Authors: Pike-See Cheah, Shilpa Prabhakar, David Yellen, Roberta L. Beauchamp, Xuan Zhang, Shingo Kasamatsu, Roderick T. Bronson, Elizabeth A. Thiele, David J. Kwiatkowski, Anat Stemmer-Rachamimov, Bence György, King-Hwa Ling, Masao Kaneki, Bakhos A. Tannous, Vijaya Ramesh, Casey A. Maguire, Xandra O. Breakefield
Summary: Tuberous sclerosis complex (TSC) results from loss of a tumor suppressor gene - TSC1 or TSC2, encoding hamartin and tuberin, respectively. These proteins formed a complex to inhibit mTORC1-mediated cell growth and proliferation. Loss of either protein leads to overgrowth lesions in many vital organs. Gene therapy was evaluated in a mouse model of TSC2 using an adeno-associated virus (AAV) vector carrying the complementary for a “condensed” form of human tuberin (cTuberin). Functionality of cTuberin was verified in culture. A mouse model of TSC2 was generated by AAV-Cre recombinase disruption of Tsc2-floxed alleles at birth, leading to a shortened lifespan (mean 58 days) and brain pathology consistent with TSC. When these mice were injected intravenously on day 21 with AAV9-cTuberin, the mean survival was extended to 462 days with reduction in brain pathology. This demonstrates the potential of treating life-threatening TSC2 lesions with a single intravenous injection of AAV9-cTuberin.
Source: Science Advances, 2021; 7 (2): eabb1703