ONE HEALTH VENTURES Presentation Nick Lewis New improved vaccine - - PowerPoint PPT Presentation

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One Health Ventures Epsilon toxin pore (Source: Savva C. The pore structure of Clostridium perfringens epsilon tox (nature communications 2019))

ONE HEALTH VENTURES Presentation Nick Lewis New improved vaccine against epsilon toxin in animals and humans Seeking joint venture or licence arrangement

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One Health Ventures 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

(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 Epsilon toxin monomer Heptameric pore

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One Health Ventures Epsilon toxin pore (Source: Savva C. The pore structure of Clostridium perfringens epsilon tox (nature communications 2019))

Evidence of a role for Epsilon Toxin

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One Health Ventures 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

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One Health Ventures 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%
• Controls 8% -15%

23 30 8 15 5 10 15 20 25 30 35 Western blotting Pepscan S/N > 2 (combined study 1 & 2) MS Control

%

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One Health Ventures Epsilon toxin pore (Source: Savva C. The pore structure of Clostridium perfringens epsilon tox (nature communications 2019))

21% 0% 0% 5% 10% 15% 20% 25% MS group MS group control

ECTRIMS Poster by S Haigh showing C perfringens grown from faecal samples of MS patients but not controls entitled: “Intestinal Colonization by Epsilon Toxin-producing Clostridium perfringens Strains is Associated with Multiple Sclerosis”

• C. perfringens (type B or D)

cultured from 6 of 28 faecal samples from MS patients and zero bacteria were cultured from controls

• No. of

samples c.28 c.20

Strains of C. perfringens producing epsilon toxin are found in the gut of MS patients

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One Health Ventures 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

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One Health Ventures 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