Team discovers patient-specific cure for dangerous
heart rhythm disorder
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
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.
cure for long QT syndrome 2
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 eprogrammed 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
eam then tested various drug compounds and discovered a drug that
could reverse the ffects of long QT syndrome 2, after a rigorous testing period
of a year.
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.
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 revolutionise how researchers look at specific treatments
for certain conditions and allow a more focused and accelerated path to drug
discovery for life-threatening conditions.
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."
long QT syndrome?
syndrome is a disorder of the heart's electrical activity which may cause one
to develop a sudden, uncontrollable, and dangerous heart rhythm. It is mainly
an inherited condition, with a prevalence of about 1 in 5,000 people in
Singapore. Non-inherited long QT syndrome may be brought on by certain
medicines or other medical conditions. Left untreated, more than half of those
with inherited long QT syndrome die within 10 years. There are about 13 gene
mutations causing variations of long QT syndrome, with long QT syndrome 2 being
one of the most common.
sudden cardiac death in the young is rare. But
when it does occur, long QT syndrome is often one of the causes," said
Associate Professor Wong, "Most patients with long QT syndrome do not
display any signs or symptoms, and they may only come to know of their
condition if a family member has it, or it was diagnosed by a doctor after a
routine electrocardiogram (ECG) or recent fainting episode."
heartbeats are controlled by electrical impulses within the heart muscle, and
this electrical system recharges itself after each heartbeat. Patients with
long QT syndrome will take longer than normal to recharge between heartbeats,
and this delay may result in a fast and chaotic heart rhythm which leads to
sudden fainting, seizures and, if prolonged, sudden cardiac death. The fainting
spells may occur without warning when patients exercise, experience intense
emotions or are startled by loud noises.
risk include people with a family history of long QT syndrome, sudden death,
unexplained fainting or seizures. The disease can be managed through a combination
of medications and lifestyle changes, such as avoiding vigorous sports. To
prevent sudden cardiac death, patients with long QT syndrome may also be
implanted with an automated implantable cardioverter defibrillator which
delivers electrical shocks to reset the heart rhythm when the heart rate
reaches dangerous levels.
landmark research by a 10-member team is supported by the National Research
Foundation Singapore under its Competitive Research Programme; the National
Medical Research Council; and the Goh Foundation administered through Duke-NUS.
2009, the NHCS research team has scored several breakthroughs in stem cell
research. In 2011, the team succeeded in creating beating heart
cells from patient's skin
cells which could be used for heart repair and drug discovery. Last
year, the team created the world's first human heart
cell model of arrhythmogenic right ventricular cardiomyopathy (ARVC) to improve
the understanding on how these mutations lead to arrhythmias and clinical
manifestations of ARVC. With this innovative discovery of a new treatment in
long QT syndrome 2, it marks a big step towards personalised medicine.
"Currently, we have been successful in providing
a medicine to treat long QT syndrome 2. Moving forward, we can use similar
disease models to introduce a gene that will correct that particular mutation in
the body," said Dr Shim, "If that is successful, there is a
possibility of permanently reversing the genetic condition without the need for
any long term medication."