Development of a novel therapeutic to treat snakebite induced necrosis in sub-Saharan Africa

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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.