Heat Shock Machinery as a Druggable Target in Tuberous Sclerosis Complex
A treatment for Tuberous Sclerosis as well as other neuropsychiatric disorders with altered cilia
Background
Tuberous Sclerosis Complex (TSC) is a neurogenetic disorder that leads to the formation of tumors in many different organs including the brain, eyes, heart, kidney, and lungs. It is caused by mutations in two genes TSC1 and TSC2 whose protein products normally inhibit the mammalian Target of Rapamycin (mTOR)–whose activity is highly elevated in TSC patients leading to abnormal cell growth and other neurological symptoms. Thus, there is a clear unmet need for new drugs based on a mechanistic understanding of TSC biology downstream of mTOR activity.
Technology Overview
Boston Children’s Hospital researchers have developed a high-content cell-based assay (HCA) to analyze the downstream pathways affected by increased mTOR signaling in neurons. Using this robust HCA, they screened for small molecules that inhibit and identified the heat shock machinery as a druggable pathway.
Neurons from brain of TSC patients and Tsc1/Tsc2 knockout mouse models show increased mTOR activity and reduced primary cilia-cellular “antenna” involved in brain development and homeostasis. Altered cilia are associated with a spectrum of neuropsychiatric disorders including TSC. Phenotypic screen in rat hippocampal neurons for inhibitors of mTORC1 activity identified the heat shock pathway as a target. Inhibition of heat shock pathway also rescued cilia numbers.
Further Detail
- Di Nardo, Alessia, et al. “Phenotypic Screen with TSC-Deficient Neurons Reveals Heat-Shock Machinery as a Druggable Pathway for MTORC1 and Reduced Cilia.” Cell Reports, vol. 31, no. 12, 2020, p. 107780, doi:https://doi.org/10.1016/j.celrep.2020.107780.
- Krueger, Darcy A., et al. “Everolimus for Treatment of Tuberous Sclerosis Complex-Associated Neuropsychiatric Disorders.” Annals of Clinical and Translational Neurology, vol. 4, no. 12, John Wiley & Sons, Ltd, Dec. 2017, pp. 877–87, doi:https://doi.org/10.1002/acn3.494.
Benefits
- Currently Everolimus (an mTOR inhibitor) is the only mechanism-specific drug approved for treatment of TSC. Though mTOR inhibitors can offer some benefit in treating TSC-associated tumors, they are ineffective in suppressing the neuropsychiatric symptoms and can have unwanted side effects.
- Targeting the heat shock pathway could be a safer and more effective therapeutic option for TSC.
Applications
- Treatment of Tuberous Sclerosis Complex patients
- Treatment of other neuropsychiatric disorders where cilia are altered
IP Status
- Patent application submitted
