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The Koyal Group: World’s first drug therapy to reverse heart disorder

The National Heart Centre Singapore (NHCS) research team has successfully and completely reversed the effects of the hERG (human ether-a-go-go-related gene) mutation in long QT syndrome 2 (LQTS 2) in patient-specific heart cells, scoring a world’s first. Long QT syndrome 2 is a dangerous heart rhythm disorder that can lead to sudden cardiac death, even in young patients.


It is caused by a mutation in a specific gene known as hERG, which helps to control the electrical activity in the heart cells and coordinate its beating rhythm. Using the patient’s own skin stem cells transformed to beating heart cells, the team tested various drug compounds and discovered that the drug, not normally tested in this condition, could reverse the effects of long QT syndrome 2.


This novel experiment paves the way for the better understanding on how drugs affect cell and intra-cell disordered function and allows safe testing of new compounds on patients’ own cells, without the risk of side effects to the patients themselves. The findings have earned the team a best poster prize at the prestigious ESC (European Society of Cardiology) Congress on 1 September 2013, the largest international cardiology meeting attended by close to 30,000 participants.


“For the first time, we have mimicked a patient’s disease condition in a petri dish, understood the mechanism of long QT syndrome 2 on this platform, and successfully tailored a drug that reverses the entire condition,” said Associate Professor Philip Wong, Director, Research and Development Unit (RDU), NHCS.


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Potential cure for long QT syndrome 2


To better study the disease, skin cells were obtained from a patient clinically diagnosed with long QT syndrome 2 caused by the hERG mutation. Using the skin cells, the NHCS research team generated human-induced pluripotent stem cells and reprogrammed these into heart cells.


Pluripotent stem cells are among the most powerful stem cells and can be reprogrammed into any type of cells.


The team found that the heart cells in a petri dish mirrored the patient’s heart condition outside the body, allowing them to study the disease and test treatments accurately and repeatedly on the cells without any risk to the patient. By applying their understanding of the condition’s fundamental disorder at the genetic level, the team then tested various drug compounds and discovered a drug that could reverse the effects of long QT syndrome 2, after a rigorous testing period of a year.


“With the efficacy aspect proven, we will be testing the therapy’s safety profile as we move towards clinical applications,” said Dr Ashish Mehta, Senior Research Scientist, RDU, NHCS, and lead investigator of the study. Accelerated research discoveries


Conventional drug discovery and development involves understanding the basic causes of a disease at the level of genes, proteins and cells, and using the knowledge to derive specific targets to develop new drugs.


The NHCS research team was able to accelerate the drug development path with their understanding of how long QT syndrome 2 develops in the patient-derived heart cells, and this helped them to efficiently shortlist drug compounds designed to correct the effects of the underlying hERG mutation.


This novel method of assessing the efficacy of new drug compounds could revolutionize how researchers look at specific treatments for certain conditions and allow a more focused and accelerated path to drug discovery for life-threatening conditions.


“Our breakthrough in hERG-related long QT syndrome 2 could potentially help to accelerate the development of new cures very much faster, perhaps within 5 to 8 years. It is a shortcut compared to the conventional drug development route which could take 10 to 15 years,” said Dr Winston Shim, Scientific Director, RDU, NHCS, “Another interesting point is that as the drug therapy is specific to the patient, there is a high chance that it will work on the individual whose skin cells were sampled for the study.” Continue Reading