TY - JOUR
T1 - The potential of RNA-based therapy for kidney diseases
AU - Bondue, Tjessa
AU - van den Heuvel, Lambertus
AU - Levtchenko, Elena
AU - Brock, Roland
N1 - Funding Information: Tjessa Bondue and Elena Levtchenko are funded by the Research Foundation—Flanders (FWO)—11A7821N and 11Y5216N. Funding Information: Elena Levtchenko and Roland Brock are funded by Health Holland—GEVAL 2020–2022. Publisher Copyright: © 2022, The Author(s), under exclusive licence to International Pediatric Nephrology Association.
PY - 2023/2/1
Y1 - 2023/2/1
N2 - Inherited kidney diseases (IKDs) are a large group of disorders affecting different nephron segments, many of which progress towards kidney failure due to the absence of curative therapies. With the current advances in genetic testing, the understanding of the molecular basis and pathophysiology of these disorders is increasing and reveals new potential therapeutic targets. RNA has revolutionized the world of molecular therapy and RNA-based therapeutics have started to emerge in the kidney field. To apply these therapies for inherited kidney disorders, several aspects require attention. First, the mRNA must be combined with a delivery vehicle that protects the oligonucleotides from degradation in the blood stream. Several types of delivery vehicles have been investigated, including lipid-based, peptide-based, and polymer-based ones. Currently, lipid nanoparticles are the most frequently used formulation for systemic siRNA and mRNA delivery. Second, while the glomerulus and tubules can be reached by charge- and/or size-selectivity, delivery vehicles can also be equipped with antibodies, antibody fragments, targeting peptides, carbohydrates or small molecules to actively target receptors on the proximal tubule epithelial cells, podocytes, mesangial cells or the glomerular endothelium. Furthermore, local injection strategies can circumvent the sequestration of RNA formulations in the liver and physical triggers can also enhance kidney-specific uptake. In this review, we provide an overview of current and potential future RNA-based therapies and targeting strategies that are in development for kidney diseases, with particular interest in inherited kidney disorders.
AB - Inherited kidney diseases (IKDs) are a large group of disorders affecting different nephron segments, many of which progress towards kidney failure due to the absence of curative therapies. With the current advances in genetic testing, the understanding of the molecular basis and pathophysiology of these disorders is increasing and reveals new potential therapeutic targets. RNA has revolutionized the world of molecular therapy and RNA-based therapeutics have started to emerge in the kidney field. To apply these therapies for inherited kidney disorders, several aspects require attention. First, the mRNA must be combined with a delivery vehicle that protects the oligonucleotides from degradation in the blood stream. Several types of delivery vehicles have been investigated, including lipid-based, peptide-based, and polymer-based ones. Currently, lipid nanoparticles are the most frequently used formulation for systemic siRNA and mRNA delivery. Second, while the glomerulus and tubules can be reached by charge- and/or size-selectivity, delivery vehicles can also be equipped with antibodies, antibody fragments, targeting peptides, carbohydrates or small molecules to actively target receptors on the proximal tubule epithelial cells, podocytes, mesangial cells or the glomerular endothelium. Furthermore, local injection strategies can circumvent the sequestration of RNA formulations in the liver and physical triggers can also enhance kidney-specific uptake. In this review, we provide an overview of current and potential future RNA-based therapies and targeting strategies that are in development for kidney diseases, with particular interest in inherited kidney disorders.
KW - Kidney disease
KW - Nanoparticles
KW - RNA
KW - RNA-therapy
UR - http://www.scopus.com/inward/record.url?scp=85129514441&partnerID=8YFLogxK
U2 - https://doi.org/10.1007/s00467-021-05352-w
DO - https://doi.org/10.1007/s00467-021-05352-w
M3 - Review article
C2 - 35507149
SN - 0931-041X
VL - 38
SP - 327
EP - 344
JO - Pediatric nephrology (Berlin, Germany)
JF - Pediatric nephrology (Berlin, Germany)
IS - 2
ER -