Improvement of multiple pathophysiological phenotypes of klotho (kl/kl) mice by adenovirus-mediated expression of the klotho gene

Background We have established a novel mouse mutant, klotho (kl), by insert ional mutation of a transgene and identified the structural gene. The mouse homozygous for the mutation exhibits multiple pathological conditions rese mbling age-related disorders in humans and can be regarded as a model of hu man premature aging syndromes. However, the pathophysiological role of Klot ho protein has not been clarified. Methods A replication-deficient adenoviral vector expressing the membrane f orm of the mouse klotho gene was constructed and we examined Klotho express ion in vitro. The recombinant adenoviral vector was then administered intra venously into klotho mice at 4-5 weeks of age and its therapeutic potential was examined. Results Expression of Klotho protein was observed in the adenoviral vector- infected CHO cells. The klotho mice infused with the recombinant adenovirus showed a significant extension of life span and gain in body weight at 1 w eek after treatment. Macroscopic and histological analyses demonstrated the improvement of multiple pathological findings such as restoration from atr ophy and cell formation and differentiation in the gonadal cells, immune ti ssues and subcutaneous fat. Conclusion We showed that local expression of the klotho gene retards or pa rtially improves pathological abnormalities in several organs of klotho mic e after onset of the phenotypes. Therefore, the recombinant adenovirus vect or will provide an important tool for investigating the molecular mechanism of the Klotho protein and give clues to understanding the individual disea se mechanisms. Copyright (C) 2000 John Wiley & Sons, Ltd.