Nephrotoxicity of marketed antisense oligonucleotide drugs

Wu, Hao; Wahane, Aniket; Alhamadani, Feryal; Zhang, Kristy; Parikh, Rajvi; Lee, Soowan; McCabe, Evan M.; Rasmussen, Theodore P.; Bahal, Raman; Zhong, Xiao‐bo; Manautou, José E.

doi:10.1016/j.cotox.2022.100373

Cited by 15 publications

(6 citation statements)

References 63 publications

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“…Because LNA mixmers typically bind tighter [52][53][54][65][66][67], it will be interesting to test L15 variants with an LNA backbone at only select locations. Unlike small molecules, modified oligonucleotides typically have poor cellular and tissue-specific delivery, limited endosomal escape and site-specific toxicity (e.g., kidney [75], neurons [76] and liver [77]) [78]. Our designed oligos would likely exhibit similar levels of toxicity as observed previously.…”

Section: Discussionmentioning

confidence: 72%

Locked Nucleic Acid Oligonucleotides Facilitate RNA•LNA-RNA Triple-Helix Formation and Reduce MALAT1 Levels

Shivakumar,

Mahendran,

Brown

2024

IJMS

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Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) and multiple endocrine neoplasia-β (MENβ) are two long noncoding RNAs upregulated in multiple cancers, marking these RNAs as therapeutic targets. While traditional small-molecule and antisense-based approaches are effective, we report a locked nucleic acid (LNA)-based approach that targets the MALAT1 and MENβ triple helices, structures comprised of a U-rich internal stem-loop and an A-rich tract. Two LNA oligonucleotides resembling the A-rich tract (i.e., A9GCA4) were examined: an LNA (L15) and a phosphorothioate LNA (PS-L15). L15 binds tighter than PS-L15 to the MALAT1 and MENβ stem loops, although both L15 and PS-L15 enable RNA•LNA-RNA triple-helix formation. Based on UV thermal denaturation assays, both LNAs selectively stabilize the Hoogsteen interface by 5–13 °C more than the Watson–Crick interface. Furthermore, we show that L15 and PS-L15 displace the A-rich tract from the MALAT1 and MENβ stem loop and methyltransferase-like protein 16 (METTL16) from the METTL16-MALAT1 triple-helix complex. Human colorectal carcinoma (HCT116) cells transfected with LNAs have 2-fold less MALAT1 and MENβ. This LNA-based approach represents a potential therapeutic strategy for the dual targeting of MALAT1 and MENβ.

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Section: Discussionmentioning

confidence: 72%

Locked Nucleic Acid Oligonucleotides Facilitate RNA•LNA-RNA Triple-Helix Formation and Reduce MALAT1 Levels

Shivakumar,

Mahendran,

Brown

2024

IJMS

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“…However, these symptoms are largely associated with SMA progression and are unable to be attributed specifically to Nusinersen treatment. In addition, coagulation abnormalities, thrombocytopenia, and renal toxicities have been associated with ASO treatments for different diseases [ 76 , 77 ]. The associated risks of bleeding complications and renal toxicity require that all patients must routinely have platelet counts and urine protein levels measured prior to treatment.…”

Section: Antisense Oligonucleotidesmentioning

confidence: 99%

Potential of Cell-Penetrating Peptide-Conjugated Antisense Oligonucleotides for the Treatment of SMA

Leckie,

Yokota

2024

Molecules

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Spinal muscular atrophy (SMA) is a severe neuromuscular disorder that is caused by mutations in the survival motor neuron 1 (SMN1) gene, hindering the production of functional survival motor neuron (SMN) proteins. Antisense oligonucleotides (ASOs), a versatile DNA-like drug, are adept at binding to target RNA to prevent translation or promote alternative splicing. Nusinersen is an FDA-approved ASO for the treatment of SMA. It effectively promotes alternative splicing in pre-mRNA transcribed from the SMN2 gene, an analog of the SMN1 gene, to produce a greater amount of full-length SMN protein, to compensate for the loss of functional protein translated from SMN1. Despite its efficacy in ameliorating SMA symptoms, the cellular uptake of these ASOs is suboptimal, and their inability to penetrate the CNS necessitates invasive lumbar punctures. Cell-penetrating peptides (CPPs), which can be conjugated to ASOs, represent a promising approach to improve the efficiency of these treatments for SMA and have the potential to transverse the blood–brain barrier to circumvent the need for intrusive intrathecal injections and their associated adverse effects. This review provides a comprehensive analysis of ASO therapies, their application for the treatment of SMA, and the encouraging potential of CPPs as delivery systems to improve ASO uptake and overall efficiency.

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“…ASO and siRNA drugs are generally considered safe and tolerable drug classes. The major and minor ADRs and toxicity have been characterized for the ASO and siRNA drugs to treat the SDLO diseases during the discovery and development in preclinical and clinical studies (Alhamadani et al, 2022;Wu et al, 2022;Ranjbar et al, 2023). Table 4 summarizes the information from the FDA's drug labeling on the "Black Box Warning", "Warnings and Precautions", common ADRs (>5%), less common ADRs (<5%), and immunogenicity of the seven FDA-approved ASO and siRNA drugs, which can be grouped into no toxicity (lumasiran and inclisiran), mild toxicity (vutrisiran, patisiran, and givosiran), and severe toxicity (inotersen and mipomersen).…”

Section: A Challenges On Adrs and Toxicity Of The Aso And Sirna Drugsmentioning

confidence: 99%

Targeting the Liver with Nucleic Acid Therapeutics for the Treatment of Systemic Diseases of Liver Origin

Gogate,

Belcourt,

Shah

et al. 2024

Pharmacological Reviews

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ABBREVIATIONS2'-F, 2'-fluoro; 2'-MOE, 2'-O-methyloxyethyl; 2'-OMe, 2'-O-methyl; 3'-UTR, 3'-untranslated region; AAT, alpha-1 antitrypsin; AATLD, alpha-1 antitrypsin deficiency-associated liver disease; ACE, angiotensin-converting enzyme; ADP, delta-aminolaevulinic acid dehydratase deficiency porphyria; ADR, adverse drug reaction; AGXT/AGT, alanine-glyoxylate aminotransferase; AHP, acute hepatic porphyria; aHUS, atypical hemolytic uremic syndrome;

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Nephrotoxicity of marketed antisense oligonucleotide drugs

Cited by 15 publications

References 63 publications

Locked Nucleic Acid Oligonucleotides Facilitate RNA•LNA-RNA Triple-Helix Formation and Reduce MALAT1 Levels

Locked Nucleic Acid Oligonucleotides Facilitate RNA•LNA-RNA Triple-Helix Formation and Reduce MALAT1 Levels

Potential of Cell-Penetrating Peptide-Conjugated Antisense Oligonucleotides for the Treatment of SMA

Targeting the Liver with Nucleic Acid Therapeutics for the Treatment of Systemic Diseases of Liver Origin

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