A new study led by the researchers at the Research Center at Icahn School of Medicine at Mount Sinai has revealed about a new gene therapy that can clip out genetic material linked to heart failure and replace it with the normal gene in human cardiac cells. The study is published in Nature Communications.
Roger J. Hajjar, MD, Director of the Cardiovascular Research Center of Mount Sinai Heart at Icahn School of Medicine at Mount Sinai said that genetic mutations are the culprits behind the weakening of heart muscles that is typically seen in patients with heart failure. He added that their study is significant because it reveals that certain forms of heart failure can now be treated by a newly devised gene therapy. This therapy acts like molecular scissors and acts by cutting out the mutated gene part and inserting a normal genetic code in its place.
When the heart muscles get weakened, it is plagued by cardiomyopathies and can lead to heart enlargement and heart failure. Often such conditions are genetically inherited. There are quite a number of inherited gene mutations that are associated with cardiomyopathies, which includes mutations in the phospholamban (PLN) gene. It is a critical regulator of healthy cardiac cell function and its calcium cycling.
For this study, the researchers concentrated on R14del mutation as it has been identified in a number of families with genetic heart failure. The characteristics of this mutation are dilated heart muscle, dysfunctional heart muscle contraction, dangerous arrhythmias, and likelihood of heart failure by middle age.
Skin samples from an R14del heart failure patient were collected for the study. These skin cells were induced to become pluripotent stem cells (iPSCs) in the lab. These stem cells, which carry the genetics of the heart failure patient, were then differentiated from the skin cells into specialized heart muscle cells called cardiomyocytes (iPSC-CMs), which also carry the patient’s genetic history. When these beating cardiac cells were examined in the laboratory, it was confirmed that R14del mutation causes common abnormalities linked to heart failure like improper pumping of calcium within cell compartments, enlargement of heart muscle tissue, electrical instability causing arrhythmias, etc.
In order to rectify the gene mutation in cardiomyocytes researchers made use of two novel methods. First, they used a specifically designed transcription activator to target and eliminate the presence of R14del-associated disease in cardiac cells. The diseased gene was cut out and was replaced with a normal PLN gene resulting in normally functioning cardiomyocytes.
Secondly, they used an adeno-associated viral-vector (AAV) gene therapy approach with the harmful part of a virus removed to safely target the inside of cardiac cells. It knocked-down the abnormal PLN gene in cardiac cells and simultaneously express normal PLN gene successfully reversing disease. This method also corrected the functional abnormalities of the cardiac cells.
Dr. Hajjar said that the findings of their study have far reaching effects as it offers potentially new strategies to target and interrupt the disease causing path of the mutation associated with cardiomyopathies and heart failure. After testing this therapy is human cardiac cells, they now aim to test this approach in vivo in animal and pre-clinical studies. Hopefully, there will come a day when this gene therapy approach will be used to correct the gene abnormality in heart failure patients.
Litsa Kranias, study co-author, PhD, of the University of Cincinnati, first discovered the PLN gene R14del mutation in a Greek family said that it was a major breakthrough in molecular medicine. She also added that it would pave way for future studies in personalized therapy for heart failure patients aiming to specifically correct their defective genes.
Folkert W. Asselbergs, MD, PhD, FESC, Department of Cardiology, Division Heart & Lungs University Medical Center in Utrecht said that it is of special significance to Netherlands because about 10 percent of their patients with dilated or arrhythmogenic cardiomyopathy carry this particular founder mutation.
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