Expanded implementation of a human-based malaria-on-a-chip phenotypic disease model for the evaluation of therapeutic efficacy and off-target toxicity

The National Institute of Allergy and Infectious Diseases awarded Hesperos, Inc. $1 million on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to expand implementation of a human-based malaria-on-a-chip phenotypic disease model for evaluating therapeutic efficacy and off-target toxicity.

Hesperos will develop and advance a microphysiological system that models Plasmodium falciparum infection across multiple organ systems to enable higher-throughput assessment of drug candidates and biomarker expression. The model reproduces the intraerythrocytic parasite life cycle in human liver and other tissue modules, providing a non-invasive, cost-effective alternative to animal testing for preclinical drug development. Initial work funded by the Gates Foundation established that the multi-organ model responds to known anti-malarial therapeutics, justifying this Phase II direct award.

Work is performed in Orlando, Florida, with a period of performance from September 1, 2026, through August 31, 2028. The award is structured as a project grant, the standard assistance type for this program.

Abstract

The initial work for this project was funded by the gates foundation and enabled US to establish a multi-organ model that reproduces the parasite life cycle and response to three known anti-malarial therapeutics. Due to the significant results achieved with the gates foundation support, we believe this justifies this direct to phase II application. Plasmodium falciparum, the parasite that causes malaria, is the deadliest plasmodium strain that infects humans. Malaria primarily burdens asia, africa, central and south america; devastating extremely vulnerable populations, particularly impoverished pregnant women and children. The proliferation of drug- resistant strains urgently necessitates developing novel malaria sequestration models and drug delivery methods. We have previously developed a human-based platform, the malaria-on-a-chip model, to provide an alternative approach to modeling this disease for pre-clinical drug development in immune suppressed mice. Even with the heightened emphasis on human-based systems using primary and induced-pluripotent stem cells, many in vitro models lack the ability to capture functional impairment and nuanced interactions of multiple cell types or external factors contributing to disease pathology. Consequently, microphysiological systems offer a non-invasive, cost-effective and accelerated method for evaluating function-based disease pathology, especially for malaria. By reducing budget and time constraints, these systems enable higher throughput assessment of clinically and biologically relevant phenotypes, along with complementary biomarker and transcriptomic expression profiles. We demonstrated this model can support all stages of the intraerythrocytic life cycle of multiple human plasmodium strains, enabling the monitoring of effects of infection on human liver, spleen, and vasculature within a single microfluidic device. In this direct to phase II application, we are proposing the malaria- on-a-chip phenotypic disease model for use in (1) extension of physiological conditions and for additional strains to better capture pathophysiological parameters of disease as IT pertains to infected erythrocyte interactions with endothelium and the immune response to parasitic particles, (2) evaluating parasite clearance and organ toxicity when treated with repeated doses of therapeutics or with combination therapies of known and new therapeutics, and (3) evaluating prophylactic measures on parasite infection and organ toxicity when treated with sequential doses prior to the introduction of infected erythrocytes to the model. These human on a chip models have proven to be acceptable alternatives to animal models in recapitulating human physiology for mechanistic and drug efficacy studies, as demonstrated in our previous IND-enabling studies for sanofi where efficacy was only from the hoac platform (NCT04658472) (rumsey ET AL. 2022) and dianthus therapeutics (NCT06282159). Final deliverables for this proposal include a novel therapeutic delivery method to generate a predictive PK/PD model to translate in vitro results to inform in vivo outcomes as well as new therapeutic candidates for different strains of the parasite.