# Podocyte-directed VEGFC gene therapy prevents increased glomerular permeability and glycocalyx damage in experimental type 1 diabetes

## TL;DR

This study shows that gene therapy targeting the VEGFC growth factor in kidney cells can prevent early kidney damage in type 1 diabetes.

## Contribution

Podocyte-directed VEGFC gene therapy is introduced as a novel strategy to prevent early DKD progression.

## Key findings

- AAV2/9-mediated VEGFC gene therapy reduced albuminuria and glomerular permeability in diabetic mice.
- VEGFC gene therapy protected the glomerular endothelial glycocalyx in type 1 diabetic mice.
- The therapy was functional in human and mouse podocytes in vitro.

## Abstract

Diabetic kidney disease (DKD) is the leading cause of end-stage renal failure, and current interventions fail to directly target the glomerulus, where the disease initiates. Vascular endothelial growth factor (VEGF)C is a key contributor to glomerular endothelial barrier function. In transgenic mice, podocyte-specific overexpression of human VEGFC was protective in early DKD. Here, we investigated the therapeutic potential of a podocyte-targeted VEGFC gene therapy in DKD. We employed an adeno-associated virus (AAV2/9) to drive human VEGFC in human and mouse podocytes. Expressed VEGFC was functional in vitro. In type 1 diabetic mice (induced by streptozotocin), systemic administration of AAV2/9 increased glomerular human VEGFC expression, ameliorating both albuminuria and increased glomerular permeability. Importantly, VEGFC gene therapy also protected the glomerular endothelial glycocalyx, the first barrier to protein in the glomerular filtration barrier. These findings demonstrate that podocyte-directed VEGFC gene delivery can restore glomerular function and protect against early DKD progression. This novel approach represents a promising therapeutic strategy, particularly for patients with type 1 diabetes at risk of DKD, where there is an unmet clinical need.

There is a critical need for novel interventions that can slow the progression of kidney disease in diabetes, particularly in type 1 diabetes. Here, Foster and colleagues show that gene therapy is a viable option for targeted delivery in the kidney in diabetes, using adeno-associated virus to deliver a growth factor (VEGFC).