Can gene therapy cure a broken heart?

17 May 2019

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CLEAR! Zap, beep, beep. We’ve all seen those scenes in our favourite medical dramas, someone has had a heart attack and the determined doctors are using defibrillators to jump-start someone’s heart. But what exactly is a heart attack?

What is a heart attack?

A heart attack occurs when the arteries that supply blood to the heart muscles get blocked. The blockages are called atherosclerotic plaques and they are caused by the build-up of cholesterol and fibrous tissue in the arteries. When the plaques rupture they cause blood clots which prevent the muscles from getting oxygen from the blood. Specialised heart muscle cells called cardiomyocytes start dying from ischemia (lack of oxygen), the death of heart tissue is called myocardial infarction. Once the tissues in the heart have been damaged they cannot fully recover. The cells that are lost during myocardial infarctions are replaced by a scar. The scar is made up of a different cell type called fibroblasts (or myofibroblasts) which are responsible for the production of collagen. During the formation of the scar, the ventricular walls get thicker (hypertrophy) and stiffer (fibrosis). The scar is not able to conduct electrical signals as efficiently as healthy tissue which prevents the muscles from contracting. This can cause irregular heartbeats (known as arrhythmias) or in the worst case cardiac arrest.

Re-growing hearts

Did you know that zebrafish and newts can regrow their hearts? Zebrafish are so good at it that amputation of 20% of the ventricle can be fully repaired without scarring within two months. How is this regeneration possible and why can’t we do it? This regeneration is all due to the presence of a specific cell known as a stem cell. Adult stem cells have the capacity to mature into very specific cell types such as cardiomyocytes. This means they can replace dead or damaged cells. Initially, it was thought that the human heart had no regenerative capabilities. This is because once the cells mature into cardiomyocytes they are no longer capable of dividing. It has since been shown that the human heart is capable of regeneration but to such a small degree that it cannot repair the tissue damage caused by myocardial infarction. Whether these cells arise from the division of cardiomyocytes or from adult stem cells is a topic of debate within the scientific community. These insights have spurred new therapeutic approaches to try to enhance this naturally occurring regenerative potential in humans.

Gene therapies

Gene therapies introduce genetic material into cells to treat various diseases. Instead of targeting the proteins within a cell (this is how most drugs work) often these therapies occur at the level of gene expression or RNA signalling. The DNA that makes up our genes encode all the information necessary to make proteins. Proteins are important because they are responsible for performing all the functions necessary for life within the cell. There are two steps that need to be completed for the cell to make proteins. The first is converting the DNA molecules into RNA, the process is called transcription. The RNA is then converted into a protein through the process known as translation. Gene therapies function in two main ways either the therapy delivers genes to make a protein, to compensate for an absent or dysfunctional one. The other approach is to prevent a protein from being made to stop it from working. Primary microRNAs are naturally occurring small RNA molecules that prevent a protein from being made by interfering with translation. Some gene therapies use microRNAs to alter signalling pathways within a cell. Interestingly mircoRNAs are involved with regulating stemness and proliferation in cardiomyocytes.

Gene Therapies can repair a broken heart

In a recent Italian study published in Letters Nature, scientists wanted to know if using microRNAs could help restore pig hearts after myocardial infarction. Scientists induced myocardial infarctions in 25 pigs. They then injected a virus carrying microRNA-199a directly into the hearts of 10 pigs. The control group was injected with a virus that did not have any microRNA. Viruses are commonly used to deliver genetic material into cells in gene therapy. They followed the pigs for a period of 8 weeks. The scientists were able to show that there was significant repair to the damaged tissues. They were able to show a reduction in the size of the scars in animals treated with the microRNA. They also showed there was an increase in the muscle mass of the hearts and better global and regional contractibility in the hearts of pigs treated with the microRNA. The repair of the hearts was due to an increase cardiomyocyte proliferation.

The Fatal flaw with this therapy

There were serve issues with this therapeutic approach however, after 8 weeks of observation 7 of the 10 pigs injected with microRNA-199 died suddenly. The pigs experienced accelerated heart rates (tachyarrhythmia). This was followed by ventricular fibrillation this is where the heart stops pumping blood and quivers instead. The scientists believed this was because the microRNA caused cells to become more like stem cells, this meant they were no longer able to perform the functions of a mature cell and respond to electrical impulses correctly.

The work presented by this group is promising, there was substantial repair to the pig hearts. However, long-term exposure to the microRNA proved to be fatal. The scientists speculate that careful dosing will be required to increase the safety of this therapeutic approach.

The lead author of the paper, Professor Mauro Giacca had this to say about their work “For the first time we see real cardiac repair in a large animal.” He additionally explained that “It will take some time before we can proceed to clinical trials”


References

  1. Talman, V. & Ruskoaho, H. Cardiac fibrosis in myocardial infarction—from repair and remodeling to regeneration. Cell and tissue research 365, 563-581 (2016).
  2. Clancy, S. B., W. . Translation: DNA to mRNA to Protein, https://www.nature.com/scitable/topicpage/translation-dna-to-mrna-to-protein-393 (2019).
  3. Raso, A. & Dirkx, E. Cardiac regenerative medicine: at the crossroad of microRNA function and biotechnology. Non-coding RNA research 2, 27-37 (2017).
  4. Wang, J. & Martin, J. F. Macro advances in microRNAs and myocardial regeneration. Current opinion in cardiology 29, 207 (2014).
  5. Giacca, M. & Zacchigna, S. Harnessing the microRNA pathway for cardiac regeneration. Journal of molecular and cellular cardiology 89, 68-74 (2015).
  6. Gabisonia, K. et al. MicroRNA therapy stimulates uncontrolled cardiac repair after myocardial infarction in pigs. Nature, 1 (2019).
  7. Wood, T. Genetic therapy heals damage caused by heart attack https://www.eurekalert.org/pub_releases/2019-05/kcl-gth050819.php (2019).