Blocking transmission

Didier Leroy
Dr Didier Leroy, Director, Drug Discovery, MMV

To reduce the overall burden of malaria we need to be able to stop transmission from person-to-person. We need to discover and develop new, well tolerated and easy-to-take transmission blocking medicines that can be combined into a Single Exposure Radical Cure and Prophylaxis (SERCaP).

In February 2012, MMV and partners published a pioneering piece of research. Researchers were able to reproduce the complex biology of the malaria parasite in the laboratory through each step of its lifecycle, creating a cascade of tests (see the Blocking Transmission infographic) to profile current medicines in development and identify promising new molecules. Today, almost 2 years since the publication of the original findings, Dr Didier Leroy, Director of Drug Discovery at MMV, explains the progress to date.

1. What has been the biggest challenge in the hunt for transmission-blocking molecules?

The biggest challenge is that historically the most informative assay, known as the Standard Membrane Feeding Assay (SMFA), was pretty labour intensive. Mosquitoes feed on malaria-infected blood – with or without the addition of a test drug – and after a week we then dissect the mosquito to see whether or not the parasite developed in its midgut. Dissecting individual mosquitoes is laborious, so we were initially only able to fully characterize the activity of one or two molecules a year with this assay.

2. How did you scale-up the standard membrane feeding assay to increase the number of molecules that can be characterized?

TropIQ, a spin-off company from Radboud University in the Netherlands, developed a rigorous, and reproducible approach, which enabled us to characterize the activities of more than 10 molecules in the last year. We have now been able to determine the potency of all the molecules in late-stage development and all of our preclinical candidates in the SMFA. The next step is to scale-up the assay to an industrial level, enabling around 40–50 molecules a year to be tested. In 2012, we collaborated with GSK to establish an insectary at Tres Cantos, Spain, where mosquitoes are bred. In this way, we now have an autonomous unit where molecules can be tested against falciparum gametocytes to determine their impact on transmission to the mosquitoes after feeding.

3. What progress has been made since the 2012 publication to identify a new transmission blocking medicine?

The most potent transmission-blocking molecule we have so far is DDD107498, (page 25) a new compound from the Drug Discovery Unit at the University of Dundee. DDD107498 is in preclinical development and is extremely potent in the standard membrane feeding assay. In addition to DDD107498 over half of our recent preclinical candidates also show some potential to block or significantly reduce transmission.