Malik, Saif Nisar; (2023) A Novel Targeted mRNA Therapy for Paediatric Glomerular Disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The glomerulus contains the blood filtering apparatus of the kidney consisting of epithelial podocytes, a basement membrane, and endothelial cells. In diseases, such as Denys-Drash syndrome (DDS), caused by mutations in the podocyte transcription factor Wilms Tumour 1 (WT1) the filtration barrier loses functional integrity. This results in children presenting with albumin in their urine, glomerulosclerosis, and subsequent progression to end stage kidney disease (ESKD) by five years of age. There are no therapies and children with glomerular disease require dialysis or transplantation. The aim of this thesis was to develop a new therapy in a mouse model with a mutation in Wt1 (Wt1+/R394W) that replicates the pathology of DDS. I developed a lipid nanocomplex formulation capable of specifically targeting integrin αvβ3 for high transfection and delivery of mRNA to wild-type Wt1+/+ and Wt1+/R394W primary podocytes in vitro. In vivo, when delivered by ultrasound guided renal artery injection, these integrin αvβ3 targeted nanocomplexes localise to the kidney at levels not possible with systemic administration. Furthermore, these nanocomplexes localise to the glomeruli in healthy and diseased animals for up to 7 days post injection. Finally, I applied the combination of the integrin αvβ3 targeted nanocomplex and the localised injection technique to deliver angiopoietin-1 mRNA, a vascular growth factor which protects the glomerulus and showed, for the first time, a therapeutic benefit to the progression of Wt1+/R394W glomerular disease. Angpt1 mRNA nanocomplexes delivered via the renal artery significantly reduced albuminuria, alleviated the progression of glomerulosclerosis, and prevented the loss of the glomerular endothelium and podocytes in Wt1+/R394W mice. Together this work provides a strong basis for the further development of this therapy, vehicle and delivery route for use in the clinic, to slow disease progression and prolong the lives of patients with WT1 glomerular disease.

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