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. 2024 Dec 1;35(12):1774-1777.
doi: 10.1681/ASN.0000000532. Epub 2024 Sep 27.

Treating the Untreatable: Antisense Oligonucleotides as an Individualized Therapy for Rare Genetic Kidney Diseases

Cedrik Tekendo-Ngongang  1 , Joseph G Gleeson  1   2   3 , Laurence Mignon  1
Affiliations

Treating the Untreatable: Antisense Oligonucleotides as an Individualized Therapy for Rare Genetic Kidney Diseases

Cedrik Tekendo-Ngongang et al. J Am Soc Nephrol. .
No abstract available

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Conflict of interest statement

Disclosure forms, as provided by each author, are available with the online version of the article at http://links.lww.com/JSN/E871.

Figures

Figure 1
Figure 1
Common post–RNA-binding mechanisms of action and distribution of ASOs in the kidney. (A) Downregulation of target transcripts by single-stranded ASOs. Commonly used antisense mechanisms to degrade target RNAs include (i) RNase H1-dependent cleavage of cytoplasmic or nuclear RNAs; (ii) AGO2-mediated RNA degradation of cytoplasmic RNAs (also known as single-stranded siRNAs); (iii) splicing modulation to induce NMD—reduction of target RNA levels by acting on pre-mRNA to alter splicing and generate mRNAs that contain premature termination codons subject to NMD; (iv and v) translation inhibition—(iv) acting on mRNA during translation initiation to trigger the NGD quality control mechanism and degrade target mRNA and (v) inhibition of ribosome scanning of mature mRNA leading to reduced translation initiation and reduction in protein production; and (vi) acting on pre-mRNA cleavage to alter polyadenylation site usage and modulate mRNA stability and levels. (B) Routes of administration of ASOs in commonly targeted organs. (C) Top: simplified anatomy of the nephron showing in green parts of the kidney with high distribution of ASO. Bottom: table showing average reduction in target RNA observed in various compartments of the kidney following ASO-mediated knockdown of the Malat-1 gene. ASO knockdown of Malat-1 results in a significant reduction in Malat-1 RNA expression in the glomerulus, cortex, and medulla, with the highest Malat-1 RNA reduction observed in the kidney cortex. ASO, antisense oligonucleotide; CNS, central nervous system; Malat-1, Metastasis Associated Lung Adenocarcinoma Transcript 1; NGD, no-go decay; NMD, nonsense-mediated mRNA decay; PNS, peripheral nervous system; siRNA, small interfering RNA.
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