Cardiac BNP Gene Delivery as a Hypertension Treatment

The laboratory rat lineage used in this study, spontaneously hypertensive rats, was bred decades ago to exhibit high blood pressure, and predates modern genetic engineering methods. So I think there are fair odds that the beneficial results shown in this paper will hold up in normal rats or other models of hypertension.

Hypertension is a highly prevalent disease associated with cardiovascular morbidity and mortality. Recent studies suggest that patients with hypertension also have a deficiency of certain cardiac peptides. Previously we demonstrated that a single intravenous injection of the myocardium-tropic adeno-associated virus (AAV) 9-based vector encoding for proBNP prevented the development of hypertensive heart disease (HHD) in spontaneously hypertensive rats (SHRs). The current study was designed to determine the duration of cardiac transduction after a single AAV9 injection and to determine whether cardiac BNP overexpression can delay the progression of previously established HHD, and improve survival in aged SHRs with overt HHD.

To evaluate the duration of cardiac transduction induced by the AAV9 vector, we used four week old SHRs. Effective long-term selective cardiac transduction was determined by luciferase expression. A single intravenous administration of a luciferase-expressing AAV9 vector resulted in efficient cardiac gene delivery for up to 18-months. In aged SHRs (9-months of age), echocardiographic studies demonstrated progression of HHD in untreated controls, while AAV9-BNP vector treatment arrested the deterioration of cardiac function at six months post-injection (15-months of age).

Aged SHRs with established overt HHD were further monitored to investigate survival. A single intravenous injection of the AAV9-vector encoding rat proBNP was associated with significantly prolonged survival in the treated SHRs (613 ± 38 days, up to 669 days) compared to the untreated rats (480 ± 69 days, up to 545 days). These findings support the beneficial effects of chronic supplementation of BNP in a frequent and highly morbid condition such as HHD.



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