Novel bacterial Cry proteins for treating parasitic nematodes in humans and animals

Gastrointestinal nematode (GIN) infections are a significant issue, particularly in animals that graze. They can have a severe impact on cattle health. GIN primarily affect the host animal's nutritional status by causing tissue lesions, inducing inflammatory reactions, or by feeding directly on the animal's blood. Helminth infections are predicted to cost the European ruminant livestock industry € 1.8 billion annually. They represent a significant health cost to dairy farmers, ranking second only to mastitis.

Challenge

Current treatments rely on the use of chemotherapeutics, usually one of three main classes of anthelmintics: benzimidazoles (such as albendazole and mebendazole), macrocyclic lactones (such as ivermectin) or nicotinic cholinergics (such as levamisole). There are no effective vaccines available. Resistance to these anthelmintics is common in animals and humans. Because of the limited number of anthelmintics available and concerns about resistance, it's important to look for new classes of anthelmintics with different modes of action.

Our Solution

The Bacillus thuringiensis (Bt) crystal proteins (Cry) represent a promising new class of anthelmintic agents with significant potential for commercialisation. The Cry proteins are highly effective in forming pores in the intestines of insect pests, and have been successfully deployed for insect control in agriculture for nearly 30 years. Their high degree of specificity, targeting only invertebrates, ensures their safety for use in vertebrates, including humans, even at high concentrations. A subgroup of Bt Cry proteins has been identified as being effective at targeting free-living and parasitic nematodes. We are pleased to introduce novel and highly potent Cry proteins, which offer excellent anthelmintic properties for potential therapy against nematodes.

Advantages

• New anthelmintic sequences (new Cry proteins) detected using deep data mining techniques (IDOPS).
• Successful validation of new Cry proteins for use against veterinary GIN parasites, e.g:
  • Haemonchus contortus (blood-feeding parasite of sheep),
  • Cyathostomins (common parasites of horses),
  • Ascaris suum (common roundworm of pigs, a very close relative (if not the same) of the human roundworm A. lumbricoides).
• Simple production and formulation using the scalable, shelf-stable, and cost-efficient IBaCC (inactivated bacteria with cytosolic crystals), a novel paraprobiotic system.
• An environmentally friendly way of treating GIN infections using Cry proteins.

Applications

New anthelmintic treatment for animals and humans.

Development Status

A wide range of in vitro and in vivo tests have been successfully carried out on a laboratory scale. Below are examples for pig intestinal parasites:

The roundworm Ascaris suum is a highly prevalent intestinal parasite of pigs worldwide. While infection can have low to moderate pathogenic effects on health, the effects on productivity cannot be ignored. A. suum can negatively impact FCE by up to 13% and reduce ADG by up to 10% (FCE: Feed Conversion Efficiency, ADG: Average Daily Gain). Furthermore, there are indirect effects on susceptibility or pathogenicity to bacterial or viral infections.

Fig. 1 shows that CryH1 (left) as well as CryH13 (right) IBaCC lysate significantly reduced motility of A. suum L4 stage (adult) worms in vitro (source: US 63/649,526).

 Fig. 2 shows that in vivo treatment with two oral doses of CryH1 (left) or CryH13 (right) IBaCC lysate significantly reduced the intestinal worm burdens of A. suum in infected mice (source: US 63/649,526).

Fig. 3 shows efficacy & Cry5Ba resistance overcome of CryH13 IBaCC against C. elegans L4 stage (EVC = empty vector control; N2 = wild-type C. elegans, bre-5(ye17) = Cry5Ba-resistant C. elegans). CryH13 readily overcomes resistant to Cry5Ba, indicating that it must use to some extent a different receptor than the bre-5-associated Cry5Ba glycosphingolipid receptor (source: US 63/649,526). 

Patent Status

A priority patent application has been filed (applicants: Georg August University of Göttingen public law foundation, University of Massachusetts Chan Medical School).

References

Diaz-Valerio et al.: IDOPS, a Profile HMM-Based Tool to Detect Pesticidal Sequences and Compare Their Genetic Context. Front. Microbiol. 2021, 12:664476. doi: 10.3389/fmicb.2021.664476.

Urban et al.: An inactivated bacterium (paraprobiotic) expressing Bacillus thuringiensis Cry5B as a therapeutic for Ascaris and Parascaris spp. infections in large animals. One Health 2021, 12:100241. doi: 10.1016/j.onehlt.2021.100241.

Li et al: Recombinant Paraprobiotics as a New Paradigm for Treating Gastrointestinal Nematode Parasites of Humans. Antimicrob. Agents Chemother. 2021, 65(3):e01469-20. doi: 10.1128/AAC.01469-20.

Hoang et al.: Bacillus thuringiensis Cry14A family proteins as novel anthelmintics against gastrointestinal nematode parasites. PLOS Neglected Tropical Diseases, 2024, accepted for publication.

Contact

Dr. Stefan Uhle
Patent & Innovation Manager Life Science
E-Mail: This email address is being protected from spambots. You need JavaScript enabled to view it.
Tel: +49 551 30724 154
Reference: BioC-2436-SUG

Tags: Therapy, Life science