Kim-1 Targeted Extracellular Vesicles as a Therapeutic Innovation for the treatment of Acute Kidney Injury

Institute of Nephrology, Zhong Da Hospital from Southeast University School of Medicine has announced a Therapeutic Innovation for the treatment of Acute Kidney Injury. This news is being released through Index of Sciences Ltd.

Nanjing, China, March 28, 2022 /PRNewswire/ -- AKI is also associated with long-term risks of Chronic Kidney Disease (CKD), End Stage Kidney Disease (ESKD), and other organ dysfunction in affected patients.

But there is a lack of definitive treatment for AKI.  A recent study by a group of research scientists (Tang & Liu et al.) from the Southeast University School of Medicine, Nanjing, China finds that RNA interference (RNAi) provides a new and potent method for gene therapy to tackle this issue. This research developed an extracellular vesicles (EV)-based delivery platform for RNAi therapeutics to protect against AKI.

Achieving efficient delivery of RNAi therapeutics to target organs or specific cell types is a major challenge. This is because the synthetic delivery nanocarriers in RNAi therapeutics such as liposomes, dendrimers and calcium phosphate nanoparticles have concerns of immunogenicity, cytotoxicity, and rapid clearance from circulation. Hence, as a more safe and effective strategy for RNAi delivery, this research group developed an efficient RNAi therapy against AKI by engineering red blood cell-derived extracellular vesicles (REVs) having targeting peptides and therapeutic siRNAs (Figure 1).

A red blood cell–derived extracellular vesicle platform targeted Kim-1 in acutely injured mouse kidney and delivered siRNAs for transcription factors P65 and Snai1, alleviating inflammation and fibrosis in the tubules. This study demonstrates that REVs targeted with the Kim-1–binding peptide allow for an efficient delivery of P65 and Snai1 siRNAs to the injured tubules. This consequently helps in mitigating kidney injury and fibrosis development in murine models of AKI after renal ischemia/reperfusion (I/R) injury or unilateral ureteral obstruction (UUO).

EVs or extracellular vesicles have recently emerged as a promising delivery system for RNA drugs. To ensure safety and less toxicity and avoid unwanted biologic effects on recipient cells, this research prepared EVs from RBCs as they are intrinsically biosafe, biocompatible, abundant, and nonimmunogenic.

Kidney injury molecule-1 (Kim-1), is a type I transmembrane glycoprotein and is selectively expressed on injured TECs, which are the nidus of injury during AKI. In vitro phage display was used to identify peptides that bind to Kim-1, which is recognized as a marker for tubular injury during AKI.

Stronger Kim-1 bands were detected in LTI, MST, MFP, IQP, and LTH relative to scrambled peptide, suggesting all five candidate peptides can bind to Kim-1, among which LTH showed the strongest binding affinity (as shown in Figure 2).

Correlational analyses revealed a negative correlation between LTI level and Kim-1 expression in I/R kidney (Figure 3), suggesting that LTI is not specific for Kim-1 in vivo.

The study evaluated the binding of MFP, IQP, and LTH to recombinant Kim-1 in vitro, and found that both IQP and LTH strongly bound to Kim-1 at high concentrations; only LTH exhibited a high binding affinity at low concentrations (Figure 4). These results indicate that LTH is a preferred candidate for Kim-1 targeting.

Peptide LTH showed high binding affinity to Kim-1 and enhanced the renal accumulation of REVs at the sites of Kim-1+ tubules in ischemic AKI (Figure 5). It was inferred that LTH efficiently guides the homing of REVLTH to the injured tubules, which could be harnessed as a promising vector for AKI therapy.

The study performed RNA-seq to clarify the critical genes in driving AKI and focused the analysis on transcription factors. RNA-sequencing (RNA-seq) characterized the transcriptome of ischemic kidney to explore potential therapeutic targets.

The study provides an efficient Kim-1–targeted delivery platform, REVLTH, for the targeted delivery of therapeutics into injured tubular cells and highlights its potential in the delivery of siP65/siSnai1 as a promising RNAi therapeutic avenue for AKI. Moreover, as TECs highly express Kim-1 not only in AKI but also in CKD, this study proposes that REVLTH could be utilized to target injured TECs in multiple kidney diseases with wide applicability.

The study suggests a transformative potential of REVLTH-siP65/siSnai1 in controlling renal inflammation and fibrosis with minimal toxicities. This is a unique platform that may accelerate the development of gene therapy in AKI and other kidney diseases.

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