Gene Therapy for Mucopolysaccharidosis Type II—A Review of the Current Possibilities

Abstract

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder based on a mutation in the IDS gene that encodes iduronate 2-sulphatase. As a result, there is an accumulation of glycosaminoglycans—heparan sulphate and dermatan sulphate—in almost all body tissues, which leads to their dysfunction. Currently, the primary treatment is enzyme replacement therapy, which improves the course of the disease by reducing somatic symptoms, including hepatomegaly and splenomegaly. The enzyme, however, does not cross the blood–brain barrier, and no improvement in the function of the central nervous system has been observed in patients with the severe form of the disease. An alternative method of treatment that solves typical problems of enzyme replacement therapy is gene therapy, i.e., delivery of the correct gene to target cells through an appropriate vector. Much progress has been made in applying gene therapy for MPS II, from cellular models to human clinical trials. In this article, we briefly present the history and basics of gene therapy and discuss the current state of knowledge about the methods of this therapy in mucopolysaccharidosis type II.

Phenotypic Correction of Murine Mucopolysaccharidosis Type II by Engraftment of Ex Vivo Lentiviral Vector-Transduced Hematopoietic Stem and Progenitor Cells

“… 1 Loss of IDS leads to disruption in the catabolism of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate, which accumulate in lysosomes leading to progressive and multisystemic disease. 2 Manifestations include organomegaly, cardiopulmonary obstruction, skeletal dysplasias, and in the most severe cases, neurodegeneration and death by adolescence. 3…”

Timing is everything: Clinical courses of Hunter syndrome associated with age at initiation of therapy in a sibling pair

“…Although it is believed that standard intravenous ERT does not appreciably cross the blood-brain barrier, reports suggest that a small fraction of enzyme is able to enter the CNS [ [34] , [35] , [36] ], with hypothesized mechanisms that include pinocytosis [ 37 ], extracellular pathways [ 38 ], more efficient uptake via mannose-6-phosphate receptors [ 32 ], or other presently unrecognized ones. The entry of enzyme into the CNS is a critical focus of therapeutic development, as recent reviews have described therapeutics in development or in trial, such as brain-penetrating ERT and gene therapies [ [39] , [40] , [41] , [42] , [43] ]. HCT is the standard of care for MPS I but has had varying outcomes for MPS II [ 44 ], with concerns about a lack of controlled clinical studies of this approach for MPS II [1] ; however, there is some evidence that earlier treatment is key [ 45 ].…”

Impact of the Timing of Enzyme Replacement Therapy Initiation and Cognitive Impairment Status on Outcomes for Patients with Mucopolysaccharidosis II (MPS II) in the United States: A Retrospective Chart Review

“…Treatments in development for neuronopathic MPS II include intracerebroventricular or intrathecal ERT, fusion proteins that facilitate blood-brain barrier penetration, and gene therapy. [46][47][48][49][50]…”