Advancing genetic medicines for inherited kidney disease

Chronic kidney disease (CKD) is a leading cause of global mortality, affecting ~13% of global population. Inherited kidney diseases (IKD) are estimated to account for a 30% of CKD cases. Despite the unprecedented development of genetic medicines in the past decades, to date no kidney gene therapy intervention is available. Renal gene therapies have encountered two main barriers: (1) its complex anatomy and function has hampered efficient and specific delivery of genetic therapies to the kidney, and (2) many IKDs are caused by mutations in large genes, and therefore, traditional gene supplementation strategies using efficient and safe in vivo vectors (such as adeno-associated viral vectors or AAV) cannot be developed due to the limited packaging capacity. The main goal of this proposal is to create solutions for these challenges by developing novel gene therapy vectors with improved kidney targeting and genome editing strategies to correct the genetic defect in large genes that cause IKDs.Recent advances in the field of discovery and engineering of gene delivery vehicles combined with CRISPR-based gene editing technologies have opened the avenue towards developing efficient and safe gene editing therapies. In this proposal, we will develop in vivo genome editing approaches for Autosomal Dominant Polycystic Kidney Disease (ADPKD), the most frequent IKD with an incidence of 1:1,000. For this, we will develop novel AAV gene delivery vectors, a technology that has been clinically validated to target several tissues, enabling an efficient delivery of CRISPR editors to the kidney. Additionally, CRISPR approaches will be designed to restore the physiological expression of the mutated PKD1 gene that causes ADPKD and tested in APDKD mouse and pig models in vivo and in patient-derived kidney organoid models in vitro. The completion of this proposal will enable the generation of personalized and universally applicable in vivo gene editing therapies for ADPKD patients.