Biotherapeutic target or sink: analysis of the macrophage mannose receptor tissue distribution in murine models of lysosomal storage diseases

Abstract

Lysosomal storage diseases (LSDs) are metabolic disorders caused by enzyme deficiencies that lead to lysosomal accumulation of undegraded substrates. Enzyme replacement therapies (ERT) have been developed as treatments for patients with Gaucher, Niemann-Pick, Fabry, and Pompe diseases. Depending on the disease, the corresponding therapeutic enzyme is designed to be internalized by diseased cells through receptor-mediated endocytosis via macrophage mannose receptors (MMR) or mannose-6-phosphate receptors (M6PR). Enzymes developed to treat Gaucher and Niemann-Pick diseases are meant to target MMR-expressing cells, and in the case of Cerezyme [recombinant human β-glucocerebrosidase (rhβGC)] for treating Gaucher disease, glycans on the enzyme are modified to increase specificity toward this receptor. Due to heterogeneity in glycosylation on enzymes intended to target the M6PR, however, there may also be some unintended targeting to MMR-expressing cells, which could act as unwanted sinks. Examples include Fabrazyme [recombinant human α-galactosidase A (rhαGal)] for treating Fabry disease and Myozyme [recombinant human acid α-glucosidase (rhGAA)] for treating Pompe disease. It is therefore of great interest to better understand the cell type and tissue distribution of MMR in murine LSD models used to evaluate ERT efficacy and mechanism of action. In this study, we generated affinity-purified polyclonal antibody against murine MMR and used it to carry out a systematic examination of MMR protein localization in murine models of Gaucher, Niemann-Pick, Fabry, and Pompe diseases. Using immunohistochemistry, immunofluorescence, and confocal microscopy, we examined MMR distribution in liver, spleen, lung, kidney, heart, diaphragm, quadriceps, and triceps in these animal models and compared them with MMR distribution in wild-type mice.

Safety Study of Adeno-Associated Virus Serotype 2-Mediated Human Acid Sphingomyelinase Expression in the Nonhuman Primate Brain

“…If this holds even with vectors that transduce nonneuronal cells, such as AAV9 (Foust et al, 2009;Gray et al, 2011), the difficulty of transducing sufficient numbers of cells in the brain of patients with NPDA to effect therapeutic benefit may prove too daunting a task. However, if one considers the experience of enzyme replacement for other LSDs, such as Gaucher disease, then engineering of the native enzyme to enhance intercellular transport and uptake may be required (Zhang et al, 2011). On the other hand, this study demonstrated that AAV2-hASM at a relatively low dose caused only slight behavioral defects if any.…”

Recombinant Human Acid Sphingomyelinase as an Adjuvant to Sorafenib Treatment of Experimental Liver Cancer

“…The higher fold difference between liver and HCC (∼20 fold), compared to subcutaneous model (∼12 fold greater activity in liver than tumor), was likely due to higher frequency of rhASM administration in the orthotopic study (5 injections per week versus 3/week). Considering that rhASM has been developed for the treatment of NPD [42], and with continued evidence regarding the importance of ASM in preventing tumor growth and development [43], [44], we decided to examine the reason for low ASM activity in the Huh7 tumors more closely.…”

siRNA Delivery to the Glomerular Mesangium Using Polycationic Cyclodextrin Nanoparticles Containing siRNA

“…Mannose receptor expression in the kidney is restricted to the mesangium [19,20] and has been demonstrated to facilitate uptake of nanoparticles by macrophages in vivo [25,26]. The transferrin receptor, although up-regulated within the mesangium of patients with IgA nephropathy [27][28][29], is not highly expressed in the healthy glomerulus, but has been demonstrated to facilitate intracellular uptake of the transferrin-targeted siRNA/CDP-NPs in other cell lines [17,21].…”

“…Therefore, we tested mesangial cell uptake of siRNA/CDP-NPs formulated with two different surface targeting ligands: (1) the sugar mannose and (2) the iron transport protein, transferrin. We chose the mannose targeting ligand because, within the kidney, the expression of the mannose receptor (MR) is restriction to mesangial cells [19,20]. The transferrin targeting ligand was chosen because we have previously demonstrated its ability to enhance intracellular uptake of the siRNA/CDP-NPs in other cell lines in vitro and in vivo [17,21].…”