Photos courtesy of DNDi and Sylvain Cherkaoui, Graham Crouch, Mariella Furrer, Institut Pasteur Korea, Benoit Marquet, Fabio Nascimento
The need for safe and effective treatments for neglected infectious diseases is only now beginning to be met, according to Julio Martin-Plaza, Ph.D., GlaxoSmithKline, Tres Cantos, Spain and Eric Chatelain, Ph.D., Drugs for Neglected Diseases initiative (DNDi), Geneva, Switzerland. Martin-Plaza and Chatelain are guest editors of the January 2015 special issue of the Journal of Biomolecular Screening on Novel Therapeutic Approaches for Neglected Infectious Diseases.
Much of the recent work of identifying new treatments for neglected infectious diseases is the result of collaborative efforts between the public and private sectors, encompassing pharmaceutical companies, academia, nonprofit organizations, NGOs, government laboratories and other partners, according to Martin-Plaza. Because DNDi is a pioneer in this endeavor, Martin-Plaza asked Chatelain to serve as co-editor.
"I believe the fact that DNDi advocated for these diseases from the moment it was formed in 2003 provided a push that induced others to enter the field, specifically in discovery R&D," Chatelain says. "This special issue reflects the growth that has occurred in combating neglected infectious diseases in the past five to 10 years, as well as current trends and projects that may come to fruition in the future." Reflecting its commitment to share information and empower further work in the area, DNDi made it possible for this special issue to become freely and fully available to everyone immediately upon publication.
One exciting advancement presented in the special issue is a novel imaging approach developed by Michael D. Lewis, Ph.D., and colleagues at London School of Hygiene and Tropical Medicine, a DNDi partner. The approach described in "A New Experimental Model for Assessing Drug Efficacy against Trypanosoma cruzi Infection Based on Highly Sensitive In Vivo Imaging" is already providing insights into Chagas disease, according to Chatelain. "Chagas disease in its most advanced form targets the heart and digestive tract; 30% to 40% of patients will evolve to the chronic phase with cardiac, digestive or cardiodigestive involvement, characterized by cardiac lesions and organ enlargement," he notes. Many investigators thought the Chagas-causing parasites, T. cruzi, were simply sitting in those organs, and so in addition to parasitemia, they looked specifically at the response in the heart and colon when testing the effects of new compounds. But results of the study reported in the special issue suggest this may not be the best way to ascertain efficacy.
The new in vivo imaging system involves the use of bioluminescent reporters that emit light above a certain threshold (600 nanomoles). For the study, the authors generated transgenic American—or T. cruzi—trypanosomes expressing a red-shifted firefly luciferase. The system is highly sensitive, in that it could detect the presence of fewer than 100 parasites in an inoculated mouse. They also created a new mouse model of Chagas disease that allows visualization of T. cruzi over time within the same mouse (rather than looking at different animals in different phases of the disease), thereby reducing the number of animals needed to test a candidate compound. The visualizations revealed that the parasite "actually moves around the body over time. It's not sitting in specific organs, creating damage," Chatelain says. If confirmed, the finding "presents a whole new aspect of the disease."
Lewis and colleagues note that "bioluminescence imaging alone will not provide a definitive measure of sterile cure, but when combined with post-treatment immunosuppression, it will provide a drastically improved approach to evaluate the efficacy of novel therapeutic compounds for the treatment of T. cruzi infections."
Subsequent work suggests that the new mouse model seems to respond similarly to humans when receiving Chagas disease therapy. Specifically, clinical studies have found that relatively new drug candidates belonging to the Azoles—posaconazole and E1224—had little to no sustained efficacy as a single treatment, whereas the current standard of care, benznidazole, was shown to be effective over the long term. These findings were reproduced recently in this animal model, Chatelain says, "so I believe it will be helpful for testing drugs, as well as for trying to understand how the pathogen works within the body."
In addition to bioluminescent live imaging, work on other new approaches to discovery for neglected infectious diseases are showcased in the special issue. For example, in "Fragment-Based Screening in Tandem with Phenotypic Screening Provides Novel Antiparasitic Hits," Antoni R. Blaazer of the Amsterdam Institute for Molecules, Medicines and Systems and colleagues describe a hybrid screening method that combines fragment-based screening—a target-based approach involving the screening of a small number of fragment-like, low molecular weight molecules—with phenotypic screening. The study revealed various small molecules with antiparasitic activity that could be starting points "with a lot of potential to grow into parasitic compounds with favorable properties such as selectivity and hydrophobicity."
"Generally, if you want to identify an antimicrobial agent, the target is the bug, not the molecule, Martin-Plaza explains. "The most straightforward approach would be phenotypic screening against the bug. But if you don't find an active compound in your libraries, it could be because you don't have the necessary chemical diversity. Then you have to target another chemical space that is not represented in your libraries through a different approach." That approach could be, as Blaazer et al. suggest, to screen fragments or smaller compounds in assays that are more sensitive and better able to pick up potential inhibitors. "When you identify those potential inhibitors, you can start to convolute and make the molecules more and more complex, so you end up with compounds that were not present in your initial chemical library, but are derived from scaffolds that were present there," Martin-Plaza says.
Screening of natural products for antiparasitic activity is another emerging area of study, according to Chatelain. Frederick Annang of ParaMet and colleagues report in "High-Throughput Screening Platform for Natural Product-Based Drug Discovery Against 3 Neglected Tropical Diseases: Human African Trypanosomiasis, Leishmaniasis, and Chagas Disease" on the development of a unique high-throughput screening platform for the identification of potential natural product-based leads against the pathogens. In a pilot project, the system confirmed 48 microbial extracts (out of 5,976 screened) with novel potent anti-kinetoplastid metabolites.
"Natural products is an interesting avenue to pursue, and has been neglected as a source of potential 'anti-kinetoplastidals' until recently. It is a highly complex and high-risk approach, but would certainly represent another starting point for diverse chemical material that could be considered for further development," Chatelain observes. Recently formed EU-sponsored consortia, New Medicines for Trypanosomatidic Infections (NMTRYPI) and Kinetoplastid Drug Development Strengthening the Preclinical Pipeline (KINDReD), among others, are pursuing this area over the next three years by screening extracts from natural sources, including fungal and plant source and marine isolates.
"Besides the availability of efficacious drugs, satisfactory treatment and management of neglected infectious diseases demand effective and rapid diagnostics at the point-of-care," Martin-Plaza says. "Currently, we lack tests that do not sacrifice sensitivity or specificity for simplicity and cost-effectiveness, and that can be used in both clinical settings and resource-poor field settings. The majority of definitive diagnoses for parasitic infections still rely on labor-intensive and time-consuming methods such as microscopy. To have the most significant diagnostic impact, new techniques and assays should be simple, inexpensive and yield rapid results. Furthermore, the tests should differentiate between current and past infections in order to properly determine disease prevalence, choose the appropriate treatment and assess the effect of treatment."
The development of such tools is in the works, as described in the 2014 JALA special issue, New Developments in Global Health Technologies and the SLAS Electronic Laboratory Neighborhood (ELN) e-zine article, Global Health: Putting Passion to Work with Novel Point-of-Care Diagnostics. However, much work still needs to be done. "Neglected infectious diseases are caused by a multitude of protozoan and helminth parasites. Therefore, the development of new diagnostic methodologies will require a multi-pronged and diversified approach," Martin-Plaza emphasizes. "The evolution of diagnoses in other therapeutic areas has been much faster than in neglected diseases. Thus, there exist tremendous opportunities for importing those technological developments."
That said, some of the newer diagnostic technologies are not standardized, nor can they be adapted for use in low-resource settings. Therefore, "diagnosticians in those settings are forced to rely on microscopic observations and culturing," Martin-Plaza acknowledges. "Neglected infectious diseases diagnostics have to move toward simple, low-cost serological and molecular methods with high specificity, sensitivity and speed. Assays able to detect multiple parasites in a single sample would be highly beneficial for patients who are co-infected."
In their 2015 special issue review article, "Diagnosis of Parasitic Infections: What's Going On?," Alessandra Ricciardi and Momar Ndao underscore the urgent global need for new diagnostics:
"Although for many years, parasitic infections had been neglected, the issue cannot be ignored any longer. In low income countries, infectious and parasitic diseases are the leading cause of years lost because of disability. Furthermore, these diseases are not restricted to the elderly, as the young populations are greatly affected as well.
"Although the disease burden attributed to parasitic infections is greatest in the developing world, this does not restrict the problem to the tropics. Moreover, some parasitic infections do not require international travel as they are already present in our own backyards.
"The Centers for Disease Control and Prevention (CDC) has targeted five neglected parasitic infections, commonly found in the United States, for public health intervention. Some of these include Chagas disease, cysticercosis, and toxoplasmosis. Parasitic infections are a reality, and it is of great importance to stress the quick and correct diagnosis of these infections to avoid deaths and further disease transmission."
Martin-Plaza adds, "We urge members of the SLAS community to do their best to figure out how to improve access to diagnostic methodologies for health professionals and for patients suffering from neglected infectious diseases in endemic areas. Knowledge sharing and collaboration are essential."
The 2015 JBS special issue, Novel Therapeutic Approaches for Neglected Infectious Diseases, features review articles and original reports on emerging approaches to identifying new agents to combat some of the 17 neglected tropical diseases prioritized by the World Health Organization because they are endemic in 149 countries and affect more than 1.4 billion people. JBS Editor-in-Chief Robert Campbell, Ph.D., notes that the open access of this special issue, courtesy of DNDi, benefits the global life sciences R&D community. SLAS CEO Gregory F. Dummer agrees and notes, "DNDi's generous open access initiative reinforces the spirit and unity of our scientific community and provides us with a memorable milestone to mark the first issue of our 20th year of publication."
The special issue is part of the SLAS commitment to improving access to information for health professionals, scientists and policy makers around the world, according to SLAS President Daniel Sipes. SLAS participates in the Health InterNetwork Access to Research Initiative (HINARI) by providing free or low-cost access to JALA and JBS to more than 6,000 publicly funded non-profit institutions in over 100 countries and territories in the developing world. In addition, deeply discounted membership rates make it easier for life sciences R&D professionals in emerging economies to join SLAS and enjoy full access to its many programs, products, services and events.
December 29, 2014