ELA32 Gene Therapy Found to Lessen PAH in Animal Study
Apelinergic system may be a potential new therapeutic target
A gene therapy designed to provide a protein implicated in heart function improvement was found to lessen pulmonary blood vessel remodeling and reduce lung blood pressure in a preclinical study of pulmonary arterial hypertension (PAH).
The study, “Apela gene therapy alleviates pulmonary hypertension in rats,” was published in The FASEB Journal.
The apelinergic system is composed of two ligands (binding molecules) known as apelin and apela, along with the apelin peptide jejunum (APJ) receptor. This protein receptor is involved in a wide range of functions, including body fluid balance, anxiety, and depression, as well as cardiovascular and metabolic disorders.
The apela ligand, also known as ELA32, plays a key role during heart development and has beneficial effects for high blood pressure and after a heart attack. Prior research showed that the levels of apela were decreased in the heart and lung tissues of people living with PH as well as in rat models of PH.
Increasing its levels in a rat model of the disease lessened heart enlargement and right ventricular systolic pressure — a measure that estimates the pressure in the artery that supplies blood to the lungs.
Promising gene therapy research for pulmonary hypertension
Gene therapy research has shown promise for pulmonary hypertension. In China, a team at Nanjing Medical University designed a gene therapy to deliver the ELA32 gene using an adeno-associated virus (AAV), a commonly used gene therapy delivery vehicle in clinical trials.
The scientists used a rat model in which PH is triggered by a toxic chemical called monocrotaline (MCT), which led to significantly higher pulmonary blood pressure relative to control rats.
The gene therapy was injected directly into the bloodstream of the rats in the first and second weeks following the administration of MCT.
The researchers first tested whether they could detect the expression of ELA32 messenger RNA (the molecule generated from DNA that serves as a template for protein production) in the rats after four weeks. Results showed that ELA32 was most elevated in the animals’ lungs, followed by the heart and liver, and absent from the brain, kidney, and testes.
Also, confirming previous studies, MCT-induced PAH led to a significant suppression of ELA32 and the APJ receptor in the lungs when compared to control rats. The gene therapy restored the levels of both ELA32 and APJ.
Gene therapy alleviated PH, as shown by a significant reduction in the heart failure biomarker NT-proBNP, mean right ventricular systolic pressure, and systolic pulmonary artery pressure. It also significantly lowered thickening of small pulmonary blood vessels.
The level of alpha-SMA, a marker of mature myofibroblasts — cells with an important role in structural alterations of heart muscle — was also significantly reduced in lung tissue of rats given the gene therapy. The opposite (an increase with treatment) was seen with von Willebrand factor, a blood protein made within endothelial cells that line the inside of blood vessels. Notably, gene therapy also increased the animals’ mean weight gain.
Relative to untreated PAH animals, lung tissue analysis showed that the gene therapy significantly increased the expression of the APJ receptor protein, along with additional proteins, namely BMPR2 and SMAD4. This suggests that “the BMPRII/SMAD4 pathway is also involved in the occurrence and development of pulmonary hypertension,” the scientists wrote. Prior studies have reported mutations in the BMPR2 gene in people with PAH.
Overall, these findings suggest that “ELA32 gene therapy can inhibit pulmonary arteriolar vascular remodeling and reduce pulmonary artery pressure in rats with PAH,” the researchers wrote.
“Our findings suggest that the apelinergic system may be a potential new target for the prevention and treatment of pulmonary hypertension,” they concluded.
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