Developing novel therapeutics for the treatment of snake venom-induced necrosis in India and sub-Saharan Africa

Every year ~400,000 snakebite victims suffer from venom-induced tissue damage that leads to surgical debridement, amputation, and substantial psychological sequelae. Current snakebite therapies are ineffective at treating venom-induced tissue damage and little is known regarding the cellular mechanisms responsible for snake venom cytotoxicity and the resulting dermonecrosis. Snakebite victims are frequently young, agriculturally productive members of impoverish communities in low-and-middle income countries and provide the main source of income for their families. Therefore, the life-degrading disabilities that result from snake venom-induced dermonecrosis is a considerable socioeconomic and health system burden.

Recently we have begun to identify and characterise cytotoxins found in snake venoms, in addition to identify endogenous mediators of cytotoxicity, biomarkers, and in vitro models that could be of use in evaluating treatments. We also received funding support from the Wellcome Trust to develop recombinant, humanised camelid VHH nanobodies targeting necrosis-inducing toxins, in collaboration with research groups in the USA (International AIDS Vaccine Initiative; IAVI), India (Indian Institute of Science; IISc), and Kenya (Kenya-Snakebite Research & Intervention Centre; K-SRIC). Current antivenoms consist of large intact, F(ab’)2, or Fab immunoglobin fragments (150, 100 and 50 kDa respectively) that are restricted in their tissue distribution, whereas much smaller camel VHH nanobodies (15 kDa) have rapid penetration of the blood/tissue barrier to reach and neutralise necrosis-inducing toxins.

The successful PhD applicant will join our project and the Centre for Snakebite Research and Interventions (CSRI) at LSTM to investigate snake venom-induced cytotoxicity and the pre-clinical evaluation of nanobodies targeting necrosis-inducing toxins. There is also the opportunity to travel to India and/or Kenya to gain additional project experience in our partner labs. Successful completion of this project has the potential to deliver lead candidate nanobodies for future translation as next generation snakebite therapeutics.

Where does the project lie on the Translational Pathway?

T1 – Basic Research

Expected Outputs

•            A better understanding of snake-venom induced cytotoxicity, and other therapeutic leads for the treatment venom-induced tissue damage

•            Preclinically-tested nanobodies with demonstrable efficacy at reducing snakebite morbidity

•            Capacity building in India and Kenya

•            REF-returnable publications

Training Opportunities

•            Training in multiple laboratory skills, from -omics to preclinical in vivo animal work

•            Opportunities to travel to and work in India and/or Kenya with project collaborators

•            Opportunities and mentorship to present biomedical research designed to address a neglected tropical disease at national and international conferences

•            Opportunities and mentorship to publish high-impact, influential papers

Skills Required

A biomedical science background would be desirable. In addition, any prior experience or knowledge of biochemistry, molecular biology, immunology, antibodies, or inflammatory processes, would be helpful, but not essential.

Key Publications associated with this project

Gutiérrez, J. M., et al. 2017 “Snakebite envenoming.” Nature Reviews Disease Primers 3: 17063.

https://www.nature.com/articles/nrdp201763

Chakrabarty, D., Sarkar, A. 2017. “Cytotoxic Effects of Snake Venoms.” In: Inagaki, H., Vogel, CW., Mukherjee, A., Rahmy, T. (eds) Snake Venoms. Toxinology. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-6410-1_34

Cook, D. A., et al. 2010. "Analysis of camelid IgG for antivenom development: Serological responses of venom-immunised camels to prepare either monospecific or polyspecific antivenoms for West Africa." Toxicon 56(3): 363-372.

https://pubmed.ncbi.nlm.nih.gov/20362604/

Bailon Calderon, H., et al. 2020. "Development of Nanobodies Against Hemorrhagic and Myotoxic Components of Bothrops atrox Snake Venom." Frontiers in immunology 11.

https://www.frontiersin.org/articles/10.3389/fimmu.2020.00655/full

LSTM Themes and Topics – Key Words

Neglected Tropical Disease.

Snakebite