Using gene therapy to treat pulmonary hypertension

Researchers have used airway gene delivery to treat pulmonary arterial hypertension in a large animal model. Led by researchers from the Icahn School of Medicine at Mount Sinai, the study was published in the May 3 edition of Journal of the American College of Cardiology.

A rare disease with no cure

Pulmonary arterial hypertension (PAH) is a rare progressive disease characterized by abnormally high blood pressure within the pulmonary artery, the vessel that carries blood from the heart to the lungs. This high pressure occurs due to the thickening and narrowing of the pulmonary artery, which can in turn damage the right ventricle of the heart. Initial symptoms include shortness of breath, dizziness, fainting spells, chest pain and swelling of the legs and ankles. Eventually, the heart can fail, leading to premature death.

The disease is rare; the United States sees about 1,000 new cases of PAH each year. However, there is currently no cure, and about 50 percent of those diagnosed will die from the disorder within five years. The disease disproportionally affects young adults and women, with female patients comprising about 72% of the affected population.

A gene to target

It is known that the narrowing of the pulmonary vessels is trigged by abnormal calcium levels within vascular cells. The sarcoplasmic reticulum calcium ATPase pump (SERCA2a) is responsible for regulating intracellular calcium ion levels. Scientists believe that using gene therapy to deliver more of the SERCA2a gene into affected vessels could help halt the progression of PAH.

In the new study, researchers delivered the SERCA2a gene using aerosolized adeno-associated viral vectors, a technique in which therapeutic genes are delivered in aerosol form. Previously, the aerosol inhalation technique had been effectively used to deliver the SERCA2a gene in a rodent model. Now, researchers applied the approach to a large animal model: a Yorkshire swine affected by pulmonary hypertension in a similar way as humans.

A potential new treatment

“This should help restore function and improve survival in human patients.”

The researchers had two objectives in this study. First, they wanted to confirm it was feasible to deliver SERCA2a in aerosol form to damaged blood vessels in the lung using an engineered adeno-associated virus as the vector. Second, they wanted to see if the aerosolized gene transfer would effectively slow or stop the vascular changes that result in PAH.

The researchers tested 20 pigs, half of which received the aerosolized viral vector treatment and half of which received a saline spray control. Two months after the procedure, the team confirmed that the SERCA2a gene delivery was indeed successful, and as a result, PAH progression had been halted in the treated pigs. In those pigs, heart and lung function had improved, while the abnormal cellular changes that lead to PAH had been reduced.

“”I’m excited that there is a potential new treatment for patients with this deadly disease,” lead author Roger J. Hajjar, MD, Professor of Medicine and Director of the Cardiovascular Research Center at the Icahn School of Medicine at Mount Sinai said in a press release. “By tailoring the gene therapy, it looks like we can halt the proliferation of smooth muscle cells in the blood vessels. This should help restore function and improve survival in human patients.”

Additional animal studies are needed before this technique can be tested in human clinical trials to ensure both safety and long-term efficacy. However, the research team is hopeful that airway gene delivery might eventually be used to help patients with a range of pulmonary vascular diseases.


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