The P. falciparum Humanized Mouse Model

TAD scientific leaders developed the first industrial-quality model of infection by P. falciparum in severely immunodeficient mice engrafted with human erythrocytes. This model has become a gold standard for efficacy studies in Malaria Drug Discovery.

P. falciparum is a human-specific pathogen that infects and destroys human erythrocytes. Therefore, the efficacy in vivo of new antimalarial drug candidates can be reliably tested in mice engrafted with human erythrocytes (humanized mouse models). The non-myelodepleted NOD/SCID/IL2Rγ–/– (NSG) immunodeficient rodent model of P. falciparum malaria (PfalcHuMouse model) has become the gold standard for the pre-clinical evaluation in vivo of new antimalarials against blood-stage antimalarial drugs (Jiménez-Díaz et al 2009. Antimicro. Agents Chemother. 53:4533-4536). In this model, NSG mice engrafted with human erythrocytes are infected with P. falciparum, which allows a precise analysis of the parasitological response to different exposure levels of drugs in vivo. Importantly, the experimental designs and pharmacodynamic data produced in this murine model are homologous to clinical trials. Thus, the Pfalc HuMouse model can produce initial estimates for all pharmacodynamic data of interest to inform powerful studies both on assessing parasite clearance and recrudescence in humans.

Support for Drug Discovery

TAD offers drug evaluation in standardized assays using the Pfalc HuMouse model, ad hoc assay development and consulting in Drug Discovery Programs.

High throughput screening in vivo

• Between 5-10 mg per compound are typically required. Customized short term assays (less than 1 week) are used. The typical testing capacity is 200 compounds per month on average, depending on the availability of mice and the experimental design.

Therapeutic Efficacy PKPD Studies

• Proof of concept, Lead Optimization, Candidate selection
  Rapid short term standardized assays in which the reduction of parasitemia and drug levels upon treatment are measured in tissues of the very same mice (PK/PD approach). By using Adaptive Experimental Designs and PK/PD modelling, the number of mice used per compound is minimized. This approach optimizes cost-effective decision making in Drug Discovery Critical Paths.
• Selection of Optimal Partners for Drug Combinations
  Rapid mapping of the compatibility of a drug with other antimalarial drugs in short term assays: Explore the compatibility of the mechanism of action of your compounds in vivo with other antimalarials. You do not need an advanced compound to address this question because it depends on the mechanism of action of your compounds… the earlier you know it…the better!!!.
• PK/PD Analysis of Drug Combinations for Human Dose Prediction
  Detailed understanding of the PK/PD drivers of efficacy of drugs, alone and in combination. The studies are intended to estimate in vivo the predicted efficacious exposure in humans. These PK/PD assays combine short term and/or long term (up to two months of following up after treatment to assess parasite elimination) in which the elimination of parasitemia and drug levels upon treatment are measured in tissues of the very same mice. These studies are useful for designing optimal clinical studies of drug combinations but also at early discovery steps to estimate parameters of efficacy as reference for optimization cycles.
  

Modelling Resistance in vivo

• Generation of resistant strains in vivo for target identification
  A rapid and simple method to generate drug-resistant P. falciparum isolates upon repeated sub-optimal treatment in vivo with drug combinations. These studies are an economical procedure to map the target of drugs at hit or lead stage.
• Modelling the generation of resistance in Sub-Optimal Drug Combinations
  PK/PD-based in vivo assays for prediction of treatment failure.

Consulting in Efficacy for Drug Discovery Programs

• If you wish an independent analysis of your data or decision pathways…a team that performs your efficacy experiments and inform your decisions…let’s talk…!!! Drug discovery is our passion…!!!