Part 4 is focused on snake bite (SB) tissue necrosis. Starting minute 30':30
SNAKE BITE TISSUE NECROSIS:
SB tissue necrosis affects three times the people that die from SB at least, so in Sub-saharan Africa is estimated that hundred thousand people that survives SB are suffering conditions like this.
This is a nine years old girl bitten by a cobra in North-East Nigeria, the tissue was debrided, this keloid contracture developed that has completely malformed the fingers of her hand... two weeks ago we saw a virtually identical thing in Kenya so, it is happening all over the place. Amputations are not uncommon, estimations of 8.000 amputations are performed on SB victims every year in Africa Sub-Saharan Africa. There is no medicinal treatment, IgG that is effective against the lethal effect in systemic circulation is ineffective against this. It is a too large molecule to rapidly cross from the blood where is intravenously delivered to the tissues, to negate this type of progression of tissue destruction. Surgical debridement / amputation is the only recourse to deal with this. Therefore, there is a compelling and I think really urgent need for research to do something about it, to come with an alternative, and we are following a route through camelids using their unique immunology.
We all have, all our immunoglobulins are heavy and light chains, this are large, 150 kDa. Camels are unique in the animal kingdom, except for sharks, and that most of their IgG lacks light chains, if lacks that is a severe disease but in camels is not a problem at all. What is really interesting for us is that this moiety that binds the foreign protein, the VHH, is only 15 kDa, is one tenth the size of conventional IgG used to treat SB patients. So we figured, we considered that if we could make and AV consisting of this, then we might have something to work with. And we entered into collaboration with the Central Veterinarian Research Labs (CVRL) in Dubai, injecting animals, extracting the blood from venom immunized camels.
Don't worry about this (figures on the slide) I just wanted to emphasize that we put a lot of effort into this, it is a over of years of immunization and of the poly-specific immunized camels, I want you to focus on this, this one camel here, which is this fellow, and what we did is we extracted the IgG, the total IgG from this animal and we then purified out just the heavy chain, only IgG, and then fractionated the VHH using papain as well, and we compared this three camel IgG entities with the most effective AV in sub-saharan Africa which is the South African product, in their ability to neutralize the lethal, the hemorrhagic and the coagulopathic effects of the saw scaled viper. And bear in mind when you look at this figures that the more effective it is, the lower the amount needed. You will see that VHH gram per gram, microgram per microgram, five times more effective than total IgG and three times more effective than AV, that the best AV in Africa, due to neutralization of hemorrhage, due to neutralization of coagulopathy.
This is by far the more affective AV ever devised because it's got ten times the binding valency than any of the other AV, because is so small, it is only 15 kDa. And we were really keen because we think that 15 kDa it will have the same tissue distribution dynamics as the venom protein but, there is always a but, we had to resolve the problem of the very low yield of VHH from IgG, it is terrific, it is not commercially viable, and so what we are going to do is clone the genes from here, take this VHH from the camel B cells and make them as recombinant proteins.
The next thing we need to do is to make an only specific, this VHH, to those venom toxins that causes necrosis, many venom proteins don't, so we can make a toxin-specific exactly in the same way that we are doing in the systemic approach and then finally decided upon a delivery way, it is absolutely clear that you could not deliver a 15 kDa VHH into the blood circulation and expect it to last any length of time at all, it will be cleared in 20 minutes, so we need another system for delivery, something that overcomes but delivers the VHH direct to where is needed in the tissues.
Basically we are following a number of different routes to try and come out with better drugs
to treat snakebite (SB) because that is what we think is needed, it will improve demand, we are calling this the next generation SB therapy because someone told us that has the right ring to it to get the Welcome Trust attention...
Key points that I want to make here today are:
- Snakebite is an important, is a neglected disease of the rural poor in Africa and Asia
- We desperate need more accurate data on mortality, morbidity and socio-economic impact to understand the disease burden and to use that disease burden data to rise awareness amongst governments and IHAs so they actually recognize it as a deeply neglected tropical disease and is worth doing something about it.
- We know that current AV therapy can be effective but there is lots of problems with it. In terms of improvement, we certainly need better regulatory control and until new drugs, next generation of AV drugs come around.
- We need urgently the investment by governments and IHAs in the production and delivery of this conventional AV but in much large scales to stop the deaths. Snakebite death is completely preventable, give AV and stop those deaths.
- We need to establish regional training centers on the clinical management of SB. That is absolutely clear from our experience in Nigeria, is very very important because SB is a very specific and very complicated thing to treat. And...
- We need governments and IHAs to support the development and delivery of effective and affordable AV and finally, just a push for the scientist,
- We need more fundings for this new tools.
I just like to thank all the various people that had been involved in this project, within my own institute The Liverpool School of Tropical Medicine, Central Vet Labs in Dubai, the EchiTab study group in Nigeria and UK, the Kenya snakebite study group that we just started there and various fundings. Thank you very much.
ॐ लोकाः समस्ताः सुखिनो भवन्तु ॥
Om Lokah Samasthah Sukhino Bhavantu
May all beings everywhere be happy and peaceful.
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