Introduction and Background of the Project

Introduction
Malaria continues to inflict a devastating burden on low-income countries, and development of effective new prophylactic agents is a priority for the antimalarial field. Antisense oligonucleotides (ASOs) are well-matched to this unmet need, as they are known to be long-acting and primarily accumulate in the liver, the entry point for malaria parasites. By acting at the messenger RNA (mRNA) level rather than at the protein level, nucleic acid-based therapeutics can provide opportunities to target genes that have been previously undruggable using vaccine-based and small molecule approaches as well as overcome issues with resistance against small molecules.
Our team previously designed and screened ASOs for validated antimalarial targets. These efforts provided proof-of-concept data demonstrating that ASOs against the parasite are efficacious in a dose and sequence-dependent manner and confer long-acting protection in causal prophylaxis challenge models for malaria.  

Project Objective
The primary objective of this project is to use bioinformatic approaches and machine learning algorithms to further expand on our previous fundings and identify ASOs against Plasmodial genes with improved potency and broader target coverage that are active across multiple parasite species.

Project Design
In this project, we will design ASOs that target conserved regions of P. falciparum and P. berghei genes using bioinformatic approaches. These ASOs will be screened against P. falciparum blood-stages and against P. berghei liver-stages using standard assays. The results will be integrated in machine-learning algorithms to further optimize ASO design. We expect that this screening will identify ASOs with improved potency and broader target coverage, which can then be validated for on-target activity using existing genetic tools.

How can your partnership (project) address global health challenges?

Despite significant advances, malaria continues to inflict a devastating public health burden on low-income countries. The World Health Organization (WHO) estimated that there were 282 million malaria cases and 610,000 deaths spread across 80 countries in 2024 (1). The development of new prophylactic agents is a priority for antimalarial development, for protection of low-income migrants and travelers, non-immune populations in the event of outbreaks or epidemics, and – notably – to replace successful seasonal malarial chemoprevention programs with a more easily delivered prophylaxis program. In each case, long action is highly desirable to reduce dosing frequency, as delivery is a large fraction of the cost of deployment, and to mitigate difficulties in ensuring multiple doses are taken to achieve continued protection. Injectable drugs that can achieve long duration, including antibodies, have therefore been the subject of increased interest. ASOs are well-matched to this unmet need, but require further investigation as antimalarials. 
Importantly, by acting at the mRNA level ASOs provide opportunities to access previously undruggable target genes, offering the potential to expand the repertoire of malaria drug targets. Extensive nucleotide divergence with the human genome also means essential Plasmodium genes can be targeted with high selectivity. As a platform technology whose toxicity and pharmacokinetic profiles are primarily driven by chemistry rather than sequence, a validated approach can enable accelerated development against additional targets. 

What sort of innovation are you bringing in your project?

This project sets out a robust investigation of ASOs as an innovative antimalarial strategy with the potential to deliver a long-acting prophylactic. Identification of potent ASOs would add a new modality with transformative potential to the antimalarial arsenal. An additional benefit would be the provision of a new tool for validation of malaria drug targets. The collaborative project team brings together cutting-edge target biology and screening capabilities with advanced nucleic acid technologies.

Role and Responsibility of Each Partner

The project will be carried out by a team consisting of scientists and project managers from Eisai and Medicines for Malaria Venture (MMV) with support from University of California San Diego (UCSD). 
As the designated development partner for this project, Eisai is responsible for delivering the work plan within the agreed timeline and budget, as well as for GHIT reporting. Eisai will also participate in design of ASOs for screening, including integration of machine learning models.
At UCSD, Prof. Winzeler’s laboratory will identify gene targets for evaluation, employ bioinformatic approaches for ASO design and use established high-throughput liver-stage and blood-stage cell culture assays for ASO profiling. 
MMV will participate in project design and provide expertise on antimalarial discovery.
All teams will collaboratively contribute to development strategy, experimental design and data analysis based on their experience in development of novel antimalarials.

Others (including references if necessary)

1. WHO (2025) World malaria report 2025, World Health Organization