RNAi-based discovery and validation of new drug targets in filarial nematodes

doi:10.1016/j.pt.2004.12.003

Trends in Parasitology

Volume 21, Issue 3, March 2005, Pages 97-100

https://doi.org/10.1016/j.pt.2004.12.003 Get rights and content

Human filarial nematodes cause river blindness and lymphatic filariasis, both of which are diseases that produce considerable morbidity. Control of these diseases relies on drug treatments that are ineffective against macrofilariae and are threatened by the development of resistance. New validated drug targets are required to allow development of new classes of antifilarial drugs. To identify and validate potential new drug targets, we propose a collaborative research strategy utilizing bioinformatic filters and assessment of gene function by RNA interference in Caenorhabditis elegans and Brugia malayi.

Introduction

Over one billion people are at risk of infection with filarial nematodes that cause two major chronic tropical diseases – lymphatic filariasis and river blindness (onchocerciasis). With nearly 140 million cases worldwide, the diseases cause considerable morbidity, estimated at 5.5 million disability adjusted life years (DALYs) for lymphatic filariasis and one million DALYs for river blindness [1]. Lymphatic filariasis, the second leading cause of long-term disability worldwide (as a result of lymphedema, elephantiasis, hydrocele and periodic fevers), is caused by mosquito-transmitted filarial worms, including Wuchereria bancrofti and Brugia malayi, which colonize the lymphatic system. Onchocerciasis, the second leading cause of infectious blindness, is caused by the microfilariae of Onchocerca volvulus, transmitted by blackflies [2]. In both diseases, the adult worms (macrofilariae) are long-lived, surviving for nearly a decade in the human host.

Section snippets

Chemotherapy

The coordinated global efforts to control both diseases rely principally on drugs. Treatments for lymphatic filariasis include annual doses of albendazole plus diethylcarbamazine (DEC), albendazole plus ivermectin, or use of DEC-fortified salt [3]. Although effective on larval stages, these treatments are fairly ineffective at killing adult worms, and provide only partial benefit to infected patients. Drug treatments aim to disrupt transmission of the infection by reducing the incidence of

Target validation

The filarial research community now has the opportunity to address the challenge by exploiting two recent scientific advances that provide new prospects for target validation in filarial worms 10, 11.

First, large-scale gene sequence information is accumulating for filarial nematodes 12, 13, including expressed sequence tags (ESTs) [14], and the soon-to-be-released 9× coverage draft genome of B. malayi [11]. The complete human genome sequence is also available for comparison [15], along with

Silencing target genes

RNAi is a process of post-transcriptional gene silencing that occurs in the cells of most, if not all, eukaryotes 25, 26, 27. Silencing target genes elicits loss-of-function phenotypes similar to those of genetic null mutants, and RNAi screening of a genome reveals many essential genes, some of which will be good targets for antinematode drug discovery. Application of RNAi provides, for the first time, a means of determining gene function in filarial worms, and allows target discovery and

Target criteria

To provide general strategic guidance to the filarial research community, the SWG recommended a Target Product Profile for new antifilarial drugs (Box 1) and a set of Target Selection and Validation Criteria (Box 2).

A strategy for identifying and validating antifilarial drug targets using RNAi in C. elegans and B. malayi was developed (summarized in Figure 1). A collaborative program is envisaged in which an expert Target Assessment Team would be established to evaluate and champion candidate

Perspective

If a collaborative process such as described here can be established, we anticipate that emerging scientific opportunities will be fully exploited to identify and provide novel, validated filarial drug targets for rapid uptake into established high-throughput drug discovery programs.

Acknowledgements

We acknowledge the participants in the WHO/TDR SWG on ‘RNA Interference as a Means of Identifying Drug Targets for Filariasis’ for their invaluable contribution to the discussion presented here and the UNICEF/UNDP/World Bank/WHO TDR for providing the opportunity to discuss this important topic.

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Trends in Parasitology

Research FocusRNAi-based discovery and validation of new drug targets in filarial nematodes

Introduction

Section snippets

Chemotherapy

Target validation

Silencing target genes

Target criteria

Perspective

Acknowledgements

Trends Parasitol.

Trans. R. Soc. Trop. Med. Hyg.

Vet. Parasitol.

Trends Parasitol.

Int. J. Parasitol.

Trends Parasitol.

Trans. R. Soc. Trop. Med. Hyg.

Trends Parasitol.

Mol. Biochem. Parasitol.

Mol. Biochem. Parasitol.

World Health Report 2002: Reducing Risks and Promoting Healthy Life

Drug therapy: antiparasitic drugs

N. Engl. J. Med.

Lymphatic filariasis elimination: progress in global programme development

Ann. Trop. Med. Parasitol.

Research Focus
RNAi-based discovery and validation of new drug targets in filarial nematodes