Lentiviral vector mediated gene therapy for type I Dent disease ameliorates Dent disease-like phenotypes for three...

Type 1 Dent disease is caused by changes in chloride voltage-gated channel 5 (CLCN5) gene on chromosome X, which causes the lack or dysfunction of chloride channel ClC-5. Affected subjects show proteinuria and hypercalciuria, and eventually develop end-stage kidney disease. Currently there is no cure for this disease. Here, we used CRISPR-Cas9 technology to develop a Clcn5 mouse model with 95% of the ClC-5 coding region deleted. These mutant mice showed obvious Dent disease-like phenotypes. We used lentiviral vectors to deliver human CLCN5 cDNA into the kidneys of mutant mice by retrograde ureter injection and observed increased megalin expression, improved diuresis, and decreased urinary calcium and protein excretion, which persisted for 3 months. The therapeutic effects diminished 4 months after gene therapy. Our data suggest that immune responses to the transgene products most likely explain the loss of gene therapy effects. This study suggests that gene therapy could be a promising approach to treat Dent disease, but more work is needed to achieve sustained therapeutic effects.