A gene therapy study carried out in pigs has demonstrated promising results for the treatment of pulmonary arterial hypertension, the form of pulmonary hypertension that involves narrowing of the blood vessels in the lungs. The therapy overexpresses SERCA2a, an approach already under development for the treatment of heart failure. When targeted to blood vessels it can produce remodeling, compensating in part for the narrowing that is the proximate cause of pulmonary arterial hypertension - though without addressing any of the root causes, as is unfortunately still the case in the majority of medical research.
Scientists have used a novel gene therapy to halt the progression of pulmonary hypertension, a form of high blood pressure in the lung blood vessels that is linked to heart failure. Pulmonary arterial hypertension (PAH) is a rare, rapidly progressing disease that occurs when blood pressure is too high in vessels leading from the heart to the lungs. There is currently no cure for PAH, and about 50 percent of people who are diagnosed will die from the disease within five years. The high pressure is caused by abnormal remodeling of the lung blood vessels that sometimes leads to failure of the right ventricle and premature death. Thickening and narrowing of pulmonary vessels is seen with all types of pulmonary hypertension and is triggered by abnormal calcium levels within the vascular cells. The sarcoplasmic reticulum calcium ATPase pump (SERCA2a) regulates intracellular calcium in vascular cells and prevents them from proliferating in the vessel wall.
There were two primary objectives for this study. First, scientists wanted to learn if it is feasible to deliver a therapeutic gene called SERCA2a in aerosol form to damaged blood vessels of the lung using an engineered adeno-associated virus as a "vector." Second, they wanted to see if there was a sustained beneficial impact, and if the transferred genes effectively slowed or stopped the vascular changes in the airways that are the hallmark of PAH and other forms of pulmonary hypertension. The current study is the first to explore this approach in a large animal - specifically, a Yorkshire swine model that closely resembles PAH in humans.
In the study, 20 pigs were divided into two groups, half of which received the aerosolized viral vector carrying the SERCA2a gene and half a saline spray. Two months after the gene delivery, scientists performed tests to see if the new therapeutic genes were present and functioning in the vessels of the animals' lungs, and whether the transfer was producing the desired effects. When they examined the animals, they found that that heart and lung function had improved and abnormal cellular changes causing PH were reduced. Additional animal studies focusing on long-term efficacy and safety are warranted before advancing this approach, known as airway gene delivery, to human clinical trials. That's because the current study involved a small number of animals, and they were assessed just eight weeks after gene delivery. Nevertheless, airway gene delivery appears to modify fundamental pathophysiology, and therefore might offer therapeutic benefit to humans with a variety of pulmonary vascular diseases.