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 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 or with Sambucus nigra lectin that are specific for α2,3- and α2,6-N-linked sialic acids, respectively. Given that these sialic acid glycoproteins facilitate the transduction of AAV1, we injected 1-month-old, RC/RC ADPKD mice intraperitonially with 2 × 10 12 particles/kg of AAV1 containing either a GFP vector or a truncated CFTR vector, Δ27-264-CFTR. 2 months after treatment the cyst area and size were significantly lower in the CFTR vector-treated mice compared to 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 NHE3 or ENaC, 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.