Gene therapy for tuberous sclerosis complex type 2 in a mouse model by delivery of AAV9 encoding a condensed form of tuberin

Cheah, Pike See; Prabhakar, Shilpa; Yellen, David; Beauchamp, Roberta L.; Zhang, Xuan; Kasamatsu, Shingo; Bronson, Roderick T.; Thiele, Elizabeth A.; Kwiatkowski, David J.; Stemmer‐Rachamimov, Anat; György, Bence; Ling, King-Hwa; Kaneki, Masao; Tannous, Bakhos A.; Ramesh, Vijaya; Maguire, Casey A.; Breakefield, Xandra O.

doi:10.1126/sciadv.abb1703

Cited by 21 publications

(14 citation statements)

References 65 publications

(73 reference statements)

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“…In a mouse model of TSC2 with prominent SEGA-like lesions, intravenous injection of an adeno-associated virus vector carrying a condensed form of tuberin led to reduced tumour volumes and improved survival. 110 …”

Section: Personalized Medicine In Mtoropathy-related Epilepsiesmentioning

confidence: 99%

Epilepsy in the mTORopathies: opportunities for precision medicine

Moloney

Cavalleri

Delanty

2021

Brain Communications

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The mechanistic target of rapamycin (mTOR) signalling pathway serves as a ubiquitous regulator of cell metabolism, growth, proliferation and survival. The main cellular activity of the mTOR cascade funnels through mTOR complex 1, which is inhibited by rapamycin, a macrolide compound produced by the bacterium Streptomyces hygroscopicus. Pathogenic variants in genes encoding upstream regulators of mTOR complex 1 cause epilepsies and neurodevelopmental disorders. Tuberous sclerosis complex is a multisystem disorder caused by mutations in mTOR regulators TSC1 or TSC2, with prominent neurological manifestations including epilepsy, focal cortical dysplasia and neuropsychiatric disorders. Focal cortical dysplasia type II results from somatic brain mutations in mTOR pathway activators MTOR, AKT3, PIK3CA and RHEB and is a major cause of drug-resistant epilepsy. DEPDC5, NPRL2 and NPRL3 code for subunits of the GTPase-activating protein (GAP) activity towards Rags 1 complex (GATOR1), the principal amino acid-sensing regulator of mTOR complex 1. Germline pathogenic variants in GATOR1 genes cause non-lesional focal epilepsies and epilepsies associated with malformations of cortical development. Collectively the mTORopathies are characterised by excessive mTOR pathway activation and drug-resistant epilepsy. In the first large-scale precision medicine trial in a genetically-mediated epilepsy, everolimus (a synthetic analogue of rapamycin) was effective at reducing seizure frequency in people with tuberous sclerosis complex. Rapamycin reduced seizures in rodent models of DEPDC5-related epilepsy and focal cortical dysplasia type II. This review outlines a personalised medicine approach to the management of epilepsies in the mTORopathies. We advocate for early diagnostic sequencing of mTOR pathway genes in drug-resistant epilepsy, as identification of a pathogenic variant may point to an occult dysplasia in apparently non-lesional epilepsy or may uncover important prognostic information including, an increased risk of sudden unexpected death in epilepsy in the GATORopathies or favourable epilepsy surgery outcomes in focal cortical dysplasia type II due to somatic brain mutations. Lastly, we discuss the potential therapeutic application of mTOR inhibitors for drug-resistant seizures in GATOR1-related epilepsies and focal cortical dysplasia type II.

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Section: Personalized Medicine In Mtoropathy-related Epilepsiesmentioning

confidence: 99%

Epilepsy in the mTORopathies: opportunities for precision medicine

Moloney

Cavalleri

Delanty

2021

Brain Communications

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“…Recently, a mouse model of TSC2 was generated by AAV-Cre recombinase disruption of Tsc2-floxed alleles at birth with a shortened lifespan and brain pathology consistent with TSC phenotype. When these mice were injected intravenously with AAV9 expressing condensed TSC2 (cTSC2), the mean survival was extended with reduction in brain pathology [31]. Nevertheless, this study does not test whether the effect of AAV-cTSC2 could be boosted by treatment with low dose Rapamycin or other Rapalogs.…”

Section: Discussionmentioning

confidence: 98%

The Characterization of a Subependymal Giant Astrocytoma-Like Cell Line from Murine Astrocyte with mTORC1 Hyperactivation

Tang,

Angst,

Haas

et al. 2021

IJMS

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Tuberous sclerosis complex (TSC) is a genetic disorder caused by inactivating mutations in TSC1 (hamartin) or TSC2 (tuberin), crucial negative regulators of the mechanistic target of rapamycin complex 1 (mTORC1) signaling pathway. TSC affects multiple organs including the brain. The neurologic manifestation is characterized by cortical tubers, subependymal nodules (SEN), and subependymal giant cell astrocytoma (SEGA) in brain. SEGAs may result in hydrocephalus in TSC patients and mTORC1 inhibitors are the current recommended therapy for SEGA. Nevertheless, a major limitation in the research for SEGA is the lack of cell lines or animal models for mechanistic investigations and development of novel therapy. In this study, we generated TSC1-deficient neural cells from spontaneously immortalized mouse astrocytes in an attempt to mimic human SEGA. The TSC1-deficient cells exhibit mTORC1 hyperactivation and characteristics of transition from astrocytes to neural stem/progenitor cell phenotypes. Rapamycin efficiently decreased mTORC1 activity of these TSC1-deficient cells in vitro. In vivo, TSC1-deficient cells could form SEGA-like tumors and Rapamycin treatment decreased tumor growth. Collectively, our study generates a novel SEGA-like cell line that is invaluable for studying mTORC1-driven molecular and pathological alterations in neurologic tissue. These SEGA-like cells also provide opportunities for the development of novel therapeutic strategy for TSC patients with SEGA.

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“…In this study, we provide direct genetic support for reducing overactive translation via 4E-BP1 to alleviate established epilepsy. Given the recent advances in gene therapy for neurodevelopmental disorders (Deverman et al, 2018; Cheah et al, 2021; Turner et al, 2021), correcting translational dysregulation by 4E-BP1 CA -targeted gene therapy may be a feasible treatment strategy for genetically defined FMCD.…”

Section: Discussionmentioning

confidence: 99%

Genetic expression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy

Nguyen

Mahadeo

et al. 2021

Preprint

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Hyperactivation of mTOR signaling during fetal neurodevelopment alters neuron structure and function, leading to focal malformation of cortical development (FMCD) and intractable epilepsy. Recent evidence suggests increased cap-dependent translation downstream of mTOR contributes to FMCD formation and seizures. However, whether reducing overactive translation once the developmental pathologies are established reverses neuronal abnormalities and seizures is unknown. Here, we found that the translational repressor 4E-BP1, which is inactivated by mTOR-mediated phosphorylation, is hyperphosphorylated in patient FMCD tissue and in a mouse model of FMCD. Expressing constitutive active 4E-BP1 to repress aberrant translation in juvenile mice with FMCD reduced neuronal cytomegaly and corrected several electrophysiological alterations, including depolarized resting membrane potential, irregular firing pattern, and aberrant HCN4 channel expression. This was accompanied by improved cortical spectral activity and decreased seizures. Although mTOR controls multiple pathways, our study shows that targeting 4E-BP1-mediated translation alone is sufficient to alleviate neuronal dysfunction and ongoing epilepsy.

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Gene therapy for tuberous sclerosis complex type 2 in a mouse model by delivery of AAV9 encoding a condensed form of tuberin

Cited by 21 publications

References 65 publications

Epilepsy in the mTORopathies: opportunities for precision medicine

Epilepsy in the mTORopathies: opportunities for precision medicine

The Characterization of a Subependymal Giant Astrocytoma-Like Cell Line from Murine Astrocyte with mTORC1 Hyperactivation

Genetic expression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy

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