Efficient Messenger RNA Delivery to the Kidney Using Renal Pelvis Injection in Mice

Abstract

Renal dysfunction is often associated with the inflammatory cascade, leading to non-reversible nephrofibrosis. Gene therapy has the ability to treat the pathology. However, the difficulty in introducing genes into the kidney, via either viral vectors or plasmid DNA (pDNA), has hampered its extensive clinical use. Messenger RNA (mRNA) therapeutics has recently attracted attention as alternative gene therapies. mRNA allows protein production into post-mitotic cells without the need for transport to the nuclei in the target cells. However, few studies have reported the delivery of mRNA to the kidney. In this study, we attempted to deliver mRNA to the kidney based on the principle of pressure stimulation, by administering mRNA-loaded polyplex nanomicelles via a renal pelvis injection, directly into the kidney. Compared with the administration of naked plasmid DNA (pDNA) and naked mRNA, the mRNA-loaded nanomicelles diffusely induced protein expression in a greater number of cells at the tubular epithelium for some days. The plasma creatinine (Cre) and blood urea nitrogen (BUN) levels after the administration remained similar to those of the sham-operated controls, without marked changes in histological sections. The safety and efficacy of mRNA-loaded nanomicelles would make distinct contributions to the development of mRNA therapeutics for the kidney.

Influence of Nanobubble Size Distribution on Ultrasound-Mediated Plasmid DNA and Messenger RNA Gene Delivery

“…Gluc mRNA was constructed as previously mentioned ( Oyama et al, 2021 ). DNA templates for in vitro transcription (IVT) of mRNA were constructed by inserting a protein-expressing fragment into a pSP73 vector (Promega, Madison, WI, United States) that included a T7 promoter.…”

Still Finding Ways to Augment the Existing Management of Acute and Chronic Kidney Diseases with Targeted Gene and Cell Therapies: Opportunities and Hurdles

“…The unique anatomy of the kidney provides various innate delivery pathways (artery, vein, and ureter) that may be ideal for hydrodynamic gene delivery. In our recent reports, this delivery method provided efficient and lengthy plasmid and viral expression in live rat kidneys [128,140,192] and facilitated protection against moderate forms of ischemia-reperfusion injury [152,193,194]. A summary of delivery methods and associated vectors is presented in Table 1.…”

Advances in Nanoparticles for Effective Delivery of RNA Therapeutics

“…Interestingly, in an attempt to deliver mRNA to the kidneys, nanomicelles were formed by the self-assembly of mRNA and PEG-polyamino acid PAsp(DET) block copolymers. After the administration of mRNA into mouse kidneys by renal pelvic injection, most of the injection bolus remained at the injection site without diffusing into circulation [48]. Besides cationic polymers, an anionic complex containing PEI, γ-polyglutamic acid, and mRNA exhibited stable and high in vitro protein expression without cytotoxicity.…”