Therapeutic targeting of mTOR in tuberous sclerosis
Therapeutic targeting of mTOR in tuberous sclerosis
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DOI：
10.1042/bst0370259
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发表时间：
2009-02-01
影响因子：
3.9
通讯作者：
Sampson, Julian R.
中科院分区：
文献类型：
--
作者：
Sampson, Julian R.
mTOR（雷帕霉素的哺乳动物靶蛋白）的调节失败似乎对遗传性疾病结节性硬化症和相关的肺部疾病LAM（淋巴管平滑肌瘤病）的发病机制至关重要。这两种疾病都是由TSC 1或TSC 2（TSC是结节性硬化症复合体）的突变引起的，这些突变损害了TSC 1-TSC 2复合体对Rheb的GAP（GTP酶激活蛋白）活性，导致mTOR 1（mTOR复合体1）下游信号传导的不适当活性。mTOR抑制剂已经用于各种临床环境，包括作为药物洗脱冠状动脉支架中的免疫抑制剂、抗癌剂和抗增殖剂。它们也代表了针对结节性硬化症和LAM中潜在分子病理学的候选疗法。mTORC 1抑制剂雷帕霉素的I/II期临床试验已经证明了结节性硬化症和LAM相关肾肿瘤（血管平滑肌脂肪瘤）的大小减少，以及LAM患者肺功能可逆改善的一些证据。据报道，一系列结节性硬化症相关脑肿瘤的病例在雷帕霉素治疗期间也缩小了。结节性硬化症表型的一个重要特征是学习困难，尽管是可变的。最近在携带杂合Tsc 2突变的小鼠模型中的研究表明，雷帕霉素治疗后记忆和学习缺陷得到改善。这些有希望的临床前和早期人体试验之后，正在进行mTOR抑制剂治疗TSC 1和TSC 2相关疾病的肾脏，肺部和脑部表现的大规模随机对照试验。
Failure in the regulation of mTOR (mammalian target of rapamycin) appears to be critical to the pathogenesis of the inherited disorder tuberous sclerosis and the related lung disease LAM (lymphangioleiomyomatosis). Both diseases are caused by mutations of TSC1 or TSC2 (TSC is tuberous sclerosis complex) that impair GAP (GTPase-activating protein) activity of the TSC1-TSC2 complex for Rheb, leading to inappropriate activity of signalling downstream of mTORC1 (mTOR complex 1). mTOR inhibitors are already used in a variety of clinical settings including as immunosuppressants, anticancer agents and anti proliferative agents in drug-eluting coronary artery stents. They also represent candidate therapies directed to the underlying molecular pathology in tuberous sclerosis and LAM. Phase I/II clinical trials of the mTORC1 inhibitor rapamycin have demonstrated reduction in size of tuberous-sclerosis- and LAM-associated renal tumours (angiomyolipomas) and some evidence for reversible improvement in lung function in patients with LAM. A case series of tuberous-sclerosis-associated brain tumours were also reported to shrink during rapamycin therapy. An important, although variable, feature of the tuberous sclerosis phenotype is learning difficulty. Recent studies in mouse models carrying heterozygous Tsc2 mutations demonstrated improvement in memory and learning deficits following treatment with rapamycin. These promising pre-clinical and early human trials are being followed by larger-scale randomized control trials of mTOR inhibitors for treatment of renal, lung and brain manifestations of TSC1- and TSC2-associated disease.