Can India lead the way in neglected diseases innovation?

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Abstract

Nirmal Kumar Ganguly and colleagues call for a comprehensive policy for neglected diseases research in India to foster innovation in drugs, diagnostics, and vaccines, critical for evolving needs of elimination programmes

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The Wolbachia endosymbiont as an anti-filarial nematode target

Barton E Slatko, Mark Taylor, Jeremy M Foster (2010)

Human disease caused by parasitic filarial nematodes is a major cause of global morbidity. The parasites are transmitted by arthropod intermediate hosts and are responsible for lymphatic filariasis (elephantiasis) or onchocerciasis (river blindness). Within these filarial parasites are intracellular alpha-proteobacteria, Wolbachia, that were first observed almost 30 years ago. The obligate endosymbiont has been recognized as a target for anti-filarial nematode chemotherapy as evidenced by the loss of worm fertility and viability upon antibiotic treatment in an extensive series of human trials. While current treatments with doxycycline and rifampicin are not practical for widespread use due to the length of required treatments and contraindications, anti-Wolbachia targeting nevertheless appears a promising alternative for filariasis control in situations where current programmatic strategies fail or are unable to be delivered and it provides a superior efficacy for individual therapy. The mechanisms that underlie the symbiotic relationship between Wolbachia and its nematode hosts remain elusive. Comparative genomics, bioinfomatic and experimental analyses have identified a number of potential interactions, which may be drug targets. One candidate is de novo heme biosynthesis, due to its absence in the genome sequence of the host nematode, Brugia malayi, but presence in Wolbachia and its potential roles in worm biology. We describe this and several additional candidate targets, as well as our approaches for understanding the nature of the host-symbiont relationship.

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The bacterium Wolbachia exploits host innate immunity to establish a symbiotic relationship with the dengue vector mosquito Aedes aegypti

Xiaoling Pan, Andrew Pike, Deepak Joshi … (2017)

A host’s immune system plays a central role in shaping the composition of the microbiota and, in return, resident microbes influence immune responses. Symbiotic associations of the maternally transmitted bacterium Wolbachia occur with a wide range of arthropods. It is, however, absent from the dengue and Zika vector mosquito Aedes aegypti in nature. When Wolbachia is artificially forced to form symbiosis with this new mosquito host, it boosts the basal immune response and enhances the mosquito’s resistance to pathogens, including dengue, Zika virus and malaria parasites. The mechanisms involved in establishing a symbiotic relationship between Wolbachia and A. aegypti, and the long-term outcomes of this interaction, are not well understood. Here, we have demonstrated that both the immune deficiency (IMD) and Toll pathways are activated by the Wolbachia strain wAlbB upon its introduction into A. aegypti. Silencing the Toll and IMD pathways via RNA interference reduces the wAlbB load. Notably, wAlbB induces peptidoglycan recognition protein (PGRP)-LE expression in the carcass of A. aegypti, and its silencing results in a reduction of symbiont load. Using transgenic mosquitoes with stage-specific induction of the IMD and Toll pathways, we have shown that elevated wAlbB infection in these mosquitoes is maintained via maternal transmission. These results indicate that host innate immunity is utilized to establish and promote host-microbial symbiosis. Our results will facilitate a long-term projection of the stability of the Wolbachia–A. aegypti mosquito system that is being developed to control dengue and Zika virus transmission to humans.

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Why miltefosine—a life-saving drug for leishmaniasis—is unavailable to people who need it the most

Temmy Sunyoto, Julien Potet, Marleen Boelaert (2018)

Miltefosine, the only oral drug approved for the treatment of leishmaniasis—a parasitic disease transmitted by sandflies—is considered as a success story of research and development (R&D) by a public-private partnership (PPP). It epitomises the multiple market failures faced by a neglected disease drug: patients with low ability to pay, neglect by authorities and uncertain market size. Originally developed as an anticancer agent in the 1990s, the drug was registered in India in 2002 to treat the fatal visceral leishmaniasis. At the time, miltefosine was considered a breakthrough in the treatment, making it feasible to eliminate a regional disease. Today, access to miltefosine remains far from secure. The initial PPP agreement which includes access to the public sector is not enforced. The reality on the ground has been challenging: shortages due to inefficient supply chains, and use of a substandard product which led to a high number of treatment failures and deaths. Miltefosine received orphan drug status in the USA; when it was registered there in 2014, a priority review voucher (PRV) was awarded. The PRV, meant to facilitate drug development for neglected disease, was subsequently sold to another company for US$125 million without, to date, any apparent impact on drug access. At the heart of these concerns are questions on how to protect societal benefit of a drug developed with public investment, while clinicians worldwide struggle with its lack of affordability, limited availability and sustainability of access. This article analyses the reasons behind the postregistration access failure of miltefosine and provides the lessons learnt.

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Author and article information

Contributors

Zakir Thomas: Role: commissioner of income taxRole: former project director

Gautam Kumar Saha: Role: scientific associate

Kappoori Madhavan Gopakumar: Role: senior researcher and legal adviser

Nirmal Kumar Ganguly: Role: president

Journal

Journal ID (nlm-ta): BMJ

Journal ID (iso-abbrev): BMJ

Journal ID (publisher-id): BMJ-UK

Journal ID (hwp): bmj

Title: The BMJ

Publisher: BMJ Publishing Group Ltd.

ISSN (Print): 0959-8138

ISSN (Electronic): 1756-1833

Publication date Collection: 2019

Publication date (Electronic): 22 January 2019

Volume: 364

Electronic Location Identifier: k5396

Affiliations

[1 ]Central Board of Direct Taxes, Department of Revenue, Ministry of Finance, New Delhi, India

[2 ]Open Source Drug Discovery, India

[3 ]Apollo Hospitals Educational and Research Foundation, New Delhi, India

[4 ]Third World Network, Geneva, Switzerland

[5 ]Indian Council of Medical Research, India

Author notes

Correspondence to: N Kumar Ganguly ganguly.nk@ 123456aherf.net

Article

Publisher ID: ganj47755

DOI: 10.1136/bmj.k5396

PMC ID: 6340354

PubMed ID: 30670384

SO-VID: 72b7e778-dcfc-46de-9dc7-fade66ae7eb2

License:

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

Can India lead the way in neglected diseases innovation?

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Most cited references 19

The Wolbachia endosymbiont as an anti-filarial nematode target

The bacterium Wolbachia exploits host innate immunity to establish a symbiotic relationship with the dengue vector mosquito Aedes aegypti

Why miltefosine—a life-saving drug for leishmaniasis—is unavailable to people who need it the most

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