Aerosol-Delivered Gene Therapy Seen to Stop Vascular Remodeling in PH Study in Pigs

Inês Martins, PhD avatar

by Inês Martins, PhD |

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A new, aerosol-delivered gene therapy has shown promising effects in a pig model of pulmonary hypertension (PH), according to a study published in the Journal of The American College of Cardiology (JACC), titled “Intratracheal Gene Delivery of SERCA2a Ameliorates Chronic Post-Capillary Pulmonary Hypertension“.

PH is characterized by pulmonary arterial remodeling that results in increased pressure in the vessels that take blood from the heart to the lungs. The thickening of pulmonary vessels is triggered by abnormal calcium levels within the vascular cells, which leads to hyper-proliferation of the muscle cells that line the blood vessels. One protein involved in the regulation of intracellular calcium levels is the sarcoplasmic reticulum calcium ATPase pump (SERCA2a), which may be a possible therapeutic target for the treatment of PH.

Researchers from Mount Sinai, and their collaborators in Boston and Spain, first aimed to understand whether it was feasible to deliver the SERCA2a gene to the narrowed blood vessels of the lung by aerosol administration of an engineered adeno-associated virus that carried the gene. Such an aerosol inhalation technique had been previously used to effectively deliver SERCA2a in a rodent animal, but this approach had never been used in large animals.

Having tested the approach, the researchers’ primary objective was to assess whether the transferred genes were able to stop the vascular remodeling in the lungs, and would have a sustained beneficial effect.

The investigators used a Yorkshire swine model that closely mimics PH in humans, and divided a total of 20 pigs into two experimental groups. One group was given the aerosolized viral vector with the SERCA2a gene, and the remaining 10 pigs received a saline spray. Two months following gene delivery, the research team examined the animals to find the virus carrying SERCA2a had been effectively delivered, leading to an improvement in the heart and lung function, and to a reduction in the cellular changes that cause PH.

“By tailoring the gene therapy, it looks like we can halt the proliferation of smooth muscle cells in the blood vessels,” Dr. Roger Hajjar, one of the study’s senior authors, said in a press release. “This should help restore function and improve survival in human patients.”

“The therapeutic potential of using gene therapy to treat pulmonary hypertension by delivery of aerosolized adeno-associated virus carrying SERCA2a to directly target vascular remodeling through the overexpression of the SERCA2a protein is very significant,” added Jane A. Leopold, MD, the co-senior study author. “In addition, as other novel targets are identified by deep phenotyping of patients with pulmonary hypertension in the National Institutes of Health/National, Heart, Lung, & Blood Institute-funded Pulmonary Vascular Disease Phenomics (PVDOMICS) study, they may be viable candidates for aerosolized gene transfer using adeno-associated viral vectors.”

In the future, Dr. Hajjar intends to perform further studies testing the long-term efficacy and safety of this gene therapy approach in animals, before advancing it to human clinical trials.

A Conversation With Rare Disease Advocates