Therapy with 2′-O-Me Phosphorothioate Antisense Oligonucleotides Causes Reversible Proteinuria by Inhibiting Renal Protein Reabsorption
Antisense oligonucleotide therapy has been reported to be associated with renal injury. Here, the mechanism of reversible proteinuria was investigated by combining clinical, pre-clinical, and in vitro data. Urine samples were obtained from Duchenne muscular dystrophy (DMD) patients treated with dris...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2019-12-01
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| Series: | Molecular Therapy: Nucleic Acids |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2162253119302446 |
| _version_ | 1818253399565533184 |
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| author | Manoe J. Janssen Tom T.G. Nieskens Tessa A.M. Steevels Pedro Caetano-Pinto Dirk den Braanker Melissa Mulder Yolanda Ponstein Shaun Jones Rosalinde Masereeuw Cathaline den Besten Martijn J. Wilmer |
| author_facet | Manoe J. Janssen Tom T.G. Nieskens Tessa A.M. Steevels Pedro Caetano-Pinto Dirk den Braanker Melissa Mulder Yolanda Ponstein Shaun Jones Rosalinde Masereeuw Cathaline den Besten Martijn J. Wilmer |
| author_sort | Manoe J. Janssen |
| collection | DOAJ |
| description | Antisense oligonucleotide therapy has been reported to be associated with renal injury. Here, the mechanism of reversible proteinuria was investigated by combining clinical, pre-clinical, and in vitro data. Urine samples were obtained from Duchenne muscular dystrophy (DMD) patients treated with drisapersen, a modified 2′O-methyl phosphorothioate antisense oligonucleotide (6 mg/kg). Urine and kidney tissue samples were collected from cynomolgus monkeys (Macaca fascicularis) dosed with drisapersen (39 weeks). Cell viability and protein uptake were evaluated in vitro using human conditionally immortalized proximal tubule epithelial cells (ciPTECs). Oligonucleotide treatment in DMD patients was associated with an increase in urinary alpha-1-microglobulin (A1M), which returned to baseline following treatment interruptions. In monkeys, increased urinary A1M correlated with dose-dependent accumulation of oligonucleotide in kidney tissue without evidence of tubular damage. Furthermore, oligonucleotides accumulated in the lysosomes of ciPTECs and reduced the absorption of A1M, albumin, and receptor-associated protein, but did not affect cell viability when incubated for up to 7 days. In conclusion, phosphorothioate oligonucleotides appear to directly compete for receptor-mediated endocytosis in proximal tubules. We postulate that oligonucleotide-induced low molecular weight proteinuria in patients is therefore a transient functional change and not indicative of tubular damage. Keywords: Antisense oligonucleotide therapy, low molecular weight proteinuria, megalin, receptor-mediated endocytosis, proximal tubule epithelial cell |
| first_indexed | 2024-12-12T16:39:27Z |
| format | Article |
| id | doaj.art-b87e4abe3c8947bda573024c4f50791f |
| institution | Directory Open Access Journal |
| issn | 2162-2531 |
| language | English |
| last_indexed | 2024-12-12T16:39:27Z |
| publishDate | 2019-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Nucleic Acids |
| spelling | doaj.art-b87e4abe3c8947bda573024c4f50791f2022-12-22T00:18:35ZengElsevierMolecular Therapy: Nucleic Acids2162-25312019-12-0118298307Therapy with 2′-O-Me Phosphorothioate Antisense Oligonucleotides Causes Reversible Proteinuria by Inhibiting Renal Protein ReabsorptionManoe J. Janssen0Tom T.G. Nieskens1Tessa A.M. Steevels2Pedro Caetano-Pinto3Dirk den Braanker4Melissa Mulder5Yolanda Ponstein6Shaun Jones7Rosalinde Masereeuw8Cathaline den Besten9Martijn J. Wilmer10Department of Pharmacology and Toxicology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the Netherlands; Corresponding author: Manoe J. Janssen, Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the Netherlands.Department of Pharmacology and Toxicology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the NetherlandsBioMarin Nederland B.V., Leiden, the NetherlandsDepartment of Pharmacology and Toxicology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the NetherlandsDepartment of Pharmacology and Toxicology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the NetherlandsBioMarin Nederland B.V., Leiden, the NetherlandsBioMarin Nederland B.V., Leiden, the NetherlandsBioMarin UK, London, UKDepartment of Pharmacology and Toxicology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the Netherlands; Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, the NetherlandsBioMarin Nederland B.V., Leiden, the NetherlandsDepartment of Pharmacology and Toxicology, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, the NetherlandsAntisense oligonucleotide therapy has been reported to be associated with renal injury. Here, the mechanism of reversible proteinuria was investigated by combining clinical, pre-clinical, and in vitro data. Urine samples were obtained from Duchenne muscular dystrophy (DMD) patients treated with drisapersen, a modified 2′O-methyl phosphorothioate antisense oligonucleotide (6 mg/kg). Urine and kidney tissue samples were collected from cynomolgus monkeys (Macaca fascicularis) dosed with drisapersen (39 weeks). Cell viability and protein uptake were evaluated in vitro using human conditionally immortalized proximal tubule epithelial cells (ciPTECs). Oligonucleotide treatment in DMD patients was associated with an increase in urinary alpha-1-microglobulin (A1M), which returned to baseline following treatment interruptions. In monkeys, increased urinary A1M correlated with dose-dependent accumulation of oligonucleotide in kidney tissue without evidence of tubular damage. Furthermore, oligonucleotides accumulated in the lysosomes of ciPTECs and reduced the absorption of A1M, albumin, and receptor-associated protein, but did not affect cell viability when incubated for up to 7 days. In conclusion, phosphorothioate oligonucleotides appear to directly compete for receptor-mediated endocytosis in proximal tubules. We postulate that oligonucleotide-induced low molecular weight proteinuria in patients is therefore a transient functional change and not indicative of tubular damage. Keywords: Antisense oligonucleotide therapy, low molecular weight proteinuria, megalin, receptor-mediated endocytosis, proximal tubule epithelial cellhttp://www.sciencedirect.com/science/article/pii/S2162253119302446 |
| spellingShingle | Manoe J. Janssen Tom T.G. Nieskens Tessa A.M. Steevels Pedro Caetano-Pinto Dirk den Braanker Melissa Mulder Yolanda Ponstein Shaun Jones Rosalinde Masereeuw Cathaline den Besten Martijn J. Wilmer Therapy with 2′-O-Me Phosphorothioate Antisense Oligonucleotides Causes Reversible Proteinuria by Inhibiting Renal Protein Reabsorption Molecular Therapy: Nucleic Acids |
| title | Therapy with 2′-O-Me Phosphorothioate Antisense Oligonucleotides Causes Reversible Proteinuria by Inhibiting Renal Protein Reabsorption |
| title_full | Therapy with 2′-O-Me Phosphorothioate Antisense Oligonucleotides Causes Reversible Proteinuria by Inhibiting Renal Protein Reabsorption |
| title_fullStr | Therapy with 2′-O-Me Phosphorothioate Antisense Oligonucleotides Causes Reversible Proteinuria by Inhibiting Renal Protein Reabsorption |
| title_full_unstemmed | Therapy with 2′-O-Me Phosphorothioate Antisense Oligonucleotides Causes Reversible Proteinuria by Inhibiting Renal Protein Reabsorption |
| title_short | Therapy with 2′-O-Me Phosphorothioate Antisense Oligonucleotides Causes Reversible Proteinuria by Inhibiting Renal Protein Reabsorption |
| title_sort | therapy with 2 o me phosphorothioate antisense oligonucleotides causes reversible proteinuria by inhibiting renal protein reabsorption |
| url | http://www.sciencedirect.com/science/article/pii/S2162253119302446 |
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