• 1.

    Davis PE, et al. Presentation and diagnosis of tuberous sclerosis complex in infants. Pediatrics 2017; 140:e20164040. doi: 10.1542/peds.2016-4040

  • 2.

    Bissler JJ, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008; 358:140151. doi: 10.1056/NEJ-Moa063564

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Bissler JJ, et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): A multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2013; 381:817824. doi: 10.1016/S0140-6736(12)61767-X

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Franz DN, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): A multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2013; 381:125132. doi: 10.1016/S0140-6736(12)61134-9

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    French JA, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): A phase 3, randomised, double-blind, placebo-controlled study. Lancet 2016; 388:21532163. doi: 10.1016/S0140-6736(16)31419-2

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Kingswood JC, et al. Review of the tuberous sclerosis renal guidelines from the 2012 Consensus Conference: Current data and future study. Nephron 2016; 134:5158. doi: 10.1159/000448293

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Siroky BJ, et al. Improvement in renal cystic disease of tuberous sclerosis complex after treatment with mammalian target of rapamycin inhibitor. J Pediatr 2017; 187:318-322.e2. doi: 10.1016/j.jpeds.2017.05.015

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Nechama M, et al. Rapamycin and dexamethasone during pregnancy prevent tuberous sclerosis complex-associated cystic kidney disease. JCI Insight 2020; 5:e136857. doi: 10.1172/jci.insight.136857

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Volovelsky O, et al. Hamartin regulates cessation of mouse nephrogenesis independently of mTOR. Proc Natl Acad Sci USA 2018; 115:59986003. doi: 10.1073/pnas.1712955115

    • Crossref
    • Search Google Scholar
    • Export Citation

Targeting the Molecular Mechanisms of Tuberous Sclerosis

  • 1 Oded Volovelsky is with the Pediatric Nephrology Unit and Research Lab, Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Israel. Bradley Dixon is with the Renal Section, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO.
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Since the completion of the Human Genome Project in 2003, an expanding understanding of the genetic basis of diseases has allowed us to target disease mechanisms at the molecular level. One example of the application of precision medicine in nephrology targets the mammalian target of rapamycin (mTOR) complex in the multisystem disease of tuberous sclerosis (TSC). Affecting roughly 1 in 6000 live births, TSC is a rare but significant cause of kidney disease in children (1). About one-half of patients with TSC are at risk of chronic kidney disease, which is the leading cause of morbidity and mortality in adults with TSC. The kidney manifestations of TSC are characterized by angiomyolipomas, benign tumors with risk of life-threatening hemorrhage, and cystic kidney disease ranging from a single cyst to polycystic kidney disease gradually encroaching upon and replacing healthy renal parenchyma.

Previously, the care of patients with TSC relied on repeated embolizations and surgical resections to remove angiomyolipomas and suspected malignant lesions in the kidney. A wealth of data (2, 3) has demonstrated the efficacy of targeting the mTOR complex in patients with TSC, where mTOR is constitutively overactive due to loss-of-function mutations in TSC1 and TSC2, in which their protein products hamartin and tuberin, respectively, serve to gate mTOR activity. Treatment with mTOR inhibitors, by inhibiting the constitutively overactive complex, decreases the kidney disease burden of angiomyolipoma as well as neurological manifestations of TSC including subependymal giant cell astrocytomas (SEGAs) and seizures (4, 5). Current recommendations direct use of this targeted intervention of mTOR inhibitors in enlarging lesions, thereby directly treating the molecular pathomechanism and sparing surrounding kidney tissue from surgical disruption and injury (6).

Recent efforts have also explored the efficacy of targeting the mTOR complex to reduce the cystic kidney disease associated with TSC, both with retrospective clinical data (7) and more recently in an animal model of TSC cystic kidney disease (8). This recent study provides experimental evidence for the efficacy of mTOR inhibitors administered during pregnancy in preventing the onset of postnatal TSC cystic kidney disease. Despite this beneficial effect of maternal mTOR inhibition on cyst formation in the offspring, non-mTOR-related pathways seem to contribute to cystogenesis, with inflammation playing a central role in the progression of the disease.

In contrast to much accumulated medical knowledge on the deleterious effects of mutations in TSC1 and TSC2, reduced mTOR level by losing a single copy of the TSC1 gene in mouse models has been shown to be beneficial in kidney development by sustaining nephron progenitor cells and increasing nephron number (9). This apparent paradox of the simultaneously detrimental and beneficial effects of a genetic alteration urges caution that even with our most precise insight on the molecular mechanisms of disease, targeted treatments may still have unanticipated consequences. As such, it is humbling to remember that the clinical application of precision medicine, although holding great promise in the individualized treatment of patients with kidney disease, is indeed still in its formative youth.

Disclosures:

Oded Volovelsky's TSC research is funded by a research grant of the TS Alliance. Bradley Dixon is a consultant for Apellis Pharmaceuticals and Alexion Pharmaceuticals.

References

  • 1.

    Davis PE, et al. Presentation and diagnosis of tuberous sclerosis complex in infants. Pediatrics 2017; 140:e20164040. doi: 10.1542/peds.2016-4040

  • 2.

    Bissler JJ, et al. Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med 2008; 358:140151. doi: 10.1056/NEJ-Moa063564

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Bissler JJ, et al. Everolimus for angiomyolipoma associated with tuberous sclerosis complex or sporadic lymphangioleiomyomatosis (EXIST-2): A multicentre, randomised, double-blind, placebo-controlled trial. Lancet 2013; 381:817824. doi: 10.1016/S0140-6736(12)61767-X

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Franz DN, et al. Efficacy and safety of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis complex (EXIST-1): A multicentre, randomised, placebo-controlled phase 3 trial. Lancet 2013; 381:125132. doi: 10.1016/S0140-6736(12)61134-9

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    French JA, et al. Adjunctive everolimus therapy for treatment-resistant focal-onset seizures associated with tuberous sclerosis (EXIST-3): A phase 3, randomised, double-blind, placebo-controlled study. Lancet 2016; 388:21532163. doi: 10.1016/S0140-6736(16)31419-2

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    Kingswood JC, et al. Review of the tuberous sclerosis renal guidelines from the 2012 Consensus Conference: Current data and future study. Nephron 2016; 134:5158. doi: 10.1159/000448293

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 7.

    Siroky BJ, et al. Improvement in renal cystic disease of tuberous sclerosis complex after treatment with mammalian target of rapamycin inhibitor. J Pediatr 2017; 187:318-322.e2. doi: 10.1016/j.jpeds.2017.05.015

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Nechama M, et al. Rapamycin and dexamethasone during pregnancy prevent tuberous sclerosis complex-associated cystic kidney disease. JCI Insight 2020; 5:e136857. doi: 10.1172/jci.insight.136857

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Volovelsky O, et al. Hamartin regulates cessation of mouse nephrogenesis independently of mTOR. Proc Natl Acad Sci USA 2018; 115:59986003. doi: 10.1073/pnas.1712955115

    • Crossref
    • Search Google Scholar
    • Export Citation
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