ONE HEALTH VENTURES Presentation Nick Lewis New improved vaccine against epsilon toxin in animals and humans Seeking joint venture or licence arrangement One Health Ventures 1 Epsilon toxin pore (Source: Savva C. The pore structure of Clostridium perfringens epsilon tox (nature communications 2019))
What is epsilon toxin? • 5 biotypes of common bacteria Clostridium perfringens Epsilon toxin monomer (A,B,C,D and E). Type A is part of human microbiome • Epsilon toxin (ETX) is pore forming toxin produced by types B and D of C. perfringens. ETX causes of serious disease in livestock - enterotoxaemia • ETX now implicated as trigger for multiple sclerosis (MS) in humans • Recent evidence shows greater presence of ETX, antibodies to ETX and types B and D C. perfringens bacteria in MS patients compared to controls Heptameric pore One Health Ventures 2 Epsilon toxin pore (Source: Savva C. The pore structure of Clostridium perfringens epsilon tox (nature communications 2019))
Evidence of a role for Epsilon Toxin One Health Ventures 3 Epsilon toxin pore (Source: Savva C. The pore structure of Clostridium perfringens epsilon tox (nature communications 2019))
Epsilon toxin is known to be neurotoxic to animals and humans • Rodents dosed with ETX show bilateral lesions in brain • ETX breaches blood-brain barrier • ETX damages oligodendrocytes, which produce myelin sheaths for axons • ETX damages lymphocytes and human red blood cells • ETX causes aquaporin 4 up-regulation from astrocytes • Myelin and Lymphocyte Protein required for ETX Binding • Evidence of link to Multiple Sclerosis Finnie 1984 One Health Ventures 4 Epsilon toxin pore (Source: Savva C. The pore structure of Clostridium perfringens epsilon tox (nature communications 2019))
Antibodies to epsilon toxin in sera from MS patients detected using 2 different tests • Multiple Sclerosis 23% - 30% 35 MS 30 Control • Controls 8% -15% 30 25 23 % 20 15 15 10 8 5 0 Western blotting Pepscan S/N > 2 (combined study 1 & 2) One Health Ventures 5 Epsilon toxin pore (Source: Savva C. The pore structure of Clostridium perfringens epsilon tox (nature communications 2019))
Strains of C. perfringens producing epsilon toxin are found in the gut of MS patients 25% ECTRIMS Poster by S Haigh showing C perfringens grown 21% from faecal samples of MS 20% patients but not controls entitled: “Intestinal Colonization by Epsilon Toxin-producing 15% Clostridium perfringens Strains is Associated with Multiple Sclerosis” 10% C. perfringens (type B or D) cultured from 6 of 28 faecal 5% samples from MS patients and zero bacteria were cultured from 0% controls 0% MS group MS group control No. of c.28 c.20 samples One Health Ventures 6 Epsilon toxin pore (Source: Savva C. The pore structure of Clostridium perfringens epsilon tox (nature communications 2019))
Rationale for Veterinary ETX Vaccine Existing Vaccines • Formaldehyde-treated bacterial culture filtrates (toxoids) – production requires the growth of Clostridium perfringens – contain proteins in addition to the Etx toxoid – yield and immunogenicity of vaccine can be low & variable • typical immunisation regimens involve an initial course of two doses of vaccine, 2-6 weeks apart • sheep are boosted at 6-12 months • goats are boosted every 3-4 months – inflammatory responses • reduced feed consumption Proposed Vaccine • Genetically modified toxoid (Y30-Y196-A186) – Grown in E. Coli – Montanide adjuvant – Good results in Sheep, rabbits and mice Worldwide Market – > 1 billion sheep – > 800 million goats One Health Ventures 7 Epsilon toxin pore (Source: Savva C. The pore structure of Clostridium perfringens epsilon tox (nature communications 2019))
Rationale for Human ETX Vaccine No known cure for Multiple Sclerosis • Affects 2.5 million people worldwide • Cost of medication in West - $20,000 - $60,000 per annum, per person No human vaccine available against ETX • Vaccine Candidate developed by One Health Ventures • Genetically modified toxoid (Y30-Y196-A168) • Grown in E. coli • Non-toxic towards Human MAL • Non-toxic to Human Red Blood Cells • Needs Phase 1 Trial Next Steps • Pre-clinical programme and establishment of GMP leading to Phase 1 Trial • One Health Ventures is seeking a Licensee or Joint Venture Partner One Health Ventures 8 Epsilon toxin pore (Source: Savva C. The pore structure of Clostridium perfringens epsilon tox (nature communications 2019))
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