Enzyme therapy in mannose receptor-null mucopolysaccharidosis VII mice defines roles for the mannose 6-phosphate and mannose receptors

Abstract

Enzyme replacement therapy (ERT) is available for several lysosomal storage diseases. Except for Gaucher disease, for which an enzyme with exposed mannosyl residues targets mannose receptors (MR) on macrophages, ERT targets primarily the mannose 6-phosphate receptor (MPR). Most recombinant lysosomal enzymes contain oligosaccharides with both terminal mannosyl and mannose 6-phosphate residues. Effective MPR-mediated delivery may be compromised by rapid clearance of infused enzyme by the MR on fixed tissue macrophages, especially Kupffer cells. To evaluate the impact of this obstacle to ERT, we introduced the MR-null mutation onto the mucopolysaccharidosis type VII (MPS VII) background and produced doubly deficient MR ؊/؊ MPS VII mice. The availability of both MR ؉/؉ and MR ؊/؊ mice allowed us to study the effects of eliminating the MR on MR-and MPR-mediated plasma clearance and tissue distribution of infused phosphorylated (P) and nonphosphorylated (NP) forms of human ␤-glucuronidase (GUS). In MR ؉/؉ MPS VII mice, the MR clearance system predominated at doses up to 6.4 mg͞kg P-GUS. Genetically eliminating the MR slowed plasma clearance of both P-and NP-GUS and enhanced the effectiveness of P-GUS in clearing storage in kidney, bone, and retina. Saturating the MR clearance system by high doses of enzyme also improved targeting to MPR-containing tissues such as muscle, kidney, heart, and hepatocytes. Although ablating the MR clearance system genetically is not practical clinically, blocking the MR-mediated clearance system with high doses of enzyme is feasible. This approach delivers a larger fraction of enzyme to MPR-expressing tissues, thus enhancing the effectiveness of MPRtargeted ERT.␤-glucuronidase deficiency ͉ immune tolerance ͉ lysosomal storage disease T he mucopolysacchridoses (MPS) are a group of lysosomal storage diseases (LSDs) in which a deficiency of one or more lysosomal enzymes interferes with the degradation of glycosaminoglycans (GAGs), resulting in their storage in the lysosome. Accumulated GAG storage in lysosomes results in progressive cellular and organ dysfunction (1). In recent years, advances have been made in the treatment of several LSDs (2-5). In these diseases, lysosomal storage can be partially or completely reversed in many target tissues by i.v. infusion of the missing lysosomal enzyme. Traditionally, it was assumed that lysosomal enzymes would be delivered to target tissues so long as the enzymes contained the mannose 6-phosphate (M6P) recognition marker (6). However, other factors can influence the delivery of lysosomal enzymes to target tissues. Among these is the presence of nonphosphorylated oligosaccharides on the enzymes and the extent to which these have been processed from high mannose to complex-type oligosaccharides (7). The latter determines the number of exposed mannose residues on the enzyme, which can target the enzyme preferentially to the mannose receptor (MR). In addition, the distribution of the MR and the mannose 6-phosphate receptor (MPR) and their relative abund...

Biochemical evidence for superior correction of neuronal storage by chemically modified enzyme in murine mucopolysaccharidosis VII

“…Similar results were obtained in the mouse model of MPS II (29), aspartylglycosaminuria (30), α-mannosidosis (31), and metachromatic leukodystrophy (32). To account for enzyme delivery to adult brain, we speculated that increasing the enzyme dose saturated the clearance receptors in visceral tissues, thus delaying clearance of the enzyme from the circulation and allowing uptake by receptors expressed on the BBB (28,33).…”

Reprogramming erythroid cells for lysosomal enzyme production leads to visceral and CNS cross-correction in mice with Hurler syndrome

“…Low levels of brain entry were implicated to account for the effects, even though disappearance of these proteins from serum was reported to occur in minutes. More recently, it has been suggested that slowing clearance of the recombinant enzyme from the circulation could further improve CNS pathology in MPS VII mice (37,38). The LV-mediated erythroid-specific gene therapy approach developed here could provide continuously higher than normal IDUA in the circulation with potential lifelong CNS therapeutical benefits, although the precise mechanisms for CNS entry are to be determined.…”

Epinephrine enhances lysosomal enzyme delivery across the blood–brain barrier by up-regulation of the mannose 6-phosphate receptor

“…Thus, alterations in the transport of a lysosomal enzyme across the BBB occur with postnatal development, which limits the effectiveness of ERT to adults. Sly et al (6) and Stahl et al (7) have demonstrated that the terminal half-life of P-GUS is Ϸ5 min after i.v. injection in MPS VII mice and plasma clearance of P-GUS is predominantly mediated by the mannose receptor in vivo.…”

“…Epinephrine is known to increase plasma mannose levels immediately after injection in rats (27). Because a large fraction of injected P-GUS is normally cleared by the mannose receptor in the liver (6,15,28), the mannose could transiently inhibit mannose receptor uptake and increase the P-GUS available to the newly expressed M6P receptors on brain capillaries.…”