Department of Biochemistry and Molecular Biology, Institute for Medical Research-Israel-Canada, The Hebrew University-Hadassah Medical School, Jerusalem, 91120, Israel.
J Mol Med (Berl). 2011 Feb;89(2):161-70. doi: 10.1007/s00109-010-0693-3. Epub 2010 Nov 16.
Medicine today offers no cure for patients suffering from mitochondrial disorders, such as lipoamide dehydrogenase (LAD; also known as E3) deficiency, and treatment is limited to symptomatic care. LAD is one of the components of the α-ketoacid dehydrogenase complexes, which are mitochondrial multienzyme complexes crucial for the metabolism of carbohydrates and amino acids. Recently, we tested the therapeutic approach for treating mitochondrial disorders whereby the activity of multicomponent complexes in the mitochondria is restored by TAT-mediated enzyme replacement therapy (ERT). The LAD deficiency disease was used before as a proof-of-principle in vitro, in patients' cells, utilizing the TAT-LAD fusion protein. In this report, we present successful TAT-mediated ERT in an in vivo mouse model using E3-deficient mice. We demonstrate the delivery of TAT-LAD into E3-deficient mice tissues and that a single administration of TAT-LAD results in a significant increase in the enzymatic activity of the mitochondrial multienzyme complex pyruvate dehydrogenase complex within the liver, heart and, most importantly, the brain of TAT-LAD-treated E3-deficient mice. We believe that this TAT-mediated ERT approach could change the management of mitochondrial disorders and of other metabolic diseases in modern medicine.
今天的医学尚无治愈患有线粒体疾病（如脂酰基辅酶 A 脱氢酶[LAD]（亦称 E3）缺乏症）患者的方法，且治疗仅限于对症治疗。LAD 是 α-酮酸脱氢酶复合物的组成部分之一，该复合物是对碳水化合物和氨基酸代谢至关重要的线粒体多酶复合物。最近，我们通过 TAT 介导的酶替代疗法（ERT）测试了治疗线粒体疾病的方法，通过该方法可恢复线粒体中多成分复合物的活性。此前，我们曾使用 LAD 缺乏症作为在体外患者细胞中利用 TAT-LAD 融合蛋白进行原理验证的范例。在本报告中，我们使用 E3 缺乏症小鼠成功地进行了体内 TAT 介导的 ERT。我们证明了 TAT-LAD 递送至 E3 缺乏症小鼠组织，并且单次给予 TAT-LAD 可导致肝脏、心脏，最重要的是，TAT-LAD 治疗的 E3 缺乏症小鼠的大脑中的丙酮酸脱氢酶复合物等线粒体多酶复合物的酶活性显著增加。我们相信，这种 TAT 介导的 ERT 方法可能会改变线粒体疾病和现代医学中其他代谢疾病的治疗管理。
