Gene Therapy Improves PAH Symptoms in Animal Models

Gene therapy may offer a promising therapeutic approach for pulmonary arterial hypertension (PAH), according to an animal study conducted by Japanese researchers.

The study “Constitutively active form of natriuretic peptide receptor 2 ameliorates experimental pulmonary arterial hypertension,” published in Molecular Therapy Methods and Clinical Development, shows that delivering a constantly active form of the natriuretic peptide receptor 2 (caNPR2) to the pulmonary arteries of PAH rat models is safe and significantly improves PAH manifestations.

Multiple drug therapies are currently available for PAH patients. Among those receiving a lot of attention, are drugs that increase levels of cyclic guanosine monophosphate (cGMP), which induces relaxation of the smooth muscle cells surrounding the blood vessels.

Several phosphodiesterase 5 (PDE5) inhibitors and soluble guanylyl cyclase (sGC) stimulators currently available are known to increase cGMP levels. However, some patients are resistant to the medications and require lung transplantation.

Recently, the authors of the current study showed that caNPR2, caused by a point mutation in the NPR2 gene, has the ability to increase cGMP levels within the cells by 10,000 times. Given that it is markedly higher that those induced by PDE5 inhibitors, the researchers aimed to investigate the therapeutic potential of caNPR2.

For the study, caNPR2 was delivered to PAH model rats by direct injection of a viral vector (that carries the mutated gene) into the left pulmonary artery. The technique was found to safely and effectively deliver caNPR2 into pulmonary arterial smooth muscle cells, which suppressed the proliferation of the cells and reduced pulmonary artery pressure, even when only the left lung was treated. Wall thickness and occlusion of small pulmonary arteries were also significantly improved in caNPR2-treated lungs.

Gene therapy effects were also examined in pulmonary arterial smooth muscle cells isolated from an idiopathic PAH patient. caNPR2 effectively induced cGMP expression and suppressed cell proliferation. Results indicated that viral delivery of caNPR2 could be effective in patients with PAH.

“There are still some safety concerns associated with gene therapies for the human lungs, particularly with virus vectors.” the authors wrote in the study paper. “Since various effective drugs are available for the treatment of PAH patients in the current era, we speculate that our gene therapy is suitable for the most severe cases of PAH, particularly for patients who are resistant to multiple drug therapies and awaiting lung transplantation to halt or at least slow disease progression.”