Kidney targeted AAV for gene therapy

Vanderbilt University Medical Center, Nashville TN

Investigators

Abstract

The kidney remains understudied as a target organ for in vivo gene transfer leading to a lack of effective gene therapies for kidney disease. Chronic kidney disease (CKD) is estimated to affect 13% of the population worldwide with high mortality and morbidity rates. Many kidney diseases have underlying genetic etiologies that may be amenable by gene therapy or genome editing, underscoring the crucial unmet need for effective and safe kidney-targeting gene delivery vehicles. Cystinuria is a common kidney inborn error of metabolism with existing mouse and canine models providing an ideal disease model for preclinical gene replacement strategies. With the approval of five AAV-based products by the FDA for treating ocular, hematological and neuromuscular disorders, there ~200 completed or active gene therapy trials. However, little progress has been made to date in achieving effective therapeutic gene transfer to kidneys due to the intrinsic filtering function, diverse cell types, complex physiology, and species differences. We have recently demonstrated successful evolution of cross-species compatible AAV capsids. The approach involves iterative evolution in multiple animal models and such new AAV variants could enable better predictive preclinical modeling and improve the therapeutic window of AAV gene therapies in humans. Here, we present promising preliminary results successfully adapting this robust approach to tackle the problem of efficient gene transfer to the kidney in multiple species. The current proposal hinges on understanding the biology of new AAVs in kidney cell types and further engineering features that can improve kidney tropism and decrease liver sequestration, thereby improving kidney targeting and safety (Aim 1). We will also develop these new kidney-tropic AAV vectors for gene transfer to phenotypically correct cystinuria in in vivo mouse models and human kidney organoid models (Aim 2). Using a battery of assays, we will evaluate the ability of gene transfer to prevent disease onset as well as treat the disease phenotype in mouse models. We will also evaluate the ability of new AAV variants and optimized vector cassettes to correct the cystinuria disease phenotype in human induced pluripotent stem cell (hiPSC) derived kidney organoids. Overall, this collaborative proposal between Vanderbilt University Medical Center and Duke University has the potential to be transformative for gene therapy of kidney disorders.