Zatkova Andrea, Ranganath Lakshminarayan, Kadasi Ludevit
Department of Human Genetics, Biomedical Research Center, Slovak Academy of Sciences, Institute of Clinical and Translational Research, Bratislava, Slovakia.
National Alkaptonuria Centre, Royal Liverpool University Hospital, Liverpool, UK.
Appl Clin Genet. 2020 Jan 23;13:37-47. doi: 10.2147/TACG.S186773. eCollection 2020.
The last 15 years have been the most fruitful in the history of research on the metabolic disorder alkaptonuria (AKU). AKU is caused by a deficiency of homogentisate dioxygenase (HGD), the enzyme involved in metabolism of tyrosine, and is characterized by the presence of dark ochronotic pigment in the connective tissue that is formed, due to high levels of circulating homogentisic acid. Almost 120 years ago, Sir Archibald Garrod used AKU to illustrate the concept of Mendelian inheritance in man. In January 2019, the phase III clinical study SONIA 2 was completed, which tested the effectiveness and safety of nitisinone in the treatment of AKU. Results were positive, and they will serve as the basis for the application for registration of nitisinone for treatment of AKU at the European Medicines Agency. Therefore, AKU might become a rare disease for which a cure will be found by 2020. We understand the natural history of the disease and the process of ochronosis much more, but at the same time there are still unanswered questions. One of them is the issue of the factors influencing the varying severity of the disease, since our recent genotype-phenotype study did not show that differences in residual homogentisic acid activity caused by the different mutations was responsible. Although nitisinone has proved to arrest the process of ochronosis, it has some unwanted effects and does not cure the disease completely. As such, enzyme replacement or gene therapy might become a new focus of AKU research, for which a novel suitable mouse model of AKU is available already. We believe that the story of AKU is also a story of effective collaboration between scientists and patients that might serve as an example for other rare diseases.
过去15年是对代谢紊乱疾病黑尿症（AKU）研究史上成果最为丰硕的时期。AKU由尿黑酸双加氧酶（HGD）缺乏引起，HGD是参与酪氨酸代谢的酶，其特征是由于循环尿黑酸水平升高，在形成的结缔组织中存在深色的褐黄病色素。近120年前，阿奇博尔德·加罗德爵士用AKU阐述了人类孟德尔遗传的概念。2019年1月，III期临床研究SONIA 2完成，该研究测试了尼替西农治疗AKU的有效性和安全性。结果是阳性的，它们将作为向欧洲药品管理局申请尼替西农治疗AKU注册的依据。因此，AKU可能成为一种到2020年有望找到治愈方法的罕见疾病。我们对该疾病的自然史和褐黄病的过程了解得更多了，但与此同时仍有一些问题未得到解答。其中之一是影响疾病严重程度差异的因素问题，因为我们最近的基因型 - 表型研究并未表明不同突变导致的尿黑酸残留活性差异是造成这种情况的原因。尽管尼替西农已被证明能阻止褐黄病的进程，但它有一些不良影响，且不能完全治愈该疾病。因此，酶替代或基因治疗可能会成为AKU研究的新重点，目前已有一种新型的合适的AKU小鼠模型。我们相信，AKU的故事也是科学家与患者有效合作的故事，可能会成为其他罕见疾病的一个范例。
