Cheah Pike-See, Prabhakar Shilpa, Yellen David, Beauchamp Roberta L, Zhang Xuan, Kasamatsu Shingo, Bronson Roderick T, Thiele Elizabeth A, Kwiatkowski David J, Stemmer-Rachamimov Anat, György Bence, Ling King-Hwa, Kaneki Masao, Tannous Bakhos A, Ramesh Vijaya, Maguire Casey A, Breakefield Xandra O
Molecular Neurogenetics Unit, Department of Neurology and Center for Molecular Imaging Research, Department of Radiology, Massachusetts General Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA, USA.
Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia.
Sci Adv. 2021 Jan 8;7(2). doi: 10.1126/sciadv.abb1703. Print 2021 Jan.
Tuberous sclerosis complex (TSC) results from loss of a tumor suppressor gene - 1 or 2, 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 was generated by AAV-Cre recombinase disruption of -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.
结节性硬化症复合体（TSC）是由肿瘤抑制基因1或2缺失引起的，这两个基因分别编码错构瘤蛋白和结节蛋白。这些蛋白质形成复合物以抑制mTORC1介导的细胞生长和增殖。任一蛋白质的缺失都会导致许多重要器官出现过度生长病变。在携带人结节蛋白“浓缩”形式（cTuberin）互补序列的腺相关病毒（AAV）载体的TSC2小鼠模型中评估了基因治疗。cTuberin的功能在培养物中得到验证。通过出生时AAV-Cre重组酶破坏floxed等位基因产生了一个小鼠模型，导致寿命缩短（平均58天）和与TSC一致的脑部病理变化。当这些小鼠在第21天静脉注射AAV9-cTuberin时，平均生存期延长至462天，脑部病理变化减轻。这证明了单次静脉注射AAV9-cTuberin治疗危及生命的TSC2病变的潜力。
