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Breakthrough in dengue drug development via ‘humanised mice’

SINGAPORE — Drug development for dengue has been an expensive and time-consuming process, as drugs that worked well in the laboratory and on animals often failed when tested on humans, due to the differences between animal and human cells. Finding a treatment for the disease has eluded scientists for decades.

An Aedes mosquito, with its distinctive black and white striping. BLOOMBERG

An Aedes mosquito, with its distinctive black and white striping. BLOOMBERG

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SINGAPORE — Drug development for dengue has been an expensive and time-consuming process, as drugs that worked well in the laboratory and on animals often failed when tested on humans, due to the differences between animal and human cells. Finding a treatment for the disease has eluded scientists for decades.

However, this could change, thanks to a development by researchers in Singapore: Mice which carry human immune cells.

As dengue generally affects only humans and specifically uses immune cells for replication, the mice provide a more conducive model to test dengue therapeutics for people.

A study on these “humanised mice” was published in the Journal of Virology last month by scientists from the Singapore-MIT Alliance for Research and Technology (SMART).

The development comes as Singapore is experiencing its worst dengue epidemic. More than 15,900 individuals have been affected so far this year.

“With this humanised mouse model, we are able to study the dengue disease and drugs or vaccines in a human cell context, which is closer to what we’ll see in real humans,” said Dr Aishwarya Sridharan, lead author of the study, at a media briefing yesterday.

Professor Jianzhu Chen, Director of Immunology at MIT and SMART lead investigator of infectious diseases, pointed out that previously, “70 per cent of drugs in trial fail at the Phase I and II human trial stages, either because they are too toxic or ineffective”.

The drugs had tested successfully in the laboratory and animal settings, suggesting a gap between these testing environments and the actual human body environment, he said.

The “humanised mouse” will serve as a better indicator of how effective a potential drug could be, before they are tested on people at a clinical trial. This will lower costs and development time as less resources are wasted on drugs that are less likely to succeed, Prof Chen said.

Currently, drugs take an average of 10 to 12 years to develop.

The researchers took mice with a genetic mutation that prevents them from producing their own immune cells, and transplanted human foetal liver stem cells into them.

They then infected the humanised mice with the dengue virus.

The mice were found to display four key symptoms of dengue infection in humans, in particular, a drop in blood platelet count. It was the world’s first display of dengue symptoms in mice, as far as scientists know.

This led to researchers identifying the cause of the drop as a disruption in platelet production in the bone marrow. With this finding, scientists can now proceed to identify potential drugs to counter or prevent the symptom, which is potentially life-threatening.

The researchers said they only conducted tests on the DEN-2 strain, Singapore’s most prevalent, of the four dengue strains.

The mice are patented and available for testing, and the team is currently in talks with some companies to begin testing potential therapeutics. Some 300 humanised mice have been bred so far.

“Basically, they are living test tubes,” Prof Chen said.

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