategies based on molecular mechanisms have achieved breakthroughs: mTOR inhibitors significantly reduce seizure frequency in TSC patients, and cannabidiol (CBD) demonstrates broad-spectrum antiepileptic efficacy in TSC and Dravet syndrome. Advances in surgical techniques, such as multimodal imaging-guided resection, improve outcomes in refractory epilepsy. However, clinical translation faces challenges including technical limitations in detecting mosaic mutations, insufficient specificity of targeted drugs, and interdisciplinary collaboration gaps. Future directions require integrating multi-omics technologies, developing novel gene therapies (e.g., CRISPR-based approaches), and establishing multicenter databases linking genotype-phenotype-treatment responses to advance personalized precision medicine.
oligonucleotides
2024-10-16 | Subependymal Giant Cell Astrocytoma: The Molecular Landscape and Treatment Advances.
Subependymal giant cell astrocytoma (SEGA) is most often found in patients with TSC (Tuberous Sclerosis Complex). Although it has been classified as a benign tumor, it may create a serious medical problem leading to grave consequences, including young patient demise. Surgery and chemotherapy belong to the gold standard of treatment. A broader pharmacological approach involves the ever-growing number of rapalogs and ATP-competitive inhibitors, as well as compounds targeting other kinases, such as dual PI3K/mTOR inhibitors and CK2 kinase inhibitors. Novel approaches may utilize noncoding RNA-based therapeutics and are extensively investigated to this end. The purpose of our review was to characterize SEGA and discuss the latest trends in the diagnosis and therapy of this disease.
2024-08-23 | miR-25-5p in exosomes derived from UVB-induced fibroblasts regulates melanogenesis via TSC2-dominated cellular organelle dysfunction.
Few reports have confirmed whether exosomes derived from fibroblasts can regulate the process of melanogenesis. We wondered whether exosomes derived from fibroblasts could have a potent regulatory effect on melanogenesis and explored the underlying mechanisms. This study aimed to find the role of fibroblasts in melanocytes and revealed the related mechanisms. RT-qPCR, Western blot analysis were conducted to measure the RNA and protein expression level of various related genes. miRNA sequencing, mass spectrum analysis and subsequent bioinformatics analysis were employed to find the underlying targets. Zebrafish were employed to measure the melanin synthesis related process in vivo. Furthermore, electron microscopy, ROS measurement and dual-luciferase reporter assay were adopted to investigate the relationship between these processes. We found that exosomes derived from human primary dermal fibroblasts were internalized by human primary melanocytes and MNT1 cells and that the melanin content and the expression of melanin synthesis-related proteins TYR and MITF was inhibited by exosomes derived from UVB-induced human primary dermal fibroblasts. The miRNA expression profile in secreted exosomes changed significantly, with miR-25-5p identified as capable of regulating TSC2 expression via the CDS region. The miR-25-5p-TSC2 axis could affect the melanin content through subsequent cellular organelle dysfunction, such as mitochondrial dysfunction, endoplasmic reticulum stress and dysregulation of lysosomal cysteine proteases. We unveiled a novel regulatory role of fibroblasts in melanocytes, facilitated by the secretion of exosomes. miR-25-5p within exosomes plays a pivotal role in regulating melanogenesis via TSC2-induced cellular organelle dysfunction.
2023-04-03 | MicroRNA Expression Profile in TSC Cell Lines and the Impact of mTOR Inhibitor.
The aim of this study was to assess the potential implication of microRNA on tuberous sclerosis (TSC) pathogenesis by performing microRNA profiling on cell lines silencing TSC1 or TSC2 genes using qPCR panels, before and after incubation with rapamycin. Significant differences in expression were observed between samples before and after rapamycin treatment in nineteen miRNAs in TSC1, five miRNAs in TSC2 and seven miRNAs in controls. Of miRNAs dysregulated before rapamycin treatment, three normalized after treatment in the TSC1 group (miR-21-3p, miR-433-3p, let-7g-3p) and one normalized in the TSC2 group (miR-1224-3p). Of the miRNAs dysregulated before rapamycin treatment in the TSC1 and TSC2 groups, two did not normalize after treatment (miR-33a-3p, miR-29a-3p). The results of the possible targets indicated that there are four common genes with seed regions susceptible to regulation by those miRNAs: ZBTB20, PHACTR2, PLXNC1 and ATP1B4. Our data show no changes in mRNA expression of these targets after rapamycin treatment. In conclusion, results of our study indicate the involvement of miRNA dysregulation in the pathogenesis of TSC. Some of the miRNA might be used as markers of treatment efficacy and autonomic miRNA as a target for future therapy.
2022-10-27 | Extracellular vesicles derived from endometrial epithelial cells deliver exogenous miR-92b-3p to affect the function of embryonic trophoblast cells via targeting TSC1 and DKK3.
Extracellular vesicles (EVs) could mediate embryo-maternal communication to affect embryo implantation by delivering biology information, including microRNA (miRNA), protein, lipid. Our previous research shows that miR-92b-3p was differentially expressed in EVs of uterine flushing fluids during the embryo implantation period. However, the role of miR-92b-3p from EVs in embryo implantation remains elusive. EVs were isolated from porcine endometrial epithelial cells (EECs) by ultracentrifugation. MiR-92b-3p mimics and EVs were used to regulate the expression of miR-92b-3p in porcine trophoblast cells (PTr2 cells). Cell proliferation, migration and adhesion analyses were used to observe the phenotype. RT-qPCR, western blot and dual-luciferase reporter assay were used to assess the targets of miR-92b-3p. In this study, EVs derived from porcine EECs were identified and could be taken up by PTr2 cells. We found that the EVs derived from EECs transfected with miR-92b-3p mimic (EVs-miR-92b-3p) significantly promoted the proliferation, migration and adhesion of PTr2 cells. We verified that Tuberous sclerosis complex subunit (TSC1) and Dickkopf 3 (DKK3) were the target genes of miR-92b-3p. Moreover, our study showed that miR-92b-3p plays a vital role in PTr2 cells via targeting TSC1 and DKK3. Furthermore, the 3'UTR vectors of TSC1 and DKK3 can rescue the effect of miR-92b-3p on PTr2 cells. Taken together, this study reveals a novel mechanism that EVs derived from porcine EECs treated with miR-92b-3p crosstalk with trophoblasts by targeting TSC1 and DKK3, leading to an enhanced ability for implantation.
2022-04-12 | Peripheral Serum Exosomes Isolated from Patients with Acute Myocardial Infarction Promote Endothelial Cell Angiogenesis via the miR-126-3p/TSC1/mTORC1/HIF-1α Pathway.
Angiogenesis is required for improving myocardial function and is a key factor in long-term prognosis after an acute myocardial infarction (AMI). Although exosomes are known to play a crucial role in angiogenesis, the role of peripheral exosomes in angiogenic signal transduction in patients with AMI remains unclear. Here, we explored the effect of exosomes extracted from the peripheral serum of AMI patients on angiogenesis and elucidated the downstream pathways. Serum exosomes were obtained from patients with AMI (AMI-Exo) and healthy individuals (Con-Exo). The exosomes were cocultured with human umbilical vein endothelial cells (HUVECs) in vitro, with aortic rings ex vivo, and were used to treat mouse hind-limb ischemia and mouse AMI model in vivo. AMI-Exo raised HUVEC proliferation, tube formation, and migration, and enhanced microvessel sprouting from aortic rings compared to Con-Exo, both in vitro and ex vivo. Quantitative reverse transcription-polymerase chain reaction revealed that the abundance of miR-126-3p, a crucial regulator of angiogenesis, was increased in AMI-Exo. The inhibition of miR-126-3p decreased the benefits of AMI-Exo treatment, and miR-126-3p upregulation enhanced the benefits of Con-Exo treatment in HUVECs, aortic rings, the mouse hind-limb ischemia model, and the mouse AMI model. Knockdown and overexpression analyses revealed that miR-126-3p regulated angiogenesis in HUVECs by directly targeting tuberous sclerosis complex 1 (TSC1). Moreover, we found that miR-126-3p could inhibit TSC1 expression, which further activated mTORC1 signaling and increased HIF-1α and VEGFA expression, ultimately promoting angiogenesis. Collectively, our results provide a novel understanding of the function of exosomes in angiogenesis post AMI. We demonstrated that exosomes from the peripheral serum of AMI patients promote angiogenesis via the miR-126-3p/TSC1/mTORC1/HIF-1α signaling pathway.
other
2026-05-31 | Long-term outcomes of selective arterial embolization in giant renal angiomyolipoma: A retrospective single-center study.
To evaluate the long-term outcomes of selective trans-arterial embolization (SAE) in patients with giant (⩾10 cm in size) renal angiomyolipomas (AMLs) at our tertiary referral center. This retrospective, single-center study included 44 patients who underwent SAE for AMLs of ⩾10 cm size between July 2018 and June 2024. Collected data included demographics, tumor characteristics, clinical symptoms, type of intervention, tumor size before and after embolization, and renal function. Outcomes assessed were tumor size reduction, preservation of renal function, reintervention rates during follow-up and complications following SAE. The study included 46 tumors in 44 patients. Mean patient age was 40.4 years (range: 23-60), with 86.3% being females. Mean follow-up duration was 25.2 months (range: 6-70 months). Eleven patients (25%) were associated with TSC, and all were offered Everolimus postoperatively. The mean tumor size decreased significantly from 13.2 ± 3.12 cm pre-embolization to 10.3 ± 2.45 cm post-embolization (p = 0.003). Renal function remained stable during follow-up, with no significant changes in serum creatinine (p = 0.6) and eGFR (p = 0.8). The overall success rate was 84.7%, with 13.6% experiencing re-intervention. Complications included post-embolization syndrome (43.1%) and allergic reactions (6.8%), while one patient required nephrectomy due to a perinephric abscess. Selective Trans-arterial Embolization is a safe and effective treatment for giant renal AMLs, resulting in significant tumor size reduction, symptom relief, and preservation of renal function. It offers a minimally invasive alternative to traditional surgical approaches, particularly for patients with high surgical risk or those requiring nephron-sparing procedure.
2026-05-01 | A case report of transcatheter arterial embolization for extra-renal retroperitoneal angiomyolipoma associated with tuberous sclerosis complex.
An 83-year-old male who underwent left nephrectomy about 40 years ago presented with a fatty mass in the retroperitoneum on CT images. The patient was diagnosed with extra-renal retroperitoneal angiomyolipoma (AML) through CT-guided retroperitoneal biopsy. Based on additional tests, the patient was also diagnosed with tuberous sclerosis complex (TSC). Given the substantial size (over 4 cm) of the tumor and the presence of an aneurysm, transcatheter arterial embolization (TAE) was performed to prevent rupture. Transcatheter embolization of the left testicular artery, left inferior phrenic artery, and left first lumbar artery did not result in any major complications. In addition, the tumor size had significantly reduced 12 months after TAE, and no aneurysm was detected. Extra-renal retroperitoneal AMLs associated with TSC are extremely rare, and may involve more feeding arteries than renal AMLs. Given the challenges in performing emergency TAE for ruptured extra-renal retroperitoneal AMLs, it is preferable to prevent rupture using this approach.
2025-11-19 | Focal postnatal deletion of Tsc2 causes epilepsy.
Tuberous sclerosis complex (TSC) is a genetic disorder caused by mutations in either the TSC1 or TSC2 genes. These mutations prevent the TSC1/TSC2 protein complex from forming, resulting in hyperactivation of the mechanistic target of rapamycin (mTOR) cell growth and protein synthesis pathway. Epilepsy is one of the most common neurological symptoms in TSC patients, often associated with focal cortical lesions. However, it is not fully established whether such focal abnormalities are sufficient on their own to generate seizures and associated behavioral deficits. Here, we created a novel mouse model to test the hypothesis that a focal, postnatal deletion of Tsc2 from cortical neurons is sufficient to induce an epileptogenic network and produce behavioral changes relevant to TSC. Tsc2 was deleted from neurons in a focal area of the frontal cortex in Tsc2 fl/fl (fTSC2 KO) mice following neonatal bilateral AAV9-CaMKII-Cre-mCherry injections on postnatal day 2. One group of adult fTSC2 KO and Tsc2 wt/wt (control) mice was implanted with cortical electrodes for combined video-EEG monitoring. A separate group of control and fTSC2 KO mice, injected with a lower viral titer, underwent video recording and behavioral exploration analysis in a novel environment. Tissue was collected for histology. All adult fTSC2 KO mice implanted with cortical electrodes had seizures, whereas no control mice did. Histological analyses showed that virally infected cells in fTSC2 KO mice had enlarged somas and increased mTOR activation (pS6 expression). These fTSC2 KO mice also had decreased parvalbumin and somatostatin interneuron densities in the surrounding cortex. fTSC2 KO mice displayed increased anxiety-like behaviors, spending significantly less time in the center of the novel environment compared to controls. A focal, postnatal deletion of Tsc2 from cortical neurons is sufficient to cause both epilepsy and behavioral deficits in mice. This model recapitulates key phenotypes of TSC, including abnormal cell growth, reduced inhibitory cell density, and increased microglia activation. This fTSC2 KO model is advantageous for delineating the cortical changes that support epilepsy and behavioral deficits in TSC, and for investigating possible targets for therapeutic intervention.
2025-10-10 | mTOR dysregulation induces IL-6 and paracrine AT2 cell senescence impeding lung repair in lymphangioleiomyomatosis.
Lymphangioleiomyomatosis (LAM) is a rare disease of women in which TSC2 deficient 'LAM cells' with dysregulated mTOR signalling and recruited fibroblasts form nodules causing lung cysts and respiratory failure. We examine if mTOR dysregulation can induce senescence and impair the response to lung injury in LAM. The senescence markers p21, p16 and the SenMayo gene set are increased in LAM lungs and colocalise with alveolar type 2 cells. LAM models induce mTOR dependent senescence in alveolar type 2 cell organoids in vitro and in vivo. IL-6 produced by LAM cells, induces p16 and p21 in alveolar type 2 cells, inhibits epithelial wound resolution and is related to lung function in LAM patients. Rapamycin and the IL-6 receptor antagonist Tocilizumab reduce alveolar type 2 cell organoid p21 accumulation and Tocilizumab enhances epithelial wound repair. Targeting IL-6 signalling in parallel with mTOR inhibition, may reduce lung damage in LAM.
2025-09-19 | High-throughput bioprinting to produce micropatterned neuroepithelial tissues and model TSC2-deficient brain malformations.
In vitro human pluripotent stem cell (hPSC)-derived models have been crucial in advancing our understanding of the mechanisms underlying neurodevelopment, though knowledge of the earliest stages of brain formation is lacking. Micropatterning of cell populations as they transition from pluripotency through the process of neurulation can produce self-assembled neuroepithelial tissues (NETs) with precise spatiotemporal control, enhancing the fidelity of hPSC models to the early developing human brain and their use in phenotypic assessments. Here, we introduce an accessible, customizable, and scalable method to produce self-assembled NETs using bioprinting to rapidly deposit reproducibly sized extracellular matrix droplets. Matrix addition to the media provides a scaffold that promotes 3D tissue folding, reflecting neural tube development. We demonstrate that these scaffolded NETs (scNETs) exhibit key architectural and biological features of the human brain during normal and abnormal development-notably, hyperproliferation and structural malformations induced by TSC2 deficiency-and provide a robust drug screening tool.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
19 orphan drug designations for Tuberous sclerosis complex, including 5 approved therapies.
19 orphan drug designations for Tuberous sclerosis complex, including 5 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
a potent, CNS active selective inhibitor of mTORC1 | small molecules | FDA | 2026-02-03 | — | LBR Regulatory and Clinical Consulting Services, Inc. |
vigabatrin | small molecules | FDA | 2024-11-02 | — | Pyros Pharmaceuticals Inc |
Ganaxolone | small molecules | EMA | 2021-10-15 | — | Immedica Pharma AB |
ganaxolone | small molecules | FDA | 2021-08-12 | — | Immedica Pharma AB |
sirolimus | small molecules | FDA | 2019-08-26 | — | AI Therapeutics, Inc. |
Cannabidiol [Epidyolex] | small molecules | EMA | 2018-01-17 | 2021-04-20 | Jazz Pharmaceuticals Ireland Limited |
Sirolimus [Hyftor] | small molecules | EMA | 2017-08-23 | 2023-05-26 | Plusultra Pharma GmbH |
Sirolimus | small molecules | EMA | 2017-06-20 | — | Desitin Arzneimittel GmbH |
sirolimus [Hyftor] | small molecules | FDA | 2017-05-17 | 2022-03-22 | NobelPharma Co., LTD |
sirolimus | small molecules | FDA | 2017-02-13 | — | Aucta Pharmaceuticals, Inc. |
cannabidiol [Epidiolex] | small molecules | FDA | 2016-04-19 | 2020-07-31 | Jazz Pharmaceuticals Research UK Limited |
rapamycin | small molecules | FDA | 2016-02-24 | — | AFT Pharmaceuticals Ltd. |
Sirolimus | small molecules | EMA | 2015-10-09 | — | Desitin Arzneimittel GmbH |
everolimus ointment | small molecules | FDA | 2015-09-10 | — | Aucta Pharmaceuticals, LLC |
Everolimus [Votubia] | small molecules | EMA | 2010-08-04 | — | Novartis Europharm Limited |
everolimus [Afinitor] | small molecules | FDA | 2009-06-08 | 2010-10-29 | Novartis Pharmaceuticals Corp. |
rapamycin | small molecules | FDA | 2007-03-20 | — | OncoImmune, Inc. |
Polyethylene glycol-modified uricase | — | FDA | 1999-09-14 | — | Swedish Orphan Biovitrum AB |
Polyethylene glycol-modified uricase | — | FDA | 1998-12-21 | — | Swedish Orphan Biovitrum AB |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.