Title: Progressing the Clinical Applicability of Adeno-Associated Virus Gene Therapy for Genetic Nephrotic Syndrome
Funder: The Academy of Medical Sciences

Abstract: Here, I aim to progress Adeno-Associated Virus(AAV) gene therapy for genetic Steroid-Resistant Nephrotic Syndrome(SRNS) towards clinical application. Monogenic SRNS is mostly resistant to medical treatment, and patients progress rapidly to end stage renal failure requiring dialysis and transplant. There is an unmet need for early treatments, and AAV gene therapy presents an elegant targeted solution. My previous work has demonstrated i) specific AAV transduction of the target cell, the podocyte. ii) AAV gene therapy delivered prior to proteinuria in a knockout mouse model of SRNS significantly improves the phenotype. A key requirement to establish clinical applicability is to reverse or halt disease after onset, in the most relevant in vivo model possible. These next steps have been guided by Cell and Gene Therapy Catapult and the MHRA. I plan to deliver AAV expressing wild-type podocin systemically after onset of proteinuria to the conditional podocin knockin mouse, which has a point mutation analogous to the most common mutation in childhood SRNS. This closely resembles the clinical context in which we envisage this gene therapy being delivered. In order to further develop podocyte gene therapies, it will be important to identify the most efficient AAV serotype, so that the lowest possible dose can be delivered to circumvent any problems with immunogenicity and toxicity. I will test novel and previously untested serotypes on human and mouse podocytes in vitro to determine the most efficient serotype. This package of work will enable progression of AAV gene therapy for genetic SRNS towards clinical application.

Lay abstract: Nephrotic Syndrome (NS) is a rare disease of the kidney where children lose massive amounts of protein in their urine. Genetic NS tends to be unresponsive to medical treatments, and these children progress more rapidly to kidney failure, requiring either dialysis or a kidney transplant. There is hence an unmet need for targeted medical therapies. Adeno-Associated Virus (AAV) gene therapy has been very successful for other genetic diseases, e.g. for Spinal Muscular Atrophy. I have been investigating AAV gene therapy for NS in a mouse model by targeting a kidney cell called the podocyte. I have shown that amount of urinary protein decreases and survival increases if the therapy is injected before onset of NS. This shows great promise but refinement of the therapy is required for progression to clinical use. First, I want to see whether there is a form of AAV (different forms are called serotypes) that might more effectively infect podocytes. This is important not only for nephrotic syndrome, but for other kidney diseases involving the podocyte. Next, I will refine the mouse experiments, and establish whether the gene therapy is beneficial if introduced after onset of nephrotic syndrome, in a mouse model with a mutation that more closely mimics the human disease. This will inform us whether the gene therapy proposed is still effective when given within a context more similar to that envisaged for patients, and enable us to progress this therapy towards clinical use.

Research activity codes: 5.1 PHARMACEUTICALS
Health categories: RENAL AND UROGENITAL