856. Neonatal Liver-Directed Gene Therapy Markedly Reduces Bone Disease in MPS I
Authors: Yuli Liu, Mango Robert, Lingfei Xu, Deborah Novack, Clay Semenkovich, Trey Coleman, Katherine Ponder
Journal: Molecular Therapy (2004)

Mucopolysaccharidosis (MPS) is due to deficiencies in enzymes that degrade glycosaminoglycans (GAGs). MPS I is due to deficient α-L-iduronidase activity (IDUA) and results in the accumulation of heparin sulfate (HS) and dermatan sulfate (DS). MPS VII is due to deficient β-glucuronidase activity and results in the accumulation of chondroitin sulfate (CS) in addition to HS and DS. Both disorders result in dysostosis multiplex in patients, which is characterized by short and thick bones. MPS can be treated with liver-directed gene therapy in which hepatocytes continuously secrete enzyme with mannose 6-phosphate, which can be taken up from blood. Although hepatic gene therapy reduced many manifestations of MPS VII, bone disease has not been completely corrected. The purpose of this study was to evaluate the effect of neonatal retroviral vector (RV)-mediated gene therapy on bone disease in MPS I mice. In contrast to untreated MPS VII mice in which long bones have only 81% to 87% of normal length, untreated MPS I mice had normal bone lengths at 6 weeks and 8 months after birth. Normal lengths were likely due to the fact that untreated MPS I mice had much less lysosomal storage material than did MPS VII mice in cartilage cells of the growth plate, which plays a pivotal role in bone elongation. This is likely due to the fact that CS is the major GAG in chondrocytes, and CS only accumulates in MPS VII. For untreated MPS I mice, bone mineral density (BMD) was normal at 6 weeks, but markedly increased at 0.069 gm/cm2 at 8 months [normal is 0.054 (p < 0.0001)]. The long bones of untreated MPS I mice had an increased diameter and were sclerotic, and there was substantial storage in osteocytes. The canine IDUA cDNA was cloned into a retroviral vector (RV) with a strong liver promoter, and the RV was injected into newborn MPS I mice at a high [1 × 109 transducing units (TU)/kg] or a low (1 × 108 TU/kg) dose. This resulted in transduction of liver cells and stable serum IDUA activity in most animals for 8 months at 1241 ± 147 and 110 ± 31 units (U)/ml for the high and low dose animals, respectively. At 8 months, mice that received a high dose of RV had normal long bone diameters without sclerosis, normal BMD [0.054 gm/cm2 (p < 0.0001 vs. values in untreated MPS I)], and marked reduction in lysosomal storage in the osteocytes. Mice that received a low dose of RV had some increase in diameter and sclerosis of the long bones, although they were not as severe as untreated MPS I mice. Similarly, the BMD (0.060 gm/cm2) was partially increased. We conclude that bone disease is much less severe in untreated MPS I mice than in untreated MPS VII mice. This is likely due to the fact that CS does not accumulate in MPS I, and CS is high in cartilage and accumulates in MPS VII. However, MPS I mice still had marked thickening and sclerosis of the bone, which were prevented with a high dose of RV at birth. However, the low dose of RV was less effective. These data help to define the serum activity necessary to prevent bone disease in MPS I.