Dose responsive effects of subcutaneous pentosan polysulfate injection in mucopolysaccharidosis type VI rats and comparison to oral treatment.

BACKGROUND: We previously demonstrated the benefits of daily, oral pentosan polysulfate (PPS) treatment in a rat model of mucopolysaccharidosis (MPS) type VI. Herein we compare these effects to once weekly, subcutaneous (s.c.) injection. The bioavailability of injected PPS is greater than oral, suggesting better delivery to difficult tissues such as bone and cartilage. Injected PPS also effectively treats osteoarthritis in animals, and has shown success in osteoarthritis patients. METHODOLOGY/PRINCIPAL FINDINGS: One-month-old MPS VI rats were given once weekly s.c. injections of PPS (1, 2 and 4 mg/kg, human equivalent dose (HED)), or daily oral PPS (4 mg/kg HED) for 6 months. Serum inflammatory markers and total glycosaminoglycans (GAGs) were measured, as were several histological, morphological and functional endpoints. Overall, weekly s.c. PPS injections led to similar or greater therapeutic effects as daily oral administration. Common findings between the two treatment approaches included reduced serum inflammatory markers, improved dentition and skull lengths, reduced tracheal deformities, and improved mobility. Enhanced effects of s.c. treatment included GAG reduction in urine and tissues, greater endurance on a rotarod, and better improvements in articular cartilage and bone in some dose groups. Optimal therapeutic effects were observed at 2 mg/kg, s.c.. No drug-related increases in liver enzymes, coagulation factor abnormalities or other adverse effects were identified following 6 months of s.c. PPS administration. CONCLUSIONS: Once weekly s.c. administration of PPS in MPS VI rats led to equal or better therapeutic effects than daily oral administration, including a surprising reduction in urine and tissue GAGs. No adverse effects from s.c. PPS administration were observed over the 6-month study period.

Corneal hysteresis in mucopolysaccharidosis I and VI.

PURPOSE: High intraocular pressure (IOP) and glaucoma are often suspected in patients with mucopolysaccharidosis (MPS). To determine corneal hysteresis (CH) and IOP in children with mucopolysaccharidosis I-Hurler (MPS I-H) and MPS VI. METHODS: Clinical measurements with ocular response analyzer (ORA). RESULTS: In seven patients, five with MPS I-H treated with stem cell transplantation (SCT), and two with MPS VI, one treated with SCT and the other with enzyme therapy, the IOP was examined with ORA. Ocular response analyzer measurements were made at a median age of 8.7 years in the patients with MPS I-H and at a median age of 9.3 years in the patients with MPS VI. Earlier measurements had raised suspicion of high IOP in one patient. The ORA showed an increased CH and a falsely high IOP values in all 14 eyes. The recalculated IOPs were normal in all 14 eyes. Mild to severe corneal opacities were present in all 14 eyes. Optic disc areas, borders and cupping were clinically normal in the 12 of 14 eyes that were possible to examine. Severe corneal opacities hampered optic disc evaluation in the older patient with MPS VI. Three eyes in two patients had normal thickness of the retinal nerve fibre layer measured with scanning laser polarimetry with corneal compensation (GDx VCC). No patient was diagnosed or treated for glaucoma. CONCLUSION: The IOPs are often falsely high because of an increased resistance of the cornea and correlate to the extent of corneal clouding. In this small, cross-sectional study, it appears that corneal resistance is directly correlated with corneal clouding, although a longitudinal study that evaluates resistance as the cornea clears with treatment would provide more direct evidence that corneal deposits are directly related to resistance. A correct measured IOP can avoid unnecessary medical or surgical hypotensive treatment.