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. Author manuscript; available in PMC: 2017 Jul 18.
Published in final edited form as: Nature. 2016 Sep 7;538(7625):344–349. doi: 10.1038/nature19804

Figure 4. In vivo efficacy studies of BRD7929 using P. falciparum and humanized mouse models.

Figure 4

a, huRBC NSG mice were inoculated with P. falciparum (3D7HLH/BRD) blood-stage parasites 48 h before treatment and BRD7929 was administered as a single 50, 25, 12.5 or 6.25 mg kg−1 oral dose at 0 h (n = 2 for each group, this study was conducted once). Infections were monitored using the in vivo imaging system (IVIS). Bioluminescent intensity was quantified from each mouse and plotted against time. The dotted horizontal line represents the mean bioluminescence intensity level obtained from all the animals before the parasite inoculation. No recrudescence was observed as low as a single 25 mg kg−1 dose of BRD7929 in the infected animals (see Extended Data Fig. 3b). b, huHep FRG-knockout mice were inoculated intravenously with P. falciparum (NF54HT-GFP-luc) sporozoites. BRD7929 was administered as a single 10 mg kg−1 oral dose 1 day after inoculation, and daily engraftment of human erythrocytes was initiated 5 days after inoculation (n = 2 for each group, this study was conducted once). Infections were monitored using IVIS. The dotted horizontal line represents the mean bioluminescence intensity level obtained from all the animals before the sporozoite inoculation. No increase in bioluminescence intensity level was observed from the mice treated with BRD7929 (see Extended Data Fig. 5a). c, huRBC NSG mice were infected with blood-stage P. falciparum (3D7HLH/BRD) parasites for 2 weeks (allowing the gametocytes to mature fully) and were treated with a single oral dose of BRD7929 (12.5 mg kg−1). Blood samples were collected for 11 days and analysed for the presence of the asexual marker SBP1 and the mature gametocyte marker Pfs25 using qRT-PCR (n = 2 for each group, this study was conducted once). The transcription of both SBP1 and Pfs25 decreased to undetectable levels 7 days after treatment, strongly suggesting that BRD7929 eliminates both asexual and gametocyte stages and is capable of preventing parasite transmission to the mosquito (data are mean ± s.d. for three technical replicates for each biological sample).