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Targeting malaria’s liver stage

15 Feb 2011

Patrick Adams

Source: TropIKA.net

Figure 1
The Draper Laboratory’s mimetic tissue device.

Researchers at the University of South Florida and the Massachusetts-based Charles Stark Draper Laboratory have received two Gates Foundation grants totalling $5.45 million to develop advanced devices capable of creating tissue models that mimic the human liver. The devices could accelerate drug discovery and vaccine development for malaria by allowing researchers to better understand the parasite’s liver stage, where it may be most vulnerable to attack.

The Draper Lab started out in the 1930s as a small teaching laboratory primarily concerned with guidance and navigation technologies for the US Department of Defense and NASA. It has since expanded its portfolio in a number of different directions, developing expertise in a broad range of domains, among them biomedical engineering.

Indeed, by leveraging its technical expertise in other areas – microelectromechanical systems (MEMS), microelectronics, advanced packaging, mechanical design and analysis, computation, chemistry and biology – the Draper Lab has developed novel biomedical devices such as point-of-care diagnostic sensors, drug delivery devices, and a prototype microfluidic device.

With Gates support, the lab is using the latter to create new models of the device capable of mimicking the human liver, where malaria sporozoites undergo the very poorly understood process of transformation into exo-erythrocytic forms (EEFs). Indeed, six decades after its discovery, malaria’s liver stage remains the most puzzling piece of the parasite life cycle.

As Kappe and Duffy put it [1], “notwithstanding the fact that whole genome sequences are now available for a number of malaria parasite species and that modern systems biology tools can now analyze microarrays and high-throughput proteomic studies that have been applied to all other life cycle stages of malaria parasites, comprehensive gene and protein expression profiles of EEFs have yet to be established”.

Moreover, the elucidation of EEFs, they add, is as critical to the malaria R&D enterprise as it is difficult to achieve. “Liver stage parasites may be the most promising target for a vaccine that completely prevents infection. Complete protection has been repeatedly demonstrated by vaccine studies using irradiation-attenuated live sporozoites, which induce complete sterile protection against challenge [2]. The protective mechanisms appear to mainly act against the liver stage.”

It isn’t just vaccine development that would benefit from a better understanding of the liver stage. With the exception of primaquine, which is indicated for the prevention of relapse in patients infected with P. vivax malaria, currently available drugs only treat the bloodstream stage of the parasite life cycle. And though effective in the liver, primaquine is not without its risks; when administered to patients with G6PD deficiency, the drug can cause severe side-effects, including potentially fatal acute renal failure [3].

Designed to support complex tissue growth, the Draper Lab’s prototype microfluidic device allows cells to grow in three dimensions and to experience physiologically relevant forces, offering what Dennis Kyle, principal investigator on the three-year Gates grant and professor of global health at USF College of Public Health, calls unique microenvironments.

“We cannot eliminate one of the most prevalent causes of malaria in the world – Plasmodium vivax – unless we come up with new drugs or vaccines that target the dormant liver forms of the parasite,” says Kyle. “Current tools – in vitro and animal models are either largely ineffective or cost-prohibitive in predicting which drugs may work best in humans. New human models are the basic building blocks needed to establish strong, credible drug and vaccine discovery programmes, not only at USF but at other universities and companies working on new ways to fight malaria.”

References

1. Kappe SH, Duffy P (2006). Malaria liver stage culture: in vitro veritas? American. Journal of Tropical Medicine & Hygiene: 74(5):706-707.Available from: http://www.ncbi.nlm.nih.gov/pubmed/16687666

2. Luke TC, Hoffman SL (2003). Rationale and plans for developing a non-replicating, metabolically active, radiation-attenuated Plasmodium falciparum sporozoite vaccine. J Exp Biol: 206:3803-3808. Available from: http://www.ncbi.nlm.nih.gov/pubmed/14506215

3. Beutler E, Duparc S (2007). Glucose-6-phosphate dehydrogenase deficiency and antimalarial drug development. Am J Trop Med Hyg: 77(4):779-789. Available from:

http://www.ncbi.nlm.nih.gov/pubmed/17978087

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