Investment

Details

Target determination and exploratory research for discovery of new drugs against Chagas disease.
  • RFP Year
    2017
  • Awarded Amount
    $882,350
  • Disease
    NTD (Chagas disease)
  • Intervention
    Drug
  • Development Stage
    Target Validation
  • Collaboration Partners
    High Energy Accelerator Research Organization (KEK), London School of Hygiene and Tropical Medicine(LSHTM), National Institute of Advanced Industrial Science and Technology, Institute of Tropical Medicine (NEKKEN) Nagasaki University

Introduction and Background of the Project

Introduction

Trypanosoma cruzi (Tc), the causative protozoan parasite of Chagas disease, does not contain the genetic machinery that facilitates an RNA interference response that has been widely used for gene specific inhibition of expression. This has been a limiting factor for studies on searching appropriate genes of Tc as targets for designing a new medicine. We have established a protocol for gene knockdown or knockout (KO) experiments aimed at candidate drug targets. Our system is an effective and high-throughput gene deletion system for Tc, which is achieved by combinational use of CRISPR/Cas9 genome editing and image-recognition technologies.

 

Project objective

Identification of candidate target Tc proteins which are essential for amastigote stage parasites to proliferate or to survive.

 

Project design

We will undertake exhaustive KO campaign for about 1,000 Tc genes in the epimastigote stage to identify those essential for parasite survival. The essentiality of selected genes will further be evaluated by the same KO experiment in trypomastigote and amastigote stages by our established stage specific KO system in vitro and in vivo. After identification of the targets, we will examine drug-like active compounds from TCATc (GSK) for their effect on target gene overexpressed Tc to elucidate the pathogenicity requirement.

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

More than 1 billion people are infected with one of the 20 NTDs listed by the World Health Organization (WHO).  Despite the major achievement in medicine in the past 50 years, kinetoplastid diseases are still without adequate treatments. In order to achieve the ambitious goals of global NTD sustainable control and/or elimination new tools are still required.

Chagas Disease: About 6 million to 7 million people, mostly in Latin America, are estimated to be infected with Tc. More than 10,000 people die every year, and an estimated 100 million people are at risk of acquiring the disease. Only two drugs are currently available for Chagas disease, benznidazole and nifurtimox – both requiring a 60-90 day treatment period. The goal is to develop effective, well-tolerated, inexpensive treatments for indeterminate-chronic phase and acute stage infections that could be used in combination. Combination therapy can improve treatment efficacy, reduce dose levels and toxicity and prevent the potential development of resistance.

What sort of innovation are you bringing in your project?

We have developed an effective and high-throughput gene deletion system for Tc, which was achieved by combinational use of CRISPR/Cas9 genome editing and image-recognition technologies.

Role and Responsibility of Each Partner

NEKKEN will be responsibel to coordinate the study including communication within the partners and GHIT office. Regular and extra-regular reports will be made by the project coordinator at NEKKEN. Each partners will be responsible for the following items described under the original project plan.

1. Prioritization of candidate genes for KO.[NEKKEN]: Generate target list will be prepared using systematic review and a bioinformatics.

2. Gene KO and evaluation [AIST]: 1) First exhaustive gene KO in epimastigotes (EPIs) and 2) Evaluation of the first KOs in the TRYPO/AMA stage [AIST , NEKKEN and LSHTM].

3. Phenotypic screening of compounds using AMA-essential gene overexpression strains [LSHTM, NEKKEN]

4. Validation of AMA-essential genes in vivo [LSHTM]: Evaluation of, at least, 10 AMA-essential genes in an in vivo system.

5. Identification of genes associated with pathogenicity in vivo [NEKKEN, AIST]: Evaluation in vivo of, at least, 10 AMA-non-essential genes.

6. overall discussion on the progress. [NEKKEN, AIST, LSHTM, KEK]