Miranda Paula S Montenegro, Bosma Piter J
AMC Liver Center, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
Curr Gene Ther. 2009 Apr;9(2):72-82. doi: 10.2174/156652309787909508.
Crigler-Najjar (CN) syndrome is a recessive inherited disorder caused by deficiency of uridine diphospho-glucuronosyl transferase 1A1. This hepatic enzyme catalyzes the glucuronidation of bilirubin, an essential step in excretion into bile of this neurotoxic compound. As a result, CN patients suffer from severe unconjugated hyperbilirubinemia and are at risk of bilirubin encephalopathy. Over the last decades ex vivo and in vivo gene therapy using viral and non-viral vectors has been used to correct hyperbilirubinemia in the relevant animal model for CN syndrome, the Gunn rat. Several of these approaches did result in long-term correction of serum bilirubin levels in this animal model. However, none have been translated into a clinical trial. In this review we will recapitulate the strategies used and discuss their suitability for clinical application in the near future. We will also address specific safety measures in the gene therapy protocol needed to prevent adverse effects such as bilirubin toxicity. Since CN seems an ideal model for other monogenetic inherited metabolic liver disorders, development of liver-directed gene-therapy has relevance beyond this rare disease.
克里格勒-纳贾尔（CN）综合征是一种隐性遗传性疾病，由尿苷二磷酸葡糖醛酸基转移酶1A1缺乏引起。这种肝脏酶催化胆红素的葡糖醛酸化，这是该神经毒性化合物排泄到胆汁中的关键步骤。因此，CN患者患有严重的非结合性高胆红素血症，并有患胆红素脑病的风险。在过去几十年中，使用病毒和非病毒载体的体外和体内基因治疗已被用于纠正CN综合征相关动物模型——冈恩大鼠的高胆红素血症。其中一些方法确实在该动物模型中实现了血清胆红素水平的长期纠正。然而，尚无一种方法转化为临床试验。在本综述中，我们将概述所使用的策略，并讨论它们在不久的将来用于临床应用的适用性。我们还将探讨基因治疗方案中为预防胆红素毒性等不良反应所需的特定安全措施。由于CN似乎是其他单基因遗传性代谢性肝脏疾病的理想模型，肝脏定向基因治疗的发展意义不仅限于这种罕见疾病。
