Developing RNA-editing based therapy for renal cystic ciliopathies

Introduction

Chronic Kidney Disease (CKD) is a significant global health burden, affecting approximately 10% of the adult population worldwide. It is estimated that 10-20% of advanced CKD cases are caused by genetic kidney diseases, with renal cystic ciliopathies being the most common genetic contributors.

Background

In the Israeli Druze population, we have identified a novel homozygous mutation in the WDR19 gene as the leading cause of end-stage kidney disease (ESKD), particularly leading to renal failure in young adults. Currently, kidney failure caused by renal cystic ciliopathies can only be treated through renal replacement therapies, such as dialysis or transplantation, as no specific therapeutic interventions are available.

Project Aim

This project aims to establish proof of concept that RNA editing can serve as a viable therapeutic strategy for genetically driven kidney failure. By employing Site-Directed RNA Editing (SDRE) through the action of Adenosine Deaminase Acting on RNA (ADAR) enzymes, we aim to correct the pathogenic WDR19 mutation (c.878G>A) at the RNA level.

Methodology

Our efforts will focus on:

1. Optimizing guide RNA (gRNA) design
2. Improving delivery mechanisms to maximize editing efficiency and therapeutic outcomes

The efficacy of this approach will be evaluated by its ability to rescue the disease phenotype in patient-derived induced pluripotent stem cell (iPSC)-derived kidney organoids and further validated in murine models.

Conclusion

If successful, this proof-of-concept project could pave the way for RNA editing-based therapies as a transformative treatment for genetic kidney diseases.