Research Awards Recipients

Lay Summary
Alport syndrome (ATS) is a clinically heterogeneous nephropathy caused by mutations in collagen IV genes and characterized by ultrastructural lesions of the glomerular basement membrane (GBM) (Gubler et al., 2008). Podocytes have a predominant role in disease onset and progression, and we have recently proven that it is possible to isolate COL4-expressing podocyte-lineage cells from urine obtained from ATS patients (Daga et al., 2018). An efficient therapy for ATS is still missing, and functional disruption of podocytes can be only partially recovered by symptomatic treatments with RAAS-inhibitors. Transformative gene-based medicines for patients with rare diseases are now aiming to cure diseases at the molecular level using innovative gene-editing tools. The proposed project is designed to use a CRISPR/Cas9 gene editing approach in order to efficiently correct a causative mutation of Alport syndrome in dogs to achieve wild-type COL4 chain production and reversion or slowing-down of the ATS phenotype. The naturally-occurring ATS dog model has a 10-base-pair deletion in the COL4A5 gene. Using podocytes derived from urine, we first aim to establish the efficiency of adeno-associated virus (AAV)2-CRISPR/Cas9 gene therapy to restore the wild-type genotype in canine ATS podocytes in-vitro. We then propose a gene therapy in-vivo preclinical pilot trial using a single femoral artery catheterization to deliver the AAV2-CRISPR/Cas9-based correction system, injecting into both renal arteries.

The proposed AAV2-CRISPR/Cas9 strategy can provide the proof-of-principle for a gene therapy strategy for ATS treatment. If evidence for efficacy and safety is found, this approach will open up the possibility of in-vivo clinical trials on ATS patients based on a personalized, transformative medicine tailored to the pathogenic mechanism and performed directly on the disease-relevant cells.