Development of a novel therapeutic to treat snakebite induced necrosis in sub-Saharan Africa
Lead Research Organisation:
Liverpool School of Tropical Medicine
Department Name: Liverpool School of Tropical Medicine
Abstract
The proposed PhD is to develop a targeted therapeutic against snake venom-induced necrosis in sub-Saharan Africa. The current, and only, treatment for snakebite (antivenom - lgG from
horses/sheep hyperimmunised with venom/s)), while effective at reversing the potentially lethal systemic effects of envenoming is ineffective at negating/reversing the tissue-necrotic effects. The global estimates are that 400'000 individuals are left disfigured or disabled every year due to venom-induced necrosis. In sub-Saharan Africa alone there are an estimated 14'000 amputations each year directly attributable to snakebite. However, little is understood about how individual venom components act to cause necrosis. Whilst there is published literature indicating which proteins are thought to be integral to the causation of necrosis, little has been done focusing on this pathology alone, especially in sub-Saharan African species.
The development of a therapy to treat venom-induced necrosis is an urgent and compelling clinical need, and a better understanding of the underlying processes will be invaluable. Three key sub- Saharan species (based on geographical distribution, frequency of human bites and severity of necrosis caused) have been identified as Echis ocel/atus, Bitis arietans and Naja nigricollis. The venoms, and individual toxins, from these three species will form the basis of the entire PhD.
The scope of the PhD covers the identification of necrosis-inducing toxins (NITs) within all three of these venoms, examining their effects in ex vivo and in vivo models, and designing (and testing) NIT targeting therapeutics. These is also the potential in expand the PhD further to include highly necrosis-inducing Asian species, such as Daboia russelii and Ca//ose/asma rhodostoma, using the same approaches.
The first year of the PhD will be dedicated to the identification and isolation of these NITs from the three sub-Saharan Africa target venoms. In order to achieve these aims several different methodologies will be applied; bioinformatics, recombinant protein expression, chromatography and bioactivity assays. Each of these different techniques constitutes its own distinct phase of work.
horses/sheep hyperimmunised with venom/s)), while effective at reversing the potentially lethal systemic effects of envenoming is ineffective at negating/reversing the tissue-necrotic effects. The global estimates are that 400'000 individuals are left disfigured or disabled every year due to venom-induced necrosis. In sub-Saharan Africa alone there are an estimated 14'000 amputations each year directly attributable to snakebite. However, little is understood about how individual venom components act to cause necrosis. Whilst there is published literature indicating which proteins are thought to be integral to the causation of necrosis, little has been done focusing on this pathology alone, especially in sub-Saharan African species.
The development of a therapy to treat venom-induced necrosis is an urgent and compelling clinical need, and a better understanding of the underlying processes will be invaluable. Three key sub- Saharan species (based on geographical distribution, frequency of human bites and severity of necrosis caused) have been identified as Echis ocel/atus, Bitis arietans and Naja nigricollis. The venoms, and individual toxins, from these three species will form the basis of the entire PhD.
The scope of the PhD covers the identification of necrosis-inducing toxins (NITs) within all three of these venoms, examining their effects in ex vivo and in vivo models, and designing (and testing) NIT targeting therapeutics. These is also the potential in expand the PhD further to include highly necrosis-inducing Asian species, such as Daboia russelii and Ca//ose/asma rhodostoma, using the same approaches.
The first year of the PhD will be dedicated to the identification and isolation of these NITs from the three sub-Saharan Africa target venoms. In order to achieve these aims several different methodologies will be applied; bioinformatics, recombinant protein expression, chromatography and bioactivity assays. Each of these different techniques constitutes its own distinct phase of work.
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| MR/N013514/1 | 01/10/2016 | 30/09/2025 | |||
| 1854739 | Studentship | MR/N013514/1 | 12/09/2016 | 30/09/2020 | Charlotte Dawson |
| Description | Conference Presentation - International Society of Toxinology |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Poster and talk given at the International Society of Toxinologys conference in Buenos Aires, Argentina. Talk entitled "Paraspecificity of Epitopes Identified to Generate a Serotherapy for Africa-specific Snake Venom-induced Necrosis" was selected as part of the students day presentations. Audience was composed of postgraduate students, academic researchers and other interested persons. A number of discussions were held at both the poster presentation, one with an antivenom producer representative on the aims of the research, and others with clinicians. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Conference Presentation, Oxford Venoms and Toxins Conference |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | International |
| Primary Audience | Other audiences |
| Results and Impact | Conference talk titled "Paraspecificity of Epitopes Identified to Generate a Serotherapy for Africa-specific Snake Venom-induced Necrosis". Talk was delivered to an international audience of snakebite researchers, campaigners and interested persons. Its intended purpose was to disseminate information relating to developing a novel therapeutic for snakebite necrosis, and its potential for generating a product with global application. Discussions after the talk were held with a number of researchers. |
| Year(s) Of Engagement Activity | 2019 |
| Description | Conference Presentation, Wellcome Trust Liverpool Glasgow Centre for Global Health Research Annual Scientific Meeting |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | National |
| Primary Audience | Other audiences |
| Results and Impact | Poster presentation on my work to produce recombinant venom toxins using E. coli, titled "Expression of Recombinant Venom Necrotoxins as a Tool to Better Define Local Tissue Damage Caused by Saw-Scaled Viper Envenoming". Poster session was open to all conference attendees, with many coming over to discuss the research, next steps and my PhD project as a whole. Poster also attracted attention from clinicians in the field who have firsthand experience in treating snakebites, and were keen to discuss the issues they have been facing in clinics. |
| Year(s) Of Engagement Activity | 2018 |
| Description | Conversation with Jeremy Lefroy, MP |
| Form Of Engagement Activity | A formal working group, expert panel or dialogue |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Policymakers/politicians |
| Results and Impact | Telephone conversation with Jeremy Lefroy, MP (the MP for my home town, Stafford) following an email introduction by a family friend. Mr Lefroy was interested to learn more about snakebite, the work done at LSTM (where he sits on the board of trustees), and ways in which he may be able to help influence policy and raise awareness. The outcome of this conversation was that a meeting of the All Party Parliamentary Group for Malaria and NTDs would be convened to talk specifically about snakebite (date still pending). |
| Year(s) Of Engagement Activity | 2018 |
| Description | School Talk (Crosby, Liverpool) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | A 45 minute talk to around 40 pupils, designed to engage them in the issues regarding snakebite and highlight potential career pathways after A-level. Students were very engaged and asked many questions at the end regarding their own career ambitions, what a PhD involves, the experiences of doing scientific research and interests they had in herpetology/snakebite. The school send a thank you card after the event, saying how well received the talk was and how engaged the students were with the material. |
| Year(s) Of Engagement Activity | 2019 |
| Description | School Visit (Stafford) |
| Form Of Engagement Activity | A talk or presentation |
| Part Of Official Scheme? | No |
| Geographic Reach | Local |
| Primary Audience | Schools |
| Results and Impact | A presentation to approx. 30 A-level students at King Edward VI High School. Talk was designed to both raise awareness of the snakebite crisis and engage the students interesting in the potential of studying Biology/Life Sciences degrees at university, and what a career path towards research can involve. The session was well received by staff and students, with a discussion afterward ranging across university experiences, the day-to-day life as a PhD student and some of the key challenges facing snakebite research |
| Year(s) Of Engagement Activity | 2018,2019 |