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TheArtOfDiscovery malaria

Why working in Malaria?

TAD scientific leaders have more than ten years of experience in Malaria Drug Discovery in big pharma.

TAD is committed to contribute its unique experience in murine models of human malaria to the Malaria Research Community for the eradication agenda of this deadly disease.

Every effort counts, we’ll do our bit…!!!

The Malaria Translational Unit

TAD has established a collaboration with the Medicines for Malaria Venture (MMV, Geneva, www.mmv.org) to set up the so called Malaria Translational Unit (MTU) at TAD facilities.

The MTU will test new antimalarials from MMV drug discovery and development programs in the PfalcHuMouse model.

In addition, the MTU will support dug discovery programs from pharmaceutical industry and academic research in any field of malaria that might require the PfalcHuMouse model.

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…!!!

 

Support for Research in Malaria Biology

Either as a CRO or Research Collaborator, TAD is a partner of choice to perform Malaria Biology experiments that require the PfalcHuMouse Model or the development of new in vivo humanized murine experimental models.

Let us know how we can help you…!!!

It’s easy completing your work with the right in vivo experiments…!!!