Development of new therapeutics to tackle snakebite-induced local tissue damage

Snakebite is a medical emergency causing rapid onset of both local tissue-destructive and potentially lethal systemic haemorrhagic and neurotoxic pathologies. Snakebite primarily afflicts remote, impoverished, rural farming communities in regions with weak medical and ambulatory infrastructures.  It annually kills approximately 138,000 people and 400,000 surviving victims suffer a substantially-reduced quality of life due to the multiple effects of permanent physical and psychological disabilities. Rapid access to effective healthcare is a major problem for these deeply disadvantaged snakebite victims, but necessary, because current antivenom treatment needs to delivered in a hospital setting.

Conventional antivenom is IgG purified from the blood of horses/sheep hyperimmunised with crude snake venoms. Since only 15% of the IgG in a vial of antivenom is venom-protein specific (most IgGs are to environmental and veterinary vaccine antigens), 85% of the IgGs are therapeutically redundant. This explains the need for multiple vial-treatments and the severe antivenom-induced adverse effects (>50% patients). Clinical management of both the severe snake envenoming pathology and antivenom-induced adverse effects requires hospital-based treatment. Unfortunately, delays in health seeking behaviour often result in antivenom therapy being ineffective at treating snakebite toxins, particularly those that cause local tissue damage around the bite site, leaving many victims with long term morbidity.

Recently we have begun to identify and characterise the cytotoxins found in various snake venoms, and that are responsible for causing local morbidity (e.g. inflammation, blistering, necrosis). Simultaneously, we have demonstrated the potential clinically utility of inhibitory small molecules as alternative treatments for snakebite. Such inhibitors show great potential for neutralising snake venom haemotoxins, and their small size potentially facilitates non-intravenous delivery outside of a clinical environment – e.g. in the community immediately after a bite.

This project will focus on exploring the potential utility of small molecules as community-based therapeutics to prevent local tissue damage following snakebite, and thus reduce the incidence of venom-induced morbidity. The project will seek to further understand the mechanisms of action of snake venom cytotoxins, and the pathophysiological consequences of their toxicity using animal models of envenoming and clinical samples collected from African snakebite victims. We will then use this information to rationally screen a panel of small molecules that exhibit modes of action of potentially utility for inhibiting the snake venom cytotoxins, or targets downstream of their modes of action.

The successful applicant will join the dynamic and well-funded team at LSTM’s Centre for Snakebite Research and Interventions (CSRI). Success in this project has the potential to deliver a small number of lead candidate small molecules of great value for future translation as next generation snakebite therapeutics. 

Where does the project lie on the Translational Pathway?

T1 – Basic Research

Expected Outputs

Technical Outputs:

- New, preclinically-tested inhibitors with demonstrable efficacy at reducing snakebite morbidity, and with translation potential to delivering this benefit globally

Institutional Impact:

- Delivery of products to reduce morbidity for rural, remote snakebite victims

- REF-returnable publications and Impact Case Study

Student Career Enhancement:

- Acquisition of a variety of laboratory technical skills

- 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 and REF-returnable papers (minimum 3 papers/PhD is expected) 

- Potential opportunity to experience different academic environments with our collaborators in Nigeria or Kenya

- Numerous opportunities at LSTM to understand the diverse cultural, fiscal and medical barriers to good health in rural remote tropical regions

Future Funding:

- If merited, the student will be encouraged & mentored to submit an Early Career Fellowship

 

Training Opportunities

The student will be exposed to a wide variety of research training opportunities, as they will join a well-funded, multi-disciplinary and dynamic team of post docs, students and technicians. Thus, they will have an opportunity to acquire additional clinical and lab skill sets to those described above. In terms of career development, the student will receive ample and diverse training commensurate with developing an appropriately competitive CV for acquiring funding to support their career after the PhD.

Skills Required

A biomedical science background would be desirable. In addition, any prior experience or knowledge of biochemistry, molecular biology, drug screening, antibodies, or inflammatory processes, would be helpful, but not essential. Critical thinking skills, a passion for research, and a meticulous nature, are highly sought after.

Key Publications associated with this project

Girish et al. 2019. Research into the causes of venom-induced mortality and morbidity identifies new therapeutic opportunities. Am. J. Trop. Med. Hyg. 100, 1043-1048.  https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6493937/

Albulescu et al. 2019. Preclinical validation of a repurposed metal chelator as a community-based therapeutic for hemotoxic snakebite. BiorXiv. https://www.biorxiv.org/content/10.1101/717280v1

Chakrabarty and Sarkar. 2017. Cytotoxic effects of snake venoms. In: “Snake Venoms”. https://link.springer.com/referenceworkentry/10.1007%2F978-94-007-6410-1_34

Bulfone et al. 2018. Developing small molecule therapeutics for the initial and adjunctive treatment of snakebite. J. Trop. Med. 2018: 4320175. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091453/

 

LSTM Themes and Topics – Key Words

Snakebite, neglected tropical diseases

The call for applications for the 2020-21 round of studentships is now OPEN. Deadline for receipt of complete application 23:59 13th February 2020

Further information on the programme and application process can be found here