Achievements and difficulties of enzyme replacement therapy for X-recessive lysosomal storage diseases

Abstract

Introduction: About 50 rare inherited metabolic disorders result from defects in lysosomal function. Most of them are inherited autosomal recessively except X-recessive Hunter syndrome and Fabry dis­ease. The first one is a mucopolysaccharidosis type II and represents a deficit/ absence of the enzyme iduronate-2-sulfatase which leads to accumulation of heparan sulfate and dermatan sulfate. Fabry disease is defined as a sphingolipidosis and characterized by deficient activity of α-galactosidase A. A possible approach to an effective treatment of these pathologies is enzyme replacement therapy (ERT). ERT for lysosomal storage diseases (LSD) is proposed by de Duve in 1964 and since then several prod­ucts have been used in clinical practice with varying success. Materials and methods: A systematic review and meta-analysis based on double-blind randomized clinical trials on ERT for Fabry and Hunter disease were conducted. The data collection was mediated by the Google Scholar platform using the keywords X-recessive LSD, ERT for Fabry and Hunter dis­ease. Results: The observation summarizes the results of recent clinical trials on idursulfase (Elaprase) on Hunter disease patients and recombinant enzymes agalsidase alfa and beta for Fabry disease. Both studies reveal promising somatic improvement, especially 90% liver volume reduction for Hunter dis­ease and renal function recovery for Fabry disease. However, no statistically significant results on ter­minating neurological progression have yet been accomplished. A meta-analysis on the risks and ben­efits of ERT shows unsatisfactory changes and increased incidence of side effects in severe phenotypes and patients with early LSD onset. Conclusions: The effectiveness of enzyme replacement therapy is dependent on early diagnosis of LSD. Clinical recognition and timely treatment with orphan drugs increase the survival and quality of life in patients with X-recessive LSD satisfactorily. Additional gene therapy for Hunter disease is al­ready accomplished.