Gene Therapy For Hypertension And Nephrotic Syndrome

In view of the characteristics of polygenic diseases such as high incidence, serious consequences, complicated mechanisms and difficulty in treatment, on the basis of somatic gene therapy, we put forward an idea of developing phenotypic gene therapy for polygenic diseases, directly treating the symptoms of diseases, without first considering their genetic backgrounds. It is just as a minimal pharmaceutical factory is established in the body and continuously provides medicine for it. It is different from routine therapy in the medicine form and administration of the drug. Moreover, it is especially helpful to the gene products with very short half-life. If the phenotypic gene therapy for polygenic disease is feasible, the adaptability and flexibility of gene therapy will be enhanced greatly.In order to evaluate the reasonability and feasibility of the strategy of the phenotypic gene therapy, atrial natriurtic peptide (ANP) gene of which the product has a wide range of physiologic effects such as a rapid diuresis and natriuresis as well as a reduction in arterial blood pressure was used as functional gene. Animal models of spontaneously hypertensive rat (SHR) and nephrotic syndrome (NS) Wistar rats induced by adriamycin (ADR) were used as the object of study. They have the similar symptoms such as high blood pressure and oliguria respectively to that of human hypertension and oliguric acute renal failure. Physiologic effects of ANP gene transferred by means of somatic gene therapy (ex vivo in young SHR and in vivo in NS rats) were investigated for the first time. A single implantation of the mixture consisted of the cells expressing ANP and collagen and the capsule filled with SHRFT cells engineered to secrete ANP in SHR caused a significant reduction in systemic blood pressure lasting 7 weeks and an obvious diuresis lasting 2-3 weeks. A single injection of a naked retrovirus vector pLT8 containing ANP gene through the tail vein resulted in a clear diuresis in NS rats and the effect continued for 2 weeks. During the course of the project, a special human somatic cell (HEFT) was found for the first time. HEFT cell overexpressed and secreted human ANP in vitro. Moreover, a significant reduction in blood pressure was observed when the cell was xenogenically transplanted into SHR by means of the collagen mixture. These results show that...