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Paradigm shift in the treatment of tuberous sclerosis: Effectiveness of everolimus
Roberto Previtali1, Giorgia Prontera2, Enrico Alfei3
1Pediatric Neurology Unit, Buzzi Children's Hospital, Milan, Italy; Department of Biomedical and Clinical Sciences, University of Milan, Milan, Italy.
Abstract:
Tuberous sclerosis complex (TSC) is an autosomal dominant disease characterised by abnormal cell proliferation and differentiation that affects multiple organs and can lead to the growth of hamartomas. Tuberous sclerosis complex is caused by the disinhibition of the protein mTOR (mammalian target of rapamycin). In the past, various therapeutic approaches, even if only symptomatic, have been attempted to improve the clinical effects of this disease. While all of these therapeutic strategies are useful and are still used and indicated, they are symptomatic therapies based on the individual symptoms of the disease and therefore not fully effective in modifying long-term outcomes. A new therapeutic approach is the introduction of allosteric inhibitors of mTORC1, which allow restoration of metabolic homeostasis in mutant cells, potentially eliminating most of the clinical manifestations associated with Tuberous sclerosis complex. Everolimus, a mammalian target of the rapamycin inhibitor, is able to reduce hamartomas, correcting the specific molecular defect that causes Tuberous sclerosis complex. In this review, we report the findings from the literature on the use of everolimus as an effective and safe drug in the treatment of TSC manifestations affecting various organs, from the central nervous system to the heart.
Insights
Tuberous sclerosis complex (TSC) is a genetic disorder caused by mTOR pathway overactivation. Everolimus, an mTOR inhibitor, effectively treats TSC manifestations by targeting the underlying molecular defect.
Area of Science:
- Genetics and Molecular Biology
- Oncology
- Pharmacology
Background:
- Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by abnormal cell growth, leading to hamartomas in multiple organs.
- The disease arises from the dysregulation of the mammalian target of rapamycin (mTOR) pathway, specifically mTOR complex 1 (mTORC1).
- Current treatments for TSC are largely symptomatic and do not address the root molecular cause, limiting their long-term efficacy.
Approach:
- This review synthesizes existing literature on the therapeutic application of everolimus, an allosteric inhibitor of mTORC1.
- Everolimus targets the specific molecular defect in TSC by inhibiting mTORC1 activity.
- The study evaluates the efficacy and safety of everolimus in managing TSC-related manifestations across various organ systems.
Key Points:
- Everolimus normalizes metabolic homeostasis in cells with TSC mutations.
- The drug has demonstrated effectiveness in reducing hamartoma growth.
- Clinical findings support everolimus as a safe and effective treatment for diverse TSC manifestations.
Conclusions:
- Everolimus represents a targeted therapeutic strategy for Tuberous sclerosis complex, addressing the underlying mTORC1 pathway abnormality.
- Its ability to correct the molecular defect offers a significant advantage over traditional symptomatic treatments.
- Everolimus shows promise in improving long-term outcomes for patients with TSC affecting organs such as the brain and heart.
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