AAV1-CFTR preferentially transduces cysts and reduces cyst size in a mouse model of ADPKD.

To overcome the challenges of developing a gene therapy for autosomal dominant polycystic kidney disease (ADPKD), we focused on the surface receptors expressed in cystic epithelia. Importantly, we detected altered localization in the cystic epithelium of wheat germ agglutinin, WGA, staining of sialic acids. Throughout the membrane of the cysts, we saw altered staining with Maackia amurensis lectin (MAL) or with Sambucus nigra lectin (SNL) that are specific for α2,3- and α2,6-N-linked sialic acids, respectively. Given that these sialic acid glycoproteins facilitate the transduction of adeno-associated virus 1 (AAV1), we injected 1-mo-old, pkd1^{R3277C/R3277C}, (RC/RC) ADPKD mice intraperitoneally with 2 × 10¹² particles/kg of AAV1 containing either a green fluorescent protein (GFP) vector or a truncated cystic fibrosis transmembrane conductance regulator (CFTR) vector, Δ27-264-CFTR. Two months after treatment, the cyst area and size were significantly lower in the CFTR vector-treated mice compared with those untreated and those receiving the GFP. We detected vector genomes and mRNA expression only in their corresponding CFTR vector- or GFP vector-treated mice. We observed co-staining for GFP and CFTR immunofluorescence with either the Na⁺/H⁺ exchanger or epithelial Na⁺ channel, indicating proximal tubule or collecting duct expression, respectively. Expression of GFP and CFTR protein expression above background levels was detected. CFTR immunofluorescence was increased in the basolateral membrane after CFTR vector instillation. Finally, these data suggest that cysts are prime targets for AAV1 gene therapy and offer an exciting prospect for ADPKD gene therapy.NEW & NOTEWORTHY Current therapies for ADPKD involve treatment of the symptoms. A direct approach would involve a gene therapy. Here we show AAV1 is tropic for cystic epithelia, which have abundant expression of sialic acid resides known to enhance AAV1 transduction. We show that a CFTR-based vector can reduce cyst size, suggesting that it may be therapeutic. These data suggest that cysts are prime targets for AAV1 and offer an exciting prospect for ADPKD gene therapy.