Cell culture studies have shown that the effects of the mutations could be reversed with a compound of medicine known as an inhibitor of phospholipase. The study was published today in the online edition of the New England Journal of Medicine.
"The most exciting thing about our study is not that we have identified a new gene involved in pulmonary hypertension, but we found a drug that can"rescue"of certain mutations," said author co-Minister Wendy K. Chung, MD, PhD, Associate Professor of Pediatrics and medicine at CMTC. "Genetics, it is common to identify a gene which is at the origin of a disease. However, it is relatively rare to find treatments for genetic diseases. ?
PAH is a progressive disease characterized by hypertension abnormally in the pulmonary artery, which reduces blood flow to the right side of the heart to the lungs. The heart may compensate by pumping more difficult, but over time, this can weaken the heart muscle and lead to right heart failure. Common symptoms of PAH are shortness of breath, dizziness and fainting. About 1,000 new cases are diagnosed in the United States each year. The disorder is twice as common in females than males. There's no cure for PAHs and few effective treatments. Most patients with PAH die within 5-7 years after diagnosis.
Some cases of PAHs are caused by inherited genetic defects. Most of these "family" cases have been linked to mutations in a gene called BMPR2 (Bone morphogenetic protein receptor, type II), which was identified at the same time in 2000 by two independent research teams, one led by the late Robin Barst and Jane Morse, researchers of the CCEM. However, the majority of the cases is idiopathic in origin (of unknown cause). Other forms of PAHs can be triggered by autoimmune diseases, congenital heart disease, infections (such as schistosomiasis) and drugs (such as the combination of food and prohibited drugs commonly known as fen-Phen).
Dr. Chung and his colleagues discovered the new mutations by sequencing exomes (a part of the genome encoding information to make proteins) families with PAH with no identified mutations. KCNK3 mutations were found in 3.2% of people with familial and 1.3% of women with idiopathic PAH.
The team found that mutations alter the function of potassium channels by reducing the activity of these channels. Potassium channels help maintain vascular tone of the pulmonary artery and help respond to low concentrations of oxygen.
"We were surprised to learn that KCNK3 seems to play a role in the function of potassium channels in pulmonary artery," said Dr Chung. "Nobody suspected that this mechanism could be associated with PAH." The second gene linked to the disorder, BMPR2, is thought to cause PAH finally promoting the growth and the proliferation of smooth muscle cells in pulmonary artery, restricting blood flow.
Dr. Chung were also found, working in collaboration with the co-senior author, Robert S. Kass, PhD, former students and David Hosack Professor of Pharmacology, Chairman of the Department and vice Dean for research at CMTC, the effects of mutations KCNK3 could be reversed with an inhibitor of phospholipase experimental called ONO-RS-082. The findings have been made in cell cultures. Further study is needed to determine if treatment with this device or other drugs affecting potassium channels could be useful in the treatment of patients with PAH, said Dr Chung.
"KCNK3 mutations are a rare cause of PAHs, so I don't want to overstate our conclusions," said Dr Chung. "Yet, it's exciting that we have found a mechanism that could lead to the disease which is a new therapeutic target. It is also possible that targeting KCNK3 may be beneficial for patients who have PAH regardless of their genetic status as KCNK3. ?
Source-Eurekalert
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