Overcoming the Challenges of Drug Discovery for Neglected Tropical Diseases: The A·WOL Experience

Abstract

Neglected tropical diseases (NTDs) are a group of 17 diseases that typically affect poor people in tropical countries. Each has been neglected for decades in terms of funding, research, and policy, but the recent grouping of them into one unit, which can be targeted using integrated control measures, together with increased advocacy has helped to place them on the global health agenda. The World Health Organization has set ambitious goals to control or eliminate 10 NTDs by 2020 and launched a roadmap in January 2012 to guide this global plan. The result of the launch meeting, which brought together representatives from the pharmaceutical industry, donors, and politicians, was the London Declaration: a series of commitments to provide more drugs, research, and funds to achieve the 2020 goals. Drug discovery and development for these diseases are extremely challenging, and this article highlights these challenges in the context of the London Declaration, before focusing on an example of a drug discovery and development program for the NTDs onchocerciasis and lymphatic filariasis (the anti- Wolbachia consortium, A·WOL).

Short-Course, High-Dose Rifampicin Achieves Wolbachia Depletion Predictive of Curative Outcomes in Preclinical Models of Lymphatic Filariasis and Onchocerciasis

“…The pharmacopeia of registered antibiotics present ‘low hanging fruit’ with the potential for rapid re-purposing 62,63 . Further, the ‘slow kill’ effect post- Wolbachia depletion, manifest first on circulating or skin mf and then adult worms, avoids the problems of inflammatory adverse reactions which are associated with fast-killing direct filaricidal agents 3,33,64–66 .…”

Glaucomics: A Call for Systems Diagnostics for 21stCentury Ophthalmology and Personalized Visual Health

“…However, it is unclear whether this approach will ensure the elimination of onchocerciasis (Hotez, 2011;Keenan et al, 2014) so that alternative approaches are being pursued, including new drugs targeting the adult worm and a vaccine development initiative, which is underway through a partnership between academia and the Sabin Vaccine Institute product development partnership (PDP) (Beaumier et al, 2013). An alternative approach relies on antibiotics that target unique bacterial endosymbionts found in the adult worm ( Johnston et al, 2014). Each of these approaches could rely on new discoveries related to the parasite and its endosymbiont genomes (Darby et al, 2012).…”

Wolbachia endosymbionts and human disease control

“…In vivo nematode screening uses established animal models of filarial infection, including Litomosoides sigmodontis in mice and B. malayi in gerbils. Screening has included registered drugs that can be repurposed, as well as diverse and focused libraries [31,33,34].…”