For the first time, delivery of genetic material induced heart cells to de-differentiate and proliferate in a large-animal model after myocardial infarction. This led to improvement in heart functions.
According to WHO, around 25 million people worldwide are affected by heart attacks. A heart attack – called myocardial infarction – is caused by a sudden blockage of one of the cardiac coronary arteries. Heart attack causes permanent structural damage to the heart of the surviving patient through scar formation and the organ is unable to overcome loss of cardiac muscles. This can frequently lead to heart failure and even death. A mammal’s heart can only regenerate itself immediately after birth unlike fish and salamander who have the ability to regenerate their heart lifelong. Cardiac muscle cells or cardiomyocytes in humans are henceforth unable to replicate and regenerate lost tissue. Stem cell therapy has been tried to regenerate heart in a large animal but with no success so far.
It has been established before that new tissue could form in the heart by de-differentiation of already existing cardiomyocytes and cardiomyocytes proliferation. Limited levels of cardiomyocyte proliferation have been seen in adult mammals including humans thus enhancing this property is seen as a potential way to achieve cardiac repair.
Previous studies in mice have shown that cardiomyocyte proliferation can be controlled by genetic manipulation therapy via microRNAs (miRNAs) by utilizing the understanding of cardiomyocyte maturation process. MicroRNAs – small non-coding RNA molecules – regulate gene expression in various biological processes. Gene therapy is an experimental technique which involves introduction of genetic material into cells to compensate for abnormal genes or to enable expression of a crucial protein(s) in order to treat or prevent a disease. The genetic material cargo is delivered by using viral vectors or carriers as they can infect the cell. Adeno-associated viruses are generally used as they have higher efficiency and capability plus, they are safe for long-term use because they do not cause a disease in humans. Previous gene therapy study in mouse model has shown that some human miRNAs can stimulate cardiac regeneration in mice after myocardial infraction.
In a new study published in Nature on May 8 researchers describe gene therapy which can induce heart cells to heal and regenerate after a heart attack for the first time in a clinically relevant large-animal model of pig. Post myocardial infarction in pigs, researchers delivered a small piece of genetic material microRNA-199a into heart of pigs through direct injection into myocardial tissue using adeno-associated viral vector AAV Serotype 6. Results showed that cardiac function in pigs was completely repaired and recovered from myocardial infarction after a period of one month compared to the control group. A total of 25 treated animals showed significant improvements in contractile function, increased muscle mass and diminished cardiac fibrosis. Scars were reduced in size by 50 percent. Known targets of miRNA-199a were seen to be downregulated in the treated animals including two factors of the Hippo pathway which is an important regulator of organ size and growth and performs roles in cell proliferation, apoptosis and differentiation. The spread of miRNA-199a was restricted only to the injected cardiac muscle. Imaging was done using cardiac magnetic resonance imaging (cMRI), utilizing late gadolinium enhancement (LGE) – LGE (cMRI).
The study points at the importance of careful dosage in this particular gene therapy. Long term, persistent and uncontrolled expression of the microRNA caused sudden arrhythmic death of majority of the pig subjects who were being treated. Thus, design and delivery of artificial miRNA mimics is required as virus-mediated gene transfer may not be able to achieve the desired purpose effectively.
The current study shows that delivering effective ‘genetic drug’ can induce cardiomyocyte de-differentiation and proliferation thus stimulating cardiac repair in a large-animal model – here pig which has heart anatomy and physiology similar to humans. The dosage would be of critical importance. The study reinforces the appeal of miRNAs as genetic tools because of their ability to regulate and control levels of several genes at the same time. The study will soon move to clinical trials. Using this therapy, new and effective treatments could be developed for severe cardiovascular diseases.
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{You may read the original research paper by clicking the DOI link given below in the list of cited source(s)}
Source(s)
1. Gabisonia K. et al. 2019. MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs. Nature. https://doi.org/10.1038/s41586-019-1191-6
2. Eulalio A. et al. 2012. Functional screening identifies miRNAs inducing cardiac regeneration. Nature. 492. https://doi.org/10.1038/nature11739
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