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Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders (LSDs) caused by a deficiency of lysosomal enzymes, leading to a wide range of various clinical symptoms depending upon the type of MPS or its severity. Enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), substrate reduction therapy (SRT), and various surgical procedures are currently available for patients with MPS. However, there is no curative treatment for this group of disorders. Gene therapy should be a one-time permanent therapy, repairing the cause of enzyme deficiency. Preclinical studies of gene therapy for MPS have been developed over the past three decades. Currently, clinical trials of gene therapy for some types of MPS are ongoing in the United States, some European countries, and Australia. Here, in this review, we summarize the development of gene therapy for MPS in preclinical and clinical trials.

Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders, which lack an enzyme corresponding to the specific type of MPS. Enzyme replacement therapy (ERT) has been the standard therapeutic option for some types of MPS because of the ability to start immediate treatment with feasibility and safety and to improve prognosis. There are several disadvantages for current ERT, such as limited impact to the brain and avascular cartilage, weekly or biweekly infusions lasting 4–5 h, the immune response against the infused enzyme, a short half-life, and the high cost. Clinical studies of ERT have shown limited efficacy in preventing or resolving progression in neurological, cardiovascular, and skeletal diseases. One focus is to penetrate the avascular cartilage area to at least stabilize, if not reverse, musculoskeletal diseases. Although early intervention in some types of MPS has shown improvements in the severity of skeletal dysplasia and stunted growth, this limits the desired effect of ameliorating musculoskeletal disease progression to young MPS patients. Novel ERT strategies are under development to reach the brain: (1) utilizing a fusion protein with monoclonal antibody to target a receptor on the BBB, (2) using a protein complex from plant lectin, glycan, or insulin-like growth factor 2, and (3) direct infusion across the BBB. As for MPS IVA and VI, bone-targeting ERT will be an alternative to improve therapeutic efficacy in bone and cartilage. This review summarizes the effect and limitations on current ERT for MPS and describes the new technology to overcome the obstacles of conventional ERT.

SUMMARY A moderate earthquake of Mw= 6.8 occurred on 2003 December 10. It ruptured the Chihshang Fault in eastern Taiwan which is the most active segment of the Longitudinal fault as a plate suture fault between the Luzon arc of the Philippine Sea plate and the Eurasian plate. The largest coseismic displacements were 13 cm (horizontal) and 26 cm (vertical). We analyse 40 strong motion and 91 GPS data to model the fault geometry and coseismic dislocations. The most realistic shape of the Chihshang fault surface is listric in type. The dipping angle of the seismic zone is steep (about 60°–70°) at depths shallower than 10 km and then gradually decreases to 40°–50° at depths of 20–30 km. Thus the polygonal elements in Poly3D are well suited for modelling complex surfaces with curving boundaries. Using the strong motion data, the displacement reaches 1.2 m dip-slip on the Chihshang Fault and decreases to 0.1 m near surface. The slip averages 0.34 m, releasing a scalar moment of 1.6E26 dyne-cm. For GPS data, our model reveals that the maximal dislocation is 1.8 m dip-slip. The dislocations decrease to 0.1 m near the surface. The average slip is 0.48 m, giving a scalar moment of 2.2E26 dyne-cm. Regarding post-seismic deformation, a displacements of 0.5 m were observed near the Chihshang Fault, indicating the strain had not been totally released, as a probable result of near-surface locking of the fault zone.