Enzyme replacement therapy for murine mucopolysaccharidosis type VII leads to improvements in behavior and auditory function.

Abstract

Mucopolysaccharidosis type VII (MPS VII; Sly syndrome) is one of a group of lysosomal storage diseases that share many clinical features, including mental retardation and hearing loss. Lysosomal storage in neurons of the brain and the associated behavioral abnormalities characteristic of a murine model of MPS VII have not been shown to be corrected by either bone marrow transplantation or gene therapy. However, intravenous injections of recombinant beta-glucuronidase initiated at birth reduce the pathological evidence of disease in MPS VII mice. In this study we present evidence that enzyme replacement initiated at birth improved the behavioral performance and reduced hearing loss in MPS VII mice. Enzyme-treated MPS VII mice performed similarly to normal mice and significantly better than mock- treated MPS VII mice in every phase of the Morris Water Maze test. In addition, the auditory function of treated MPS VII mice was dramatically improved, and was indistinguishable from normal mice. These data indicate that some of the learning, memory, and hearing deficits can be prevented in MPS VII mice if enzyme replacement therapy is initiated early in life. These data also provide functional correlates to the biochemical and histopathological improvements observed after enzyme replacement therapy.

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

“…10,16 This can be seen in untreated MPS VII mice, where the auditory-evoked brainstem response (ABR) threshold increases at all frequencies with age, resulting in profound hearing loss by adulthood ( Figure 6). In contrast, mice who have been treated with neonatal AAV injection …”

“…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.…”

“…A number of studies have examined the benefits of neonatal versus adult treat-ments in the MPS VII mouse, using BMT, ERT, or a combination of the two. [10][11][12][13] These experiments have demonstrated that many of the functional deficits are amenable to therapy early in life, and that irreversible developmental damage does not occur in utero. 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.…”

“…6,13,15 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.…”

Treatment of lysosomal storage disease in MPS VII mice using a recombinant adeno-associated virus

“…These include enzyme replacement, 7,8 a variety of cell transplantation approaches, 6,[9][10][11][12][13][14] and direct administration of adenoviral vectors. 15,16 All of these treatments provided measurable improvement, but none was entirely satisfactory.…”