CORRECTION OF RENAL TUBULAR-ACIDOSIS IN CARBONIC-ANHYDRASE II-DEFICIENT MICE WITH GENE-THERAPY

Carbonic anhydrase II (CAII) deficiency in humans is associated with a syndrome of renal tubular acidosis, osteopetrosis, and cerebsal calci fication, A strain of mice of CAII deficiency due to a point mutation also manifests renal tubular 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 expression cassett e to drive human CAII cDNA, into the renal pelvis of CAII-deficient mi ce results in expression of CAII in the kidney. The levels of both the CAII gene and its corresponding mRNA were highest by day 3 after trea tment, diminishing thereafter, but remaining detectable by 1 mo, After gene therapy, CAII-deficient mice restored the ability to acidify uri ne after oral administration of ammonium chloride, The ability to acid ify urine was maintained at 3 wk after gene therapy, and was eventuall y lost by 6 wk, Immunohistochemistry studies using anti-CAII antibodie s showed that CAII was expressed in tubular cells of the outer medulla and corticomedullary junction. The gene therapy was not associated wi th 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 defect s.