Stabilin-1 and Stabilin-2 are specific receptors for the cellular internalization of phosphorothioate-modified antisense oligonucleotides (ASOs) in the liver

Miller, Colton M.; Donner, Aaron J; Blank, Emma E.; Egger, Andrew W.; Kellar, Brianna M.; Østergaard, Michael E.; Seth, Punit P.; Harris, Edward N.

doi:10.1093/nar/gkw112

Cited by 145 publications

(148 citation statements)

References 60 publications

(72 reference statements)

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“…Importantly, one of the markers for SECs in zebrafish embryos and adult mammals, Stabilin-2, has been identified as the main HA clearance receptor in the mouse liver. 40 In vitro, Stabilin-2 and its paralog Stabilin - 1 have been shown to bind to a large variety of endogenous (mostly anionic) macromolecules 41 as well as phosphothiorate-modified antisense oligonucleotides (PS-ASO), 42 apoptotic cell bodies, 43 biotinylated albumin, 44 and carbon nanotubes. 45 In vivo , Stabilin-1 and Stabilin-2 were shown to mediate sequestration (but not uptake) by LSECs of aged erythrocytes in a phosphatidylserine-dependent manner.…”

Section: Resultsmentioning

confidence: 99%

“…Similarly, clearance of PS-ASOs was recently shown to be dominated by Stab2 in the mouse liver. 42 To test the generality of stab2 function, several other polyanionic nanoparticles were injected in wild-type and stab2 ibl2 mutant embryos as well as following dextran sulfate injection (Figure 4a–l). These included endogenous (DOPS liposomes, a model for apoptotic cell fragments), viral (Cowpea Chlorotic Mottle Virus-like particles, CCMV VLPs), 53 polymeric (polymersomes 54 and polystyrene beads), and inorganic (quantum dots, QDs) nanoparticles.…”

Section: Resultsmentioning

confidence: 99%

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Directing Nanoparticle Biodistribution through Evasion and Exploitation of Stab2-Dependent Nanoparticle Uptake

et al. 2018

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Up to 99% of systemically administered nanoparticles are cleared through the liver. Within the liver, most nanoparticles are thought to be sequestered by macrophages (Kupffer cells), although significant nanoparticle interactions with other hepatic cells have also been observed. To achieve effective cell-specific targeting of drugs through nanoparticle encapsulation, improved mechanistic understanding of nanoparticle–liver interactions is required. Here, we show the caudal vein of the embryonic zebrafish (Danio rerio) can be used as a model for assessing nanoparticle interactions with mammalian liver sinusoidal (or scavenger) endothelial cells (SECs) and macrophages. We observe that anionic nanoparticles are primarily taken up by SECs and identify an essential requirement for the scavenger receptor, stabilin-2 (stab2) in this process. Importantly, nanoparticle–SEC interactions can be blocked by dextran sulfate, a competitive inhibitor of stab2 and other scavenger receptors. Finally, we exploit nanoparticle–SEC interactions to demonstrate targeted intracellular drug delivery resulting in the selective deletion of a single blood vessel in the zebrafish embryo. Together, we propose stab2 inhibition or targeting as a general approach for modifying nanoparticle–liver interactions of a wide range of nanomedicines.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Directing Nanoparticle Biodistribution through Evasion and Exploitation of Stab2-Dependent Nanoparticle Uptake

et al. 2018

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“…54 The ASOs used in this study were fully modified with the phosphorothioate backbone modification and had a central gap region of ten DNA nucleotides flanked on either end with three constrained ethyl (cEt) nucleotides. 32,34 The phosphorothioate modification enhances ASO metabolic stability and promotes binding to plasma and cell surface proteins, 55 which helps the ASO distribute from the site of injection to peripheral tissues. The DNA gap region supports RNase H-mediated cleavage of cRNA, whereas the cEt nucleotides enhance ASO metabolic stability and boost binding affinity for cRNA.…”

Section: Discussionmentioning

confidence: 99%

Antisense Reduction of Mutant COMP Reduces Growth Plate Chondrocyte Pathology

et al. 2017

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Mutations in cartilage oligomeric matrix protein cause pseudoachondroplasia, a severe disproportionate short stature disorder. Mutant cartilage oligomeric matrix protein produces massive intracellular retention of cartilage oligomeric matrix protein, stimulating ER and oxidative stresses and inflammation, culminating in post-natal loss of growth plate chondrocytes, which compromises linear bone growth. Treatments for pseudoachondroplasia are limited because cartilage is relatively avascular and considered inaccessible. Here we report successful delivery and treatment using antisense oligonucleotide technology in our transgenic pseudoachondroplasia mouse model. We demonstrate delivery of human cartilage oligomeric matrix protein-specific antisense oligonucleotides to cartilage and reduction of cartilage oligomeric matrix protein expression, which largely alleviates pseudoachondroplasia growth plate chondrocyte pathology. One antisense oligonucleotide reduced steady-state levels of cartilage oligomeric matrix protein mRNA and dampened intracellular retention of mutant cartilage oligomeric matrix protein, leading to a reduction of inflammatory markers and cell death and partial restoration of proliferation. This novel and exciting work demonstrates that antisense-based therapy is a viable approach for treating pseudoachondroplasia and other human cartilage disorders. INTRODUCTIONTreatments of skeletal dysplasia/dwarfing conditions, including pseudoachondroplasia (PSACH), are few and fraught with problems because of the inaccessibility of chondrocytes within the cartilage matrix and the relative avascular nature of the cartilage environment. PSACH is clinically characterized by disproportionate short stature, rhizomelic shortening of the long bones, brachydactyly, and extreme joint laxity. 1,2 Joint pain in childhood and osteoarthritis (OA) in early adulthood are the most debilitating features of PSACH; only symptomatic treatments are available and have limited efficacy. 2,3 The diagnosis is made between 2-3 years of age when linear growth slows and a waddling gait develops. 1,2 Because the diagnosis, in most cases, is made post-natally, treatments aimed at resolving the pathology will have to be started immediately after diagnosis.PSACH is caused by mutations in cartilage oligomeric matrix protein (COMP), a pentameric extracellular matrix (ECM) glycoprotein abundant in musculoskeletal tissues. 4,5 Functionally, COMP facilitates type II collagen fibril assembly, enhances chondrocyte attachment in vitro, and interacts with other ECM proteins, including type II and IX collagens, matrilin 3, and SPARC. [6][7][8][9][10][11][12] In contrast, mutations in COMP cause misfolding of the protein, preventing export from the chondrocyte and resulting in massive retention within the endoplasmic reticulum (ER). 10,[13][14][15] Although this finding has long been appreciated, there was little understanding of the pathologic molecular mechanisms, which are critical to develop mechanism-driven therapeutics. To circumvent this proble...

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“…5 The MBB designs were evaluated because they were expected to show lower nonspecific binding to membrane proteins as compared to ASOs with full PS designs. 28 Both, the MBB2 and MBB3 ASO-conjugates were able to displace 125 I-ASOR efficiently with inhibitory constants of 40 and 15 nM, respectively ( Fig. 2 and Table 2).…”

mentioning

confidence: 89%

Conjugation of mono and di-GalNAc sugars enhances the potency of antisense oligonucleotides via ASGR mediated delivery to hepatocytes

Kinberger

Prakash

et al. 2016

Bioorganic & Medicinal Chemistry Letters

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Stabilin-1 and Stabilin-2 are specific receptors for the cellular internalization of phosphorothioate-modified antisense oligonucleotides (ASOs) in the liver

Cited by 145 publications

References 60 publications

Directing Nanoparticle Biodistribution through Evasion and Exploitation of Stab2-Dependent Nanoparticle Uptake

Directing Nanoparticle Biodistribution through Evasion and Exploitation of Stab2-Dependent Nanoparticle Uptake

Antisense Reduction of Mutant COMP Reduces Growth Plate Chondrocyte Pathology

Conjugation of mono and di-GalNAc sugars enhances the potency of antisense oligonucleotides via ASGR mediated delivery to hepatocytes

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