Gene therapy for central diabetes insipidus: effective antidiuresis by muscle-targeted gene transfer.

Central diabetes insipidus, characterized by severe polyuria and polydipsia, is a disorder resulting from deficient secretion of the small neuropeptide hormone vasopressin in the neurohypophysis. The standard therapy is daily and life-long administration of vasopressin analog (desmopressin acetate), but gene therapy is potentially alternative to the conventional replacement therapy. To obtain the therapeutic neuropeptide more feasibly, we tried to express vasopressin in nonneuronal tissues using nonviral gene transfer techniques. We found that the unprocessed large precursor form, provasopressin, was predominantly produced in nonendocrine cells transfected with the wild-type vasopressin gene, because of the lack of neuroendocrine cell-specific endopeptidases. In sharp contrast, appropriately processed bioactive vasopressin can be efficiently produced even in nonendocrine cells with a modified vasopressin gene containing a ubiquitous endoprotease furin cleavage site. We also succeeded in maintaining a long-term antidiuretic effect on vasopressin-deficient (Brattleboro) rats by direct introduction of the furin-processible gene into skeletal muscle by electroporation. Altogether, our data clearly show that skeletal muscle is a useful target tissue for continuous delivery of bioactive neuropeptide. Furthermore, our strategies may be applicable to future gene therapies for central diabetes insipidus and other peptide hormone deficiencies.