Correction of Renal Tubular Acidosis in Carbonic Anhydrase II–deficient Mice with

Carbonic anhydrase II (CAII) deficiency in humans is asso-ciated with a syndrome of renal tubular acidosis, osteo-petrosis, and cerebral calcification. A strain of mice of CAII deficiency due to a point mutation also manifests renal tu-bular acidosis. We report here that retrograde injection of cationic liposome complexed with a CAII chimeric gene, us-ing a cytomegalovirus (CMV) promoter/enhancer as an ex-pression cassette to drive human CAII cDNA, into the renal pelvis of CAII-deficient mice results in expression of CAII in the kidney. The levels of both the CAII gene and its cor-responding mRNA were highest by day 3 after treatment, diminishing thereafter, but remaining detectable by 1 mo. After gene therapy, CAII-deficient mice restored the ability to acidify urine after oral administration of ammonium chloride. The ability to acidify urine was maintained at 3 wk after gene therapy, and was eventually lost by 6 wk. Immu-nohistochemistry studies using anti-CAII antibodies showed that CAII was expressed in tubular cells of the outer me-dulla and corticomedullary junction. The gene therapy was not associated with nephrotoxicity as assessed by blood urea nitrogen levels and renal histology. To our knowledge, this is the first successful gene therapy of a genetic renal disease. Our results demonstrate the potential of gene therapy as a novel treatment for hereditary renal tubular defects. ( J