Oligonucleotide-Based Therapies for Renal Diseases

Abstract

The global burden of chronic kidney disease (CKD) is increasing every year and represents a great cost for public healthcare systems, as the majority of these diseases are progressive. Therefore, there is an urgent need to develop new therapies. Oligonucleotide-based drugs are emerging as novel and promising alternatives to traditional drugs. Their expansion corresponds with new knowledge regarding the molecular basis underlying CKD, and they are already showing encouraging preclinical results, with two candidates being evaluated in clinical trials. However, despite recent technological advances, efficient kidney delivery remains challenging, and the presence of off-targets and side-effects precludes development and translation to the clinic. In this review, we provide an overview of the various oligotherapeutic strategies used preclinically, emphasizing the most recent findings in the field, together with the different strategies employed to achieve proper kidney delivery. The use of different nanotechnological platforms, including nanocarriers, nanoparticles, viral vectors or aptamers, and their potential for the development of more specific and effective treatments is also outlined.

Pharmacokinetics and Absorption, Distribution, Metabolism and Excretion of RGLS4326 in Mouse and Monkey, an Anti–miR-17 Oligonucleotide for the Treatment of Polycystic Kidney Disease

“…PS modifications also increase interaction with intracellular proteins, which may favor accumulation in the target tissue (kidney). Furthermore, the use of naked RGLS4326 by systemic administration has demonstrated the feasibility of targeting the kidney by this approach and has been the option chosen in many studies targeting the kidney with oligonucleotides-based therapies (Cartón-García et al, 2021).…”

Nucleic Acid Nanotechnology for Diagnostics and Therapeutics in Acute Kidney Injury

“…Pathophysiology of AKI is rather complex, including extensive tubular oxidative stress, excessive release of inflammatory cytokines, activation of complement system, ferroptosis, necroptosis, cell cycle arrest and so on [ 88 , 89 , 90 , 91 ]. Albeit the springing up of various preclinical research of AKI therapeutics, they are still impeded by several factors, such as the poor targeting ability and the subsequent low efficiency, causing off-target effects in other organs and adverse drug reaction due to a higher administration dose to meet the expected efficacy [ 92 , 93 ]. Furthermore, the immunogenicity and biostability have also been a concern.…”

“…Experiments have shown a beneficial effect of p53 -targeted siRNAs towards ischemia and cisplatin-induced AKI, presenting a dose and time-dependent attenuation of apoptotic signaling [ 116 ]. However, the application of these p53 -aiming siRNAs is still complicated with poor pharmacokinetics, susceptibility to nuclease degradation and off-target effects due to non-specific delivery, calling for more possible vehicle nanoplatforms and appropriate modifications aiming at more well-directed efficacy and fewer side effects in AKI treatment [ 92 ].…”

Synthetic Non-Coding RNA for Suppressing mTOR Translation to Prevent Renal Fibrosis Related to Autophagy in UUO Mouse Model

“…Among several strategies of treatment for renal tubular injury, the oligonucleotide (ODN) technique uses synthetic double-stranded non-coding ribonucleic acids (ncRNAs), also called ODNs, that contain antisense sequences for mTOR messenger ribonucleic acid (mRNA) to block mTOR activity. ODNs have been proposed as effective novel therapeutic tools in specific molecular target medicine for several diseases [ 18 , 19 , 20 ]. According to several previous studies, ring-type ODNs have a significant effect on regulating protein or transcription factors [ 21 , 22 , 23 ].…”