Abstract
Chronic kidney disease (CKD) is a global public health issue that places an increasing burden on the healthcare systems of both the developed and developing countries. CKD is a progressive and irreversible condition, affecting approximately 10% of the population worldwide. Patients that have progressed to end-stage renal disease (ESRD) require expensive renal replacement therapy, i.e., dialysis or kidney transplantation. Current CKD therapy largely relies on the use of angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs). However, these treatments by no means halt the progression of CKD to ESRD. Therefore, the development of new therapies is urgently needed. Antisense oligonucleotide (ASO) has recently attracted considerable interest as a drug development platform. Thus far, eight ASO-based drugs have been granted approval by the US Food and Drug Administration for the treatment of various diseases. Herein, we review the ASOs developed for the identification of CKD-relevant genes and/or the simultaneous development of the ASOs as potential therapeutics towards treating CKD.
Highlights
In the mice with type 1 diabetes, Antisense oligonucleotide (ASO) treatment inhibited a variety of indices of renal disease, for instance, the development of renal hypertrophy was significantly attenuated in that the diabetes-induced increase of kidney weight was reduced by 32%, increases of serum creatinine and urinary albumin which are pathological features of diabetic nephropathy were reduced by 32% and 52%, respectively, and the diabetes-induced expansion of the mesangial matrix was attenuated by 43%, which was associated with the reduced synthesis of collagen 1, fibronectin, and TGF-β1 [114]
The upregulation of α-smooth muscle actin (α-Spinal muscular atrophy (SMA), a marker of myofibroblast activity) induced by obstructive nephropathy was inhibited by the Kirsten rat sarcoma viral oncogene homolog (KRAS)-targeting ASOs so that the α-SMA expression was reduced from 53% to 3.9% and 20% by ISIS 104440 and ISIS 104419, respectively, indicating that an ASO-mediated KRAS knockdown could prevent the onset of fibrosis in rat models of unilateral ureteric obstruction [115]
This study demonstrated that the combined inhibition of both mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) holds therapeutic potential for autosomal dominant polycystic kidney disease (PKD) [116], and an ASO-based mammalian target of rapamycin (mTOR) inhibitor can be a promising approach for treating the disease owing to its capability of combined mTORC1/2 knockdown
Summary
Antisense oligonucleotides (ASOs) are one of the most classical synthetic therapeutic oligonucleotides that are able to modify gene expression. The US Food and Drug Administration (FDA) has granted approval for eight ASO drugs for clinical usage (Table 1 and Table S1) [9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25] These successful clinical translations inspire both the academia and pharmaceutical industry to develop ASO-based drugs for the treatment of various diseases, either by the downregulation of disease-causing gene expression or rescuing the expression of essential but defective genes. Rescue the expression of dystrophin through exon-51 skipping of the mRNA of DMD gene [13,14,15,16]. Rescue the expression of dystrophin through exon-53 skipping of the mRNA of [23]
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