Confronting neglected protozoan diseases: understanding the challenges, developing the solutions

16 Nov 2010

Allison Thorpe

Source: TropIKA.net

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Scientists interested in research on neglected protozoan diseases were recently given an opportunity to hear presentations from leaders in the field, and to consider the emerging findings and progress of eight major research projects.

The Institut Pasteur hosted the international colloquium on neglected protozoan diseases on Friday, 24th September 2010. The eight research projects receiving particular attention are all funded by the European Commission (EC) under the aegis of the 7th Framework Programme (FP7). FP7 is the current European Union framework programme for research, which started in 2007 and will go on until 2013. Through FP7, the EC provides support to research activities, with a focus on collaborative research. The EC is the third largest global funder of research in poverty and neglected infectious diseases.

Throughout the day, delegates were encouraged to reflect on strategies, priorities and initiatives across the funding landscape, and engage in discussions between stakeholders from different communities such as academic researchers, industry, public–private product development partnerships (PDPs), the UN Special Programme for Research and Training in Tropical Diseases (TDR) and the EC.

The presentations on the specific projects demonstrated the continued challenge of such issues as how to affect translational research and develop research capacity, and provided an insight into strategies for addressing emerging technical challenges related to realizing their research objectives. Participants exchanged views and experience on a broad range of topics across the agenda, with a particular emphasis on sharing knowledge, and focusing and leveraging funding for research. The discussions were carried on throughout the day, with poster sessions focused on the work of the eight research projects, providing an opportunity for delegates to engage with the research teams in more depth about areas of specific interest.

From the opening speech by Professor Anthony Pugsley, Scientific Director of the Institut Pasteur, to the closing plenary, the colloquium maintained and developed a very simple core message – scientists play a key role in ‘confronting neglected protozoan diseases’. This is not just through realizing the products of their scientific endeavour, but also through their broader ability to bring pressure to bear to do things which are worthwhile, based on the evidence, and through their commitment to coordinated working to ensure that limited resources are pooled for maximum health impact.

This message was further developed by Anna Lonnroth of the EC. Her update on the funding landscape stressed the EC’s continued commitment to arguing the case for research and resources within this area, supporting international collaboration, and cross-sectoral working. Whilst acknowledging the frustrations experienced by researchers, with the scope of the agenda being in apparent tension with the scale of the resources available to support activity, and the potentially competing agendas and priorities that can cause tension between the scientific and political communities, she emphasized the key advocacy role of the scientific community.

This challenge provided a robust platform for the rest of the conference to build upon, with consecutive speakers providing both an insight into their organizational strategies and state of their current research activity.

There were four thematic sessions, and a poster session that ran throughout the day.

New tools for controlling neglected protozoan diseases

Solomon Nwaka provided an upbeat assessment of the role of networks in building the research value chain, focusing particularly on the example of the African Network for Drugs and Diagnostics Innovation (ANDI) and its role in supporting coherence, collaboration and creation of options for action in Africa. He called for continued and sustained effort to build the research value chain, looking at new knowledge, new tools, interventions, strategies and health impact – but also supporting capacity building and knowledge management. He suggested three principles were necessary for successful effort: coherence, collaboration and creation of options for action.

Jean-Claude Dujardin continued the theme of identifying options for action. His presentation emphasized the need for continuity in research and surveillance. The focus was the Kaladrug-R project, which is one of three EC-funded research consortia looking at developing new or safeguarding existing drugs for leishmaniasis. He described preliminary conclusions from the project, which is monitoring emerging drug resistance on the Indian subcontinent. This demonstrated the value of looking at drug resistance emergence through the lens of the past, whilst tracking the present and anticipating the future. This work demonstrates the key role monitoring and surveillance can play in increasing our understanding of developing drug resistance patterns, and signposts the need for effective communication of these messages. Having the infrastructure in place to monitor treatment effectiveness in the field is crucial.

Michael Miles focused on the work of the Chagas EPInet consortium. Chagas disease, which is caused by Trypanosoma cruzi, is a major health problem in Latin America. Whilst work has been undertaken to agree a consensus nomenclature for the six distinct genetic lineages of T. cruzi, a key gap has been around methodology for identifying the distinction of the genetic lineages, their deployment in endemic areas and their comparative epidemiology. Chagas Epinet has been looking at methods to study the population and molecular genetics of the organism, with an ultimate aim of improving understanding, diagnosis and ultimately prevention of Chagas disease through technology development, as well as establishing an international T.cruzi cryobank and accompanying database.

Vaccine development for leishmaniasis

There were four presentations, which together provided an insight into the complexities of vaccine development for protozoan diseases, from the management of biological resources from cells through to product development. Whilst sharing a desire to create a vaccine for leishmaniasis, the projects had taken very different approaches, giving delegates an opportunity to consider the challenges and opportunities presented by each proposal, and to reflect on the progress to date within each of the projects.

Steve Reed provided an update on the work being taken forward by the US-based Infectious Disease Research Institute (IDRI). Their work programme is currently focusing on inducing long lasting T-cell response against appropriate antigens, with the ultimate aim of creating a vaccine which gives long term immunity and is prophylactically and therapeutically active, and effective against more than one form of leishmaniasis. They are working with three antigens – two for human vaccines and one for canine use.

Paul Kaye contrast focused on a product development project, funded by a Wellcome Trust translation award. His team were asked to take the ‘state of the art’ at the time of the award, and use it as the baseline for development of a new product which could be used in investigations of human immunology and clinical studies.

The key advice offered by Paul Kaye for anyone considering working at the interface between preclinical and clinical work, was to hire the clinical trials manager as early in the process as possible, and initiate the dialogue between scientists, product developers and clinicians.

Gerard Marie Papierok drew upon the work of RAPSODI – an EC-funded consortium, which is looking to develop a vaccine for humans, drawing upon the knowledge gained through the development of a canine vaccine – CANILEISH – which is due to be launched in 2011. The team are using a polysialic acid (PSA)-based human vaccine candidate as PSA is present in all Leishmania species, with an aim to develop a vaccine which could potentially protect the population against most or all the clinical phenotypes – visceral leishmaniasis (VL) cutaneous leishmaniasis (CL) and mucocutaneous leishmaniasis (ML).

Dr Farrokh Modabber presented the LeishDNAvax project, which focuses on developing a DNA-based vaccine, with the objective of the project being to complete pre-clinical development of a vaccine candidate against human VL and CL for both prophylactic and therapeutic use. The vaccine will be based on the minimalistic immunologically defined gene expression vector (MIDGE) developed for efficient induction of cellular immune responses. Citing a gap in translational activity, the team had chosen to work with antigens that had already been identified, rather than seek new ones, collecting data through literature on the antigens, sequencing the genes of the selected antigens and translating into protein sequences. This process generated seven candidate antigens, of which three antigens have been selected, with a further two still under consideration. Studies in animal models are still ongoing, but the team hope to be at a stage of moving to clinical trials within the next 18 months.

Drug discovery and development

Manica Balasegaram provided an insight into the portfolio business model and lead consortium approach adopted by DNDi, with most of the research and development undertaken by partners spread across the globe. He highlighted activity across the whole of the DNDi portfolio, providing a brief insight into progress in a number of projects.

Michael Barrett focused on new developments in drugs for human African trypanosomiasis (HAT). He looked at the potential approaches that could be used to inform drug development – from a historical perspective, looking at whether existing regimens could be improved, with the development of derivatives, through pharmacokinetics, target-based approaches and finishing with systems-based approaches.

Gerald Späth provided an introduction to the work being taken forward by the Leishdrug Consortium, another EC-funded project. This project starts from the recognition that during the infectious cycle, Leishmania shows two different development stages – the promastigote and amastigote stages. The consortium uses a multi-disciplinary approach to exploit parasite specific kinases for anti-leishmanial drug development.

Helge Bode focused on the activities of GameXP, another EC-funded consortium. Uniquely for this conference, the project was not focused specifically on protozoan diseases, but rather was looking at bioprospecting, using genomic approaches to metabolite exploration, to identify and isolate novel natural products from entomopathogenic bacteria and to determine the biological activity of these natural products.

He provided an overview of the project’s progress to date, focusing particularly on the process followed by the team.

Dolores Gonzales Pacanowska gave an overview of the work of the Trypobase Consortium, again an EC-funded initiative. This consortium has seven partners, and seven work packages, focusing on HAT, leishmaniasis and Chagas disease, with the core objective being the identification of new nucleobase derivatives for the treatment of leishmaniasis and trypanosmiases, with the intention of identifying as many hits as possible and then narrowing down by specific disease. The ultimate aim is to produce a preclinical drug candidate during the three-year project period, although it is recognized that the most likely outcome is a compound series with drug like properties with efficacy in a rodent model of infection. The Trypobase Consortium have taken a dual approach, using both phenotypic screening to identify new leads active against the three major protozoa by screening libraries to identify compounds with antiprotozoal activity , and a target based drug design approach, identifying compounds which are active against dUTPase.

Ole Olesen provided feedback from a workshop, which had been held on 23rd September, to consider how Europe should be supporting work in the field of neglected protozoan diseases, how the agenda should be shaped and what the overall themes should be within future programmes. The workshop had been organized around a series of specific questions, encouraging participants to give their views on who should determine research direction, which instruments were needed to support research, and where the major funding gaps were within this area. A mailbox had been set up to enable delegates at the conference to give their views and feedback on EC research activities in neglected protozoan diseases (RTD-NID-conference@ec.europa.eu).

Diagnostics and biomarkers

Joseph N’dungu of the Foundation for Innovative New Diagnostics (FIND) is working with partners on a number of projects to develop diagnostic platforms for staging HAT with improved accuracy to guide treatment, and for follow-up to determine treatment success. Special attention is being given to ensuring that the diagnostics are developed with a user friendly format, which does not require lab-trained operators. Other important factors are speed, simplicity, cost, and reliability of the new tests, as well as ensuring that diagnosis can be done as close to home as possible with reduced invasiveness. The first prototypes are now being screened for specificity and sensitivity.

Krister Kristensson focused on results obtained from the EC-funded project, NEUROTRYP, which ended in September 2009. The aim of the project had been to unravel basic cellular and molecular processes that underlie the brain penetration of African trypanosomes to discover:

molecules that may be considered as markers for an effective staging of HAT
design new therapies by using drugs which have already passed clinical trials in humans for other indications.

During his presentation, he highlighted the underlying mechanisms by which trypanosomes pass across the blood brain barrier, and the effects of treatment of HAT with minocyline.

In terms of next steps, the team found that their screening of a library of nucleoside analogues (obtained from Medivir AB, Sweden) did not disclose a better compound than cordycepin. Work is now focusing on devising deaminase-resistant cordycepin analogues to avoid the necessity of using a duplet for the treatment.

Christine Clayton provided an insight into the contribution transcriptomic approaches in culture and in the host can play in drug development and discovery, highlighting their utility for looking at global changes of metabolisms upon infection to understand the significance of genes and enzymes involved in the individual pathways in parasitic and pathophysiological trypanosomiasis. The presentation summarized the process by which trypanosome differentiation takes place, showing that metabolism and surface proteins change drastically, control of gene expression was essential, and that switching on just one procyclic protein could kill the parasite.

Stefan Magez of Nanotryp (also EC-funded) gave the final presentation of the day. His project was based on the discovery of a nanobody that can recognize several different trypanosome variant surface glycoproteins. (Nanobodies are small antibody fragments derived from heavy-chain camelid antibodies, produced as recombinant proteins, using bacterial expression systems.) The Nanotryp project aims to develop further, similar nanobodies able to recognize the surface of trypanosomes, and use these as the basis for new simple diagnostic tests.

Key learning points

The conference provided a unique opportunity for conference delegates to engage directly with some of the leaders in research on neglected protozoan diseases, and provided an insight into the broad range and scope of the research landscape.

There were, however, some more general learning points scattered throughout the day which deserve highlighting. Concerted action to ‘confront neglected protozoan diseases’ requires all of the following.

Scientific endeavour – working at the cutting edge of technology, and pushing boundaries.
Optimism Whilst funding was considered to be a key challenge for vaccine development, conference presenters suggested that through working effectively with donors, and collaboratively with other teams, it was possible to raise resources and maintain momentum in this area.
Advocacy Whilst recognizing that there can be tensions between the expectations of different stakeholders, and between political and scientific priorities, scientists need to use every opportunity to advocate for work in this area, and use the evidence to argue for change.
Continued and sustained effort is needed to build the research value chain This is not just a role for individual scientists or research consortia, but means looking broadly across the research landscape, at partners, opportunities for joint working, and capacity and capability development. Coherence, communication and coordination are all key elements of this process.
Options for action and increasing sustainability One of the key challenges is supporting and enhancing effective industry engagement, with the requirement for return on investment remaining a limiting factor. However, there are opportunities for joint working, and diagnostic platforms provide novel piggy-back opportunities for neglected diseases, with limited extra investment.

For more information on the conference and a link to presentations and abstracts, please go to: http://ec.europa.eu/research/health/infectious-diseases/neglected-diseases/index_en.html