Gene therapy and kidney diseases

Abstract

Chronic kidney disease (CKD) poses a significant global health challenge, projected to become one of the leading causes of death by 2040. Current treatments primarily manage complications and slow progression, highlighting the urgent need for personalized therapies targeting the disease-causing genes. Our increased understanding of the underlying genomic changes that lead to kidney diseases coupled with recent successful gene therapies targeting specific kidney cells have turned gene therapy and genome editing into a promising therapeutic approach for treating kidney disease. This review paper reflects on different delivery routes and systems that can be exploited to target specific kidney cells and the ways that gene therapy can be used to improve kidney health.

Keywords: gene therapy; kidney disease; nanodelivery systems; targeted gene delivery; viral vectors.

Graphical abstract

Figure 1

Gene augmentation for ADPKD treatment and delivery methods (A) The potential of gene augmentation in treating ADPKD caused by mutation in PKD1 allele. In ADPKD, PKD1 haploinsufficiency (a condition when there is only one functional copy of a gene instead of the usual two in diploid organisms) leads to a reduced amount or altered function of the polycystin-1 protein. Low polycystin-1 levels disrupt normal cellular processes and lead to the formation of cysts in the kidneys. Delivering a functional copy of the PKD1 gene into the cells of the affected individual can increase levels of polycystin-1 protein, compensating for the haploinsufficiency. (B) Different routes for kidney gene delivery. These routes include (A) subcapsular injection, (B) direct injection into the renal pelvis, (C) infusion into the renal artery, (D) retrograde infusion into the renal vein, (E) retrograde infusion into the ureter, and (F) local injection.

Figure 2

The main delivery site lentiviral particles in mouse kidney can differ based on the chosen delivery route With regard to the local intraparenchymal injection (A), the distribution of the components is limited to the area around the injection track, and within this area the transgene expression is predominantly detected in the proximal convoluted tubules located in the cortex and outer medulla. Compared to the renal vein and artery injection (C), administration through renal ureter (B) encompasses a larger area, with the former being confined to the inner medulla and the latter expanding to the outer medulla and corticomedullary junction. Green areas show the main target of the delivery route in the nephron structure.

Figure 3

Optimizing kidney gene therapy based on disorder and delivery method (A) The type of kidney disorder plays an important role in choosing the suitable vector and administration route; for example, if the tubule abnormality is the cause of disease development, given that collecting ducts come together and make the renal pelvis, injection can be made through the renal pelvis to circumvent the filtration that happens in the glomerular filtration barrier and that reduces the delivery efficiency. (B) Subcapsular injection is a better alternative for having the injected material diffused throughout the kidney parenchyma; with regard to the subcapsular (above) and local (below) delivery of the genes, while the latter can lead to the accumulation of the components in the area near the injection site, which can cause high drug deposition exposing the organ to toxic concentrations. The former is associated with the sustained release of the delivered agents preventing tissue injury and improving the therapeutic efficiency.

Figure 4

Impact of infusion rate into the renal artery on delivery target: Faster rates direct to proximal tubules, while slower rates favor glomerular delivery The rate of infusion into the renal artery of rats plays an important role in determining the main delivery site; although infusion with a flow rate of 1–2 min/mL targets the proximal tubules with no transfection in the glomeruli, a slow infusion leads to the most components delivered to the glomeruli.

Figure 5

Generic perfusion system for pre-transplant kidney preservation and ex vivo gene therapy to enhance graft survival and reduce renal pathologies A generic perfusion system used before kidney transplantation to preserve organ quality; this system can be used to do ex vivo organ gene therapy aiming to reduce renal pathologies and improve graft survival. The key components of this system are a glass heat exchanger, an oxygenator, a roller pump, and a circulating water bath.