What is Tuberous Sclerosis Complex?

Tuberous Sclerosis Complex (TSC) is a rare autosomal dominant genetic disorder that primarily affects multiple organs including the brain, skin, kidneys, heart, and lungs. The typical features of TSC include cortical tubers, seizures, intellectual disability, facial angiofibromas, renal angiomyolipomas (AML), and other manifestations. With a global incidence of approximately 1/6,000 to 1/10,000, TSC represents the most common neurocutaneous syndrome.
 

Pathogenesis

The core mechanism underlying tuberous sclerosis involves abnormal activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, originating from loss-of-function mutations in either the TSC1 or TSC2 gene. The hamartin protein encoded by TSC1 and the tuberin protein encoded by TSC2 form a stable heterodimeric complex within cells. This complex functions as a GTPase-activating protein (GAP) for the small GTPase Rheb, maintaining Rheb in its inactive GDP-bound state under physiological conditions through promotion of GTP hydrolysis, thereby exerting potent inhibition on the downstream mTORC1 signaling pathway.

When pathogenic mutations in TSC1 or TSC2 lead to loss of protein complex function, Rheb-GTP accumulates abnormally and persistently activates mTORC1. Activated mTORC1 phosphorylates its key downstream substrates 4E-BP1 and S6K1/2, subsequently relieving translational inhibition and enhancing ribosomal biogenesis. This drives abnormal cell growth, proliferation, and metabolic reprogramming, ultimately resulting in the formation of hamartomas and structural lesions in multiple organs.

Additionally, growth factors can further regulate TSC1/TSC2 complex function through activation of the PI3K-AKT pathway. Following growth factor binding to receptors, PI3K is activated via adaptor proteins such as IRS, catalyzing the generation of the second messenger PIP3 from membrane phospholipid PIP2. PIP3 recruits PDK1 and AKT to the cell membrane, where AKT is phosphorylated at Thr308 by PDK1 and activated. Activated AKT can phosphorylate multiple sites on TSC2, inhibiting the GAP activity of the TSC1/TSC2 complex, thereby temporarily relieving mTORC1 inhibition under physiological conditions to accommodate cell growth requirements. However, in TSC patients, the basal function of the TSC1/TSC2 complex is already lost due to gene mutations, causing upstream AKT signaling to lose its regulatory target and resulting in sustained, uncontrolled activation of the mTORC1 pathway, leading to the development of tuberous sclerosis complex.
 

Image Source TSC1 and TSC2 gene mutations and their implications for treatment in Tuberous Sclerosis Complex: a review

 

Gene Therapy

AAV-mediated gene replacement therapy: This approach utilizes adeno-associated virus vectors to deliver functional TSC1 genes to the central nervous system, compensating for protein function lost due to mutations and thereby restoring inhibition of the mTORC1 pathway. Preclinical studies have demonstrated that intracranial injection of AAV9-TSC1 can effectively reverse pathological phenotypes in Tsc1 conditional knockout mice, including reduction of cortical tubers, extended survival, and suppression of seizures. This method currently represents one of the most promising curative strategies for TSC1 mutations, while delivery of the TSC2 gene (due to its large cDNA size) remains a key technical challenge in the field.
 

Mouse Models

GFAP-Cre TSC1^flox/flox mice: These mice feature conditional knockout of the TSC1 gene in astrocytes and their precursor cells. The mice exhibit astrocyte proliferation, abnormal neuronal synaptic function, spontaneous seizures, and learning/memory and social behavior impairments. This model is suitable for studying the mechanisms of TSC-related epileptogenesis and the cellular basis of neuropsychiatric comorbidities.

Nestin-Cre TSC2^flox/flox mice: These mice have specific knockout of the TSC2 gene in neural precursor cells, leading to severe neurodevelopmental abnormalities including disrupted brain structure, impaired neuronal migration, reduced myelination, and intractable epilepsy. This model serves as a classic system for investigating the mechanisms of cortical tuber formation and early intervention strategies.
 

MingCeler Biotech Supports Gene Therapy

While gene therapy offers hope for rare diseases, its development and validation depend critically on animal model support. MingCeler Biotech has developed multiple rare disease mouse models using its proprietary TurboMice™ technology. The TurboMice™ platform overcomes technical challenges associated with long mouse model generation cycles and low success rates for complex models, enabling editing at virtually any target gene locus and producing complete homozygous gene-edited mouse models directly from embryonic stem cells in as little as 2 months.

MingCeler Biotech can customize various TSC mouse models according to client needs, including GFAP-Cre Tsc1^flox/flox mice, Nestin-Cre Tsc2^flox/flox mice, and others. We welcome inquiries from researchers!
 

References:

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[2] Rosset C, Netto CBO, Ashton-Prolla P. TSC1 and TSC2 gene mutations and their implications for treatment in Tuberous Sclerosis Complex: a review. Genet Mol Biol. 2017 Jan-Mar;40(1):69-79. doi: 10.1590/1678-4685-GMB-2015-0321. Epub 2017 Feb 20. PMID: 28222202; PMCID: PMC5409767.

[3] Chen CS, Aylett CHS. New insights into tuberous sclerosis complex: from structure to pathogenesis. Front Cell Dev Biol. 2025 Jun 27;13:1595867. doi: 10.3389/fcell.2025.1595867. PMID: 40655946; PMCID: PMC12245910.

[4] Prabhakar S, Zhang X, Goto J, Han S, Lai C, Bronson R, Sena-Esteves M, Ramesh V, Stemmer-Rachamimov A, Kwiatkowski DJ, Breakefield XO. Survival benefit and phenotypic improvement by hamartin gene therapy in a tuberous sclerosis mouse brain model. Neurobiol Dis. 2015 Oct;82:22-31. doi: 10.1016/j.nbd.2015.04.018. Epub 2015 May 24. PMID: 26019056; PMCID: PMC5070799.

[5] Zeng LH, Xu L, Gutmann DH, Wong M. Rapamycin prevents epilepsy in a mouse model of tuberous sclerosis complex. Ann Neurol. 2008 Apr;63(4):444-53. doi: 10.1002/ana.21331. PMID: 18389497; PMCID: PMC3937593.

[6] Scheidenhelm DK, Gutmann DH. Mouse models of tuberous sclerosis complex. J Child Neurol. 2004 Sep;19(9):726-33. doi: 10.1177/08830738040190091401. PMID: 15563020.

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Disclaimer: Some materials are sourced from the internet. Contact us for removal if infringement is found. This article is for informational purposes only and does not constitute treatment recommendations. The views expressed do not represent the official stance of MingCeler Biotech. For treatment guidance, please consult a qualified healthcare professional at a formal medical institution.