Lena Serghides (PhD) is a Scientist at the Sandra Rotman Centre, and an Assistant Scientist at the Toronto General Research Institute, University Health Network. Lena received her PhD from the Institute of Medical Sciences at University of Toronto, and completed post-doctoral training at the Department of Immunology at the University of Toronto. Her work focuses on understanding the molecular basis of the host response to pathogens in an effort to develop novel and innovative therapeutic approached to diseases of global health importance.
On World Malaria Day I would like to celebrate the successes of the global efforts to control and eliminate malaria that have significantly reduced malaria mortality worldwide. I would also like to note that despite all these great efforts, well over half a million people, mostly children under the age of 5, died of the disease last year. This is an unacceptably high number.
Grand Challenges Canada, which is funded by the Government of Canada, supported our team to tweak the host response to malaria to save the brains of children.
The landmark SEQUAMAT and AQUAMAT trials convincingly demonstrated that parenteral artesunate was superior to quinine for the treatment of severe malaria. However, artesunate did not improve the incidence of persistent neurological sequelae compared to quinine. Neurological sequelae are seen in about 1/3 of survivors of cerebral malaria (a severe complication of malaria infection). Children surviving cerebral malaria can have deficits in learning, memory, and executive function, problems with verbal fluency, impaired motor function, and ADHD-like symptoms. Persistent neurological impairment at this scale (millions of survivors) can have a profound public health and economic impact.
Volumetric differences seen in the brains of mice treated with anti-malarials with rosiglitazone compared to mice treated with anti-malarials alone.
The host response to infection plays as much a role in the development of cerebral malaria as does the parasite. An over-aggressive immune response can damage tissues, including the brain, and contribute to the development of cerebral malaria and neurological impairment. Current anti-malaria therapies only target the parasite and do little to modulate the host response. For many years we have been working to develop therapies for cerebral malaria that target the host response, tweaking it in way that it is still effective at battling the malaria infection but it does not injure the brain. Our hope is that these types of therapies can be given at the same time as anti-malarials leading to improved outcome for malaria survivors.
My colleagues and I at the Sandra Rotman Centre for Global Health believe we have a candidate drug for this indication: rosiglitazone, an anti-diabetic drug. In a mouse model of cerebral malaria, we were able to show that treating mice suffering with cerebral malaria with a combination of anti-malarial plus rosiglitazone protected them from death compared to mice treated with anti-malarials alone. Our most exciting findings were in mice that survived cerebral malaria. The surviving mice that were treated with anti-malarials alone had long-term memory and motor impairment as a result of their malaria infection, while the mice that received rosiglitazone in addition to anti-malarials had no impairment. When we looked at the brains of these mice with MRI, we saw brain atrophy in the mice treated with anti-malarials alone, while the mice that received rosiglitazone had normal brains showing no atrophy. Finally, we were able to show that the same pathways that led to protection in the rosiglitazone treated mice are also active in malaria patient treated with rosiglitazone, suggesting that what we saw in the mice may also be applicable to patients.
Mice with cerebral malaria treated with anti-malarials or anti-malarials plusrosiglitazone. Blue indicates breakdown of the blood brain barrier
We believe our findings are very exciting and strongly support the testing of rosiglitazone in patients with cerebral malaria. A great feature of rosiglitazone is that it is already approved for human use and patent rights on its use have expired. This will avoid much of the cost and time associated with bringing this treatment to patients, and should minimize the market price making it accessible to the developing world market.
Grand Challenges Canada has been a great supporter of these studies, granting me a Stars in Global Health seed grant to support my research. Out of the box ideas need out of the box funding initiatives. Maybe 20 years from now malaria will be eliminated. In the meantime, developing therapies that can help prevent and repair the damage to the brain caused by malaria is a worthy goal.
For an overview of all our malaria related projects, read our blog post “Canada is helping to fight malaria by investing in the future through 40 innovative projects”. Join the conversation on Twitter by using hashtag #WorldTBday.
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