TuberOus SClerosis registry to increAse disease awareness (TOSCA) Post-Authorisation Safety Study of Everolimus in Patients With Tuberous Sclerosis Complex

Kingswood, J. Chris; Belousova, Elena; Benedik, Mirjana P; Budde, Klemens; Carter, Thomas; Cottin, Vincent; Curatolo, Paolo; Dahlin, Maria; D’Amato, Lisa; d’Augères, Guillaume Beaure; Vries, Petrus J. de; Ferreira, José Carlos; Feucht, Martha; Fladrowski, Carla; Hertzberg, Christoph; Jóźwiak, Sergiusz; Lawson, John A.; Macaya, Alfons; Marques, Rúben; Nabbout, Rima; O'Callaghan, Finbar; Qin, Jiong; Sander, Valentin; Sauter, Matthias; Shah, Seema; Takahashi, Yukitoshi; Touraine, Renaud; Youroukos, Sotiris; Zonnenberg, Bernard A.; Jansen, Anna; Investigators, Tosca

doi:10.3389/fneur.2021.630378

Cited by 11 publications

(29 citation statements)

References 22 publications

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“…Adverse events were manageable with dose reduction or temporary discontinuation, with a 95% retention rate over 5 years of observation. 91 Similarly, in a survey-based study on the perspectives of patients with TSC treated with everolimus, adverse events were reported by 70% of participants. Overall tolerability was acceptable, with retention rates exceeding 80% after 3 years.…”

Section: Personalized Medicine In Mtoropathy-related Epilepsiesmentioning

confidence: 99%

“… 88–90 , 94 Real-world data from TOSCA found that patients treated with everolimus displayed age-appropriate sexual maturation. 91 Metabolic complications, like hypercholesterolaemia and hypertriglyceridaemia occur in approximately 10% of patients treated with mTOR inhibitors, necessitating regular monitoring. 12 , 91 Significant elevations in lipids or cholesterol can be managed by mTOR inhibitor dose reduction or anticholesterol agents.…”

Section: Personalized Medicine In Mtoropathy-related Epilepsiesmentioning

confidence: 99%

“… 91 Metabolic complications, like hypercholesterolaemia and hypertriglyceridaemia occur in approximately 10% of patients treated with mTOR inhibitors, necessitating regular monitoring. 12 , 91 Significant elevations in lipids or cholesterol can be managed by mTOR inhibitor dose reduction or anticholesterol agents. The long-term incidence of malignancy in solid organ transplant recipients taking mTOR inhibitors is low compared with those taking other immunosuppressive agents.…”

Section: Personalized Medicine In Mtoropathy-related Epilepsiesmentioning

confidence: 99%

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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%

Section: Personalized Medicine In Mtoropathy-related Epilepsiesmentioning

confidence: 99%

Section: Personalized Medicine In Mtoropathy-related Epilepsiesmentioning

confidence: 99%

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Epilepsy in the mTORopathies: opportunities for precision medicine

Moloney

Cavalleri

Delanty

2021

Brain Communications

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“…TSC is an autosomal dominant disorder that can cause disabling neurological disorders, such as epilepsy and TSC-related neuropsychiatric disorders ( Luo et al, 2022 ). mTOR inhibitors (rapamycin/everolimus) show great potential in the treatment of TSCs, but there are two adverse effects that hinder their widespread use ( Kingswood et al, 2021 ; Luo et al, 2022 ). Although classical antidepressants have been found to increase the expression and function of neurotrophic factors and activate mTOR, the pathogenesis of depression and the mechanism of action of current antidepressants are unclear ( Ignácio et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Prospects and hot spots for mammalian target of rapamycin in the field of neuroscience from 2002 to 2021

Xia

Luo

et al. 2022

Front. Integr. Neurosci.

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Mammalian target of rapamycin (mTOR) is an important molecule that regulates cell metabolism, growth, and proliferation in the nervous system. This study aimed to present the current study hot spots and predict the future development trend of the mTOR pathway in neurologic diseases using bibliometrics. We referred to the publications in the Web of Science Core Collection database. VOSviewer and CiteSpace programs were used to evaluate countries/regions, institutions, authors, journals, keywords, and citations showing the current study focus and predicting the future trend of mTOR in neuroscience. The search date ended on 19 June 2022, and there were 3,029 articles on mTOR in neuroscience from 2002 to 2021. Visual analysis showed that although the number of publications declined slightly in some years, the number of publications related to mTOR generally showed an upward trend, reaching its peak in 2021. It had the largest number of publications in the United States. Keywords and literature analysis showed that protein synthesis regulation, ischemia, mitochondrial dysfunction, oxidative stress, and neuroinflammation may be hot spots and future directions of the nervous system in mTOR studies. Recently, the most studied neurological diseases are Alzheimer’s disease (AD), tuberous sclerosis complex (TSC), and depression, which are still worthy of further studies by researchers in the future. This can provide a useful reference for future researchers to study mTOR further in the field of neuroscience.

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“…However, few articles have systematically summarized the efficacy and safety of mTOR inhibitors for the treatment of TSC. A recent article systematically summarized only the adverse events (AEs) of everolimus based on the TOSCA cohort [ 15 ]. Herein, we discussed the role of the activation of the mTOR signaling pathway in the pathogenesis of TSC, and focused on both efficacy and safety of mTOR inhibitors in the treatment of various clinical manifestations of TSC.…”

Section: Introductionmentioning

confidence: 99%

Perfect match: mTOR inhibitors and tuberous sclerosis complex

Luo

Shi

et al. 2022

Orphanet J Rare Dis

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Tuberous sclerosis complex (TSC) is an autosomal dominant syndrome that presents with diverse and complex clinical features and involves multiple human systems. TSC-related neurological abnormalities and organ dysfunction greatly affect the quality of life and can even result in death in patients with TSC. It is widely accepted that most TSC-related clinical manifestations are associated with hyperactivation of the mammalian target of rapamycin (mTOR) pathway caused by loss‑of‑function mutations in TSC1 or TSC2. Remarkable progress in basic and translational research has led to encouraging clinical advances. Although mTOR inhibitors (rapamycin/everolimus) demonstrate great potential in TSC management, two major concerns hamper their generalized application. One is the frequent manifestation of adverse events, such as stomatitis, infections, and menstrual disorders; and the other is the poor response in certain patients. Thus, indicators are required to effectively predict the efficacy of mTOR inhibitors. Herein, we have summarized the current utilization of mTOR inhibitors in the treatment of TSC and focused on their efficacy and safety, in an attempt to provide a reference to guide the treatment of TSC.

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TuberOus SClerosis registry to increAse disease awareness (TOSCA) Post-Authorisation Safety Study of Everolimus in Patients With Tuberous Sclerosis Complex

Cited by 11 publications

References 22 publications

Epilepsy in the mTORopathies: opportunities for precision medicine

Epilepsy in the mTORopathies: opportunities for precision medicine

Prospects and hot spots for mammalian target of rapamycin in the field of neuroscience from 2002 to 2021

Perfect match: mTOR inhibitors and tuberous sclerosis complex

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