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Preclinical Studies of Rapamycin for TSC Brain Disease


Tuberous sclerosis (TSC) is an autosomal dominant hamartoma syndrome due to mutations in either TSC1 or TSC2. During childhood the predominant morbidity in TSC is neurologic, due to involvement of the brain by the cortical tubers and subependymal giant cell astrocytomas. Seizures are seen in 90% of patients, and mental retardation and a variety of development disorders including autism are common. Hamartomas in TSC are thought to arise through a two hit mechanism that results in complete loss of either TSC1 or TSC2. Molecular studies in cultured cells and on tumors arising in TSC patients and mouse models indicate that loss of either tuberin or hamartin leads to a molecular signature of activation of mTOR. mTOR is specifically inhibited by rapamycin and related compounds, and in vitro rapamycin completely reverts the biochemical abnormalities present in Tsc1 null or Tsc2 null cells. We have created conditional alleles of Tscl and Tsc2, and used brain-specific recombinase expressing alleles to generate mice with Tsc1 or Tsc2 null cells in the brain. These mice have multiple features matching those of TSC patients: developmental abnormalities, seizures, and premature mortality. Brain pathology shows enlarged cells similar to those seen in TSC cortical tubers and subependymal giant cell astrocytomas. We propose to systematically explore the potential benefit of rapamcyin therapy, in two different mouse models of TSC brain disease, using survival, development, seizure frequency, and biochemical studies and pathology on brain samples as therapeutic endpoints. We will then test two newer analogues of rapamycin, CCI-779 and everolimus, in these models. These studies will provide critical preclinical data that will support the use of rapamycin or analogues in the treatment of TSC patients with cortical tubers and subependymal giant cell astrocytomas.


Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.