Clinical response to persistent, low‐level β‐glucuronidase expression in the murine model of mucopolysaccharidosis type VII

Abstract

Mucopolysaccharidosis type VII (MPS VII) is a lysosomal storage disease caused by beta-glucuronidase (GUSB) deficiency. This disease exhibits a broad spectrum of clinical signs including skeletal dysplasia, retinal degeneration, cognitive deficits and hearing impairment. Sustained, high-level expression of GUSB significantly improves the clinical course of the disease in the murine model of MPS VII. Low levels of enzyme expression (1-5% of normal) can significantly reduce the biochemical and histopathological manifestations of MPS VII. However, it has not been clear from previous studies whether persistent, low levels of circulating GUSB lead to significant improvements in the clinical presentation of this disease. We generated a rAAV2 vector that mediates persistent, low-level GUSB expression in the liver. Liver and serum levels of GUSB were maintained at approximately 5% and approximately 2.5% of normal, respectively, while other tissue ranged from background levels to 0.9%. This level of activity significantly reduced the secondary elevations of alpha-galactosidase and the levels of glycosaminoglycans in multiple tissues. Interestingly, this level of GUSB was also sufficient to reduce lysosomal storage in neurons in the brain. Although there were small but statistically significant improvements in retinal function, auditory function, skeletal dysplasia, and reproduction in rAAV-treated MPS VII mice, the clinical deficits were still profound and there was no improvement in lifespan. These data suggest that circulating levels of GUSB greater than 2.5% will be required to achieve substantial clinical improvements in MPS VII.

Synergistic effects of treating the spinal cord and brain in CLN1 disease

“…3A). Such enzyme levels might normally be sufficient to correct the disease phenotype in lysosomal storage diseases (41,42). However, it may be that a higher The levels of various cytokines were measured in brain homogenates from treated and untreated WT and Ppt1 −/− animals.…”

Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy

“…There seems to be a very low threshold of activity in LSDs above which lysosomal enzymes are capable of coping with substrate influx and avoiding accumulation. Preclinical studies of ERT or gene therapy approaches in other forms of MPS have demonstrated that low levels of circulating enzyme (as low as 5% of normal) can mediate the correction of GAG accumulation in most somatic tissues (54,55). This low enzymatic activity requirement for disease correction is further supported by clinical evidence; a clear correlation between MPS IIIA clinical manifestations and the patients' underlying mutations have recently been demonstrated in a large cohort of MPS IIIA-affected individuals (2).…”

Widespread biochemical correction of murine mucopolysaccharidosis type VII pathology by liver hydrodynamic plasmid delivery

“…Nevertheless, the circulating GUSB activity after 60 days (below 5% of normal activity) could be unsufficient to achieve substantial clinical improvement in this work, as it has been shown earlier with 2.5% of circulating GUSB activity. 11 More specially, higher enzyme restoration may be required to completely reverse some pathological changes, such as brain or articular abormalities, as we observed poor improvements of morphological abnormalities after plasmid injection.…”

“…5 Second, it is also known that 1-5% only of the normal level of GUSB activity are sufficient to reduce biochemical and histopathological abnormalities of the MPS VII disease in some organs. [6][7][8][9][10][11] Therefore, the gene transfer localized to a depot organ such as the liver or the muscle could enable the secretion of the affected enzyme into circulation at a therapeutic level, leading to the global correction of lysosomal storage. Gene therapy of MPS has been pursued primarily using viral vectors.…”