Enzyme replacement therapy for murine mucopolysaccharidosis type VII.

Abstract

Recombinant mouse el-glucuronidase administered intravenously to newborn mice with mucopolysaccharidosis type VII (MPS VII) is rapidly cleared from the circulation and localized in many tissues. Here we determine the tissue distribution of injected enzyme and describe its effects on the histopathology in 6-wk-old MPS VII mice that received either one injection of 28,000 U recombinant 5-glucuronidase at 5 wk of age or received six injections of 28,000 U given at weekly intervals beginning at birth. These mice were compared with untreated 6-wk-old MPS VII mice. The single injection decreased lysosomal distention in the fixed tissue macrophage system. MPS VII mice that received multiple injections had 27.8, 3.5, and 3.3% of normal levels of f-glucuronidase in liver, spleen, and kidney, respectively. Brain had detectable f-glucuronidase, ranging from 2.0-12.1% of normal. Secondary elevations of agalactosidase and fl-hexosaminidase in brain, spleen, liver, and kidney were decreased compared with untreated MPS VII mice. Although no improvement was observed in chondrocytes, glia, and some neurons, the skeleton had less clinical and pathological evidence of disease and the brain had reduced lysosomal storage in meninges and selected neuronal groups. These data show that recombinant f-glucuronidase treatment begun in newborn MPS VII mice provides enzyme to most tissues and significantly reduces or prevents the accumulation of lysosomal storage during the first 6 wk of life. Whether therapy begun later in life can achieve this level of correction remains to be established.

Prevention of systemic clinical disease in MPS VII mice following AAV-mediated neonatal gene transfer

“…Although not quantified, persistent GUSB activity was also seen in the retinal pigmented epithelium by histochemical staining (data not shown). Levels of GUSB activity greater than 1-5% normal have previously been shown to be sufficient to correct histopathologic disease in many tissues, 6,9,18 and tissue sections from 1-year-old animals in this study showed a marked reduction of lysosomal storage similar to that previously described 17 (data not shown). Persistence of transduced cDNA was documented by PCR in most tissues at 1 year of age ( Figure 2), with the notable exception of the spleen, suggesting that the persistence of splenic GUSB activity is primarily due to cross-correction.…”

“…High levels of GUSB are initially achieved in most tissues following ERT, leading to reversal of lysosomal distention and improvements in higher mental and auditory functions. [8][9][10] However, this effect is transient, and as the infused GUSB activity decreases lysosomal distention will recur. 11 To provide a more persistent source of GUSB activity, BMT using syngeneic GUSB-positive bone marrow has been examined.…”

“…It has been shown that reversal of lysosomal storage can be accomplished in most organs by either neonatal or adult treatments, although the duration of the histopathologic correction varies depending on the tissue and treatment method. 6,9,11,12 A notable exception to this statement is the brain, where the blood-brain barrier blocks ERTmediated correction in adult life. 9,13,14 Improvements in survival and retinal function can also be achieved by treatment in either the adult or neonatal period.…”

“…6,9,11,12 A notable exception to this statement is the brain, where the blood-brain barrier blocks ERTmediated correction in adult life. 9,13,14 Improvements in survival and retinal function can also be achieved by treatment in either the adult or neonatal period. 6,13,15 However, improvements in bone length, auditory function, or higher mental functions have only been documented following neonatal BMT or ERT.…”

“…6,13,15 However, improvements in bone length, auditory function, or higher mental functions have only been documented following neonatal BMT or ERT. 9,10,12,16 Despite the successes seen in this mouse model, both ERT and BMT have aspects which limit their clinical applicability to humans. As mentioned above, the effects of ERT are transient, requiring repeated administrations of GUSB throughout life to maintain activity in vivo.…”