LOX-1 Inhibition in ApoE KO Mice Using a Schizophyllan-based Antisense Oligonucleotide Therapy

1 in their article titled " A new therapeutic approach using a schizophyllan-based drug delivery system for inflammatory bowel disease " recently reported a novel therapeutic approach for inflammatory bowel disease using an innovative delivery system for antisense oligonucleotides (ODNs) that is based on Schizophyllan (SPG), a polysaccha-ride that belongs to the β-(1-3) glucan family. 1 These authors demonstrated that this system has several advantages over the effective suppression of targeted RNA. The SPG complex is stable in vivo and is not a substrate for deoxyribonu-clease; furthermore, it is efficiently taken up by macrophages through the dectin-1 receptor. In particular, Takedatsu et al. 1 administered an antisense migration inhibitory factor/SPG complex that significantly ameliorated intestinal inflammation in a mouse model. 1 The development of this new delivery system is very important because therapeutic applications of antisense ODNs have recently been shown to be effective against many different types of disease, including inflammatory, oncological, and genetic disorders. In particular, the use of antisense ODNs exploiting antisense-mediated exon skipping, has been successfully developed to modulate splicing of the dystrophin gene in Duchenne muscular dystrophy. 2 Here, we utilized SPG to inhibit the lectin-like oxidized low-density lipoprotein (LDL) receptor 1 (LOX-1) gene in vivo as a possible treatment for atherosclerosis. LOX-1, which is encoded by the oxidized LDL receptor 1 (OLR1) gene, 3 is the major receptor for ox-LDL in endothelial cells. As such, LOX-1 is responsible for the binding, uptake, and degradation of oxLDLs. 4 LOX-1 is also expressed in macrophages, vascular smooth muscle cells, platelets, and cardiomyocytes. 4 Multiple lines of evidence have implicated LOX-1 in the pathogenesis of atherosclerosis, 5 and LOX-1 has emerged as a promising therapeutic target for athero-sclerosis and related diseases within the last several years. 6 Specific antisense ODNs targeting LOX-1 mRNA have previously been used for in vitro experiments to study the pathophysiological relevance of LOX-1. 7 Here, we extend these findings, showing for the first time that LOX-1 antisense ODNs are effective as a therapeutic strategy in vivo. In collaboration with NapaJen (NapaJen Pharma, Koganei, Japan) and as described by Takedatsu et al., 1 we created a new SPG complex consisting of an antisense phosphorothio-ate ODN targeting the coding sequence (exon 7) of the murine Olr1 mRNA and two single SPG chains (SPG/Olr1AS). The inhibitory effect of the SPG/Olr1AS complex was first assessed in vitro in RAW 264.7 murine macrophages. RAW 264.7 cells were …