1:Health Research Institute of Santiago de Compostela; 2:University of Santiago de Compostela

Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited kidney disease, with a prevalence of 1 in 1000 live births. It is characterized by the appearance of cysts in the kidneys and by an increase in the size of the kidneys, leading irrevocably to end-stage renal disease.

Most of the mutations observed in the genes that cause this disease (PKD1 and PKD2) are missense mutations, which makes possible the application of Prime Editing technology to correct these mutations. The correction of the ADPKD-causing mutation should allow a reversion of the ADPKD phenotype, since it has been demonstrated that the kidney is an organ that has plasticity, that is, the correct re-expression of the Pkd1 and Pkd2 genes in cystic kidneys results in a rapid reversal of ADPKD.

The overall objective is to use Prime Editing technology to correct the ADPKD-causing mutation in two different mouse models. To achieve this objective, the following specific objectives will be performed: 1) In silico design of pegRNAs; 2) In vitro testing of pegRNAs in renal cells of both mouse models; 3) Bioinformatics study and selection of the pegRNAs with the highest editing efficiency; 4) In vivo editing of the two mouse models with the selected pegRNAs.

Our work is aimed at laying the foundations of gene therapy in the field of renal genetics and specifically in ADPKD, which is the central axis of the project.