Department of Experimental Medicine, University of Perugia, P.le Gambuli 1, 06132, Perugia, Italy.
Department of Neurosciences, Biomedicine and Movement Sciences, Section of Biological Chemistry, University of Verona, Strada le Grazie 8, 37134, Verona, VR, Italy.
Urolithiasis. 2019 Feb;47(1):67-78. doi: 10.1007/s00240-018-1089-z. Epub 2018 Nov 14.
Primary hyperoxalurias (PHs) are rare inherited disorders of liver glyoxylate metabolism, characterized by the abnormal production of endogenous oxalate, a metabolic end-product that is eliminated by urine. The main symptoms are related to the precipitation of calcium oxalate crystals in the urinary tract with progressive renal damage and, in the most severe form named Primary Hyperoxaluria Type I (PH1), to systemic oxalosis. The therapies currently available for PH are either poorly effective, because they address the symptoms and not the causes of the disease, or highly invasive. In the last years, advances in our understanding of the molecular bases of PH have paved the way for the development of new therapeutic strategies. They include (i) substrate-reduction therapies based on small-molecule inhibitors or the RNA interference technology, (ii) gene therapy, (iii) enzyme administration approaches, (iv) colonization with oxalate-degrading intestinal microorganisms, and, in PH1, (v) design of pharmacological chaperones. This paper reviews the basic principles of these new therapeutic strategies and what is currently known about their application to PH.
原发性高草酸尿症（PH）是一种罕见的肝脏乙醛酸代谢遗传性疾病，其特征是内源性草酸的异常产生，草酸是一种代谢终产物，通过尿液排出。主要症状与尿路草酸钙晶体的沉淀有关，随着病情的进展会导致肾脏损伤，在最严重的形式（即原发性高草酸尿症 1 型，PH1）中还会导致全身性草酸中毒。目前可用于 PH 的治疗方法要么效果不佳，因为它们仅针对疾病的症状，而不能针对病因；要么具有高度侵袭性。近年来，我们对 PH 的分子基础的认识的进步为新的治疗策略的发展铺平了道路。这些策略包括：（i）基于小分子抑制剂或 RNA 干扰技术的底物减少疗法；（ii）基因治疗；（iii）酶替代疗法；（iv）用能够降解草酸的肠道微生物进行定植；以及在 PH1 中，（v）设计药理学伴侣。本文综述了这些新治疗策略的基本原理，以及目前已知的将其应用于 PH 的情况。
