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Inhalable gene therapy for PAH

08 Oct, 2013

Pulmonary arterial hypertension may be reversible using an inhalable gene therapy according to an international team of researchers led by scientists at the Cardiovascular Research Center at the Mount Sinai Medical Center in New York.

Pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a heart and lung condition, characterised by tightened blood vessels leading to and in the lungs, that affects hundreds of thousands of people each year. Although some treatments such as blood thinners and circulation boosters are available, over time, PAH usually ends in heart failure.

PAH most commonly results from heart failure in the left side of the heart or from a pulmonary embolism, when clots in the legs travel to the lungs and cause blockages. When the lung is damaged from these conditions, the tissue starts to quickly produce new and enlarged cells, which narrows pulmonary arteries. At a cellular level, SERCA2a enzyme supply is reduced, calcium stays longer in the cells than it should, and it creates pathways that lead to the overgrowth of these new and enlarged cells.

Adeno-associated viral vector

Using rat models of the disease, the researchers used a nebuliser-like inhalation device, fuelled with AAV1.SERCA2a gene therapy to completely reverse PAH. The gene therapy uses a modified adeno-associated viral vector that is derived from a parvovirus to deliver a healthy SERCA2a gene into cells.

In the lab, using pulmonary artery PAH patient tissue samples, the researchers also demonstrated reduced expression of SERCA2a, an enzyme critical for proper pumping of calcium in calcium compartments within cells.

Delivery through simple inhalation

In a press release from the Mount Sinai Medical Centre, the study co-senior investigator Dr Roger Hajjar said, “The gene therapy could be delivered very easily to patients through simple inhalation – just like the way nebulisers work to treat asthma. We are excited about testing this therapy in PAH patients who are in critical need of intervention.”

Interestingly, the same SERCA2a gene dysfunction often also occurs in heart failure. The same gene therapy is currently being tested in patients to reverse congestive heart failure in a large phase III clinical trial in the United States and Europe.

“What we have shown is that gene therapy restores function of this crucial enzyme in diseased lungs,” says Dr Hajjar. “We are delighted with these new findings because it suggests that a gene therapy that is already showing great benefit in congestive heart failure patients may be able to help PAH patients who currently have no good treatment options – and are in critical need of a life sustaining therapy.”

According to researchers, the delivery of the SERCA2a gene produces SERCA2a enzymes, which help both heart and lung cells restore their proper use of calcium.

Towards clinical trials

The researchers say they are moving towards PAH patient clinical trials in the near future, with studies in large animal models now under way. SERCA2a gene therapy has already been approved for human study by the National Institutes of Health.

“The clinical trials in congestive heart failure have shown already that the gene therapy is very safe,” says Dr Hadri.

The clinical application of the gene therapy for patients with PAH will most likely differ from those with heart failure. With heart failure patients, the replacement gene needs to be injected through the coronary artery using catheters, while in PAH patients, the gene will be administered through inhalation.


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