Antihelminthic medications for pathogenic nematodes

Patent metadata

Field	Value
Publication number	US-10729690-B2
Application number	US-201716069399-A
Country	US
Kind code	B2
Filing date	Jan 12, 2017
Priority date	Jan 13, 2016
Publication date	Aug 4, 2020
Grant date	Aug 4, 2020

Abstract

Inappropriate activation of innate immune responses in nematode intestinal epithelial cells underlies the pathophysiology of some inflammatory disorders. Immunostimulatory xenobiotics are known to protect nematodes from bacterial infection (e.g., Pseudomonas aeruginosa ). Conversely, these same xenobiotics are toxic to uninfected nematodes. These xenobiotics were subjected to a forward genetic screen in uninfected nematodes to identify nematode mutants that were resistant to the deleterious effects of these xenobiotics. These resistant nematode strains contained hypomorphic mutations in each of the known components of the p38 MAP kinase cassette (tir-1, nsy-1, sek-1 and pmk-1), demonstrating that hyperstimulation of p38 MAPK innate immune responses may be responsible for the induced toxicity. A second genetic screen using dominant activators of the p38 MAPK pathway identified a single allele that had a gain-of-function (gf) mutation in nsy-1, the MAP kinase kinase kinase that acts upstream of p38 MAPK pmk-1.

First claim

I claim:

1. A method, comprising:
a) providing:
i) a patient exhibiting at least one nematode infection symptom;
ii) a nematode comprising a p38 mitogen activated protein kinase immune response pathway, wherein said nematode lacks a toxic bacterial infection;
and

iii) a p38 mitogen activated protein kinase immune response pathway inducer selected from the group consisting of an RPW-24 compound, RPW-24 structural analogs and a cell surface G protein-coupled receptor RNAi molecule;

b) administering said inducer to said patient; and
c) reducing said at least one nematode infection symptom.

2. The method of claim 1 , wherein said cell surface G protein-coupled receptor RNAi molecule targets a gene selected from the group consisting of orln, nsy, pmk, tir, sek and vhp.

3. The method of claim 1 , wherein said p38 mitogen activated protein kinase immune response pathway activates an immune response.

4. The method of claim 1 , wherein said p38 mitogen activated protein kinase immune response pathway inducer has specific affinity for a cell surface G protein-coupled receptor.

5. The method of claim 4 , wherein said cell surface G protein-coupled receptor is an OLRN-1 receptor.

6. The method of claim 1 , wherein said nematode is an adult nematode.

7. The method of claim 1 , wherein said nematode is selected from the group consisting of C. elegans, Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale, Trichuris trichiura, Sirongyloides stercoralis, Onchocera, Wucheria bancrofti and Loa loa.

8. A method, comprising:
a) providing:
i) a patient comprising a plurality of nematodes, wherein said plurality of nematodes comprise a p38 mitogen activated protein kinase immune response pathway and lacks a toxic bacterial infection; and
ii) a p38 mitogen activated protein kinase immune response pathway inducer selected from the group consisting of an RPW-24 compound, RPW-24 structural analogs and a cell surface G protein-coupled receptor RNAi molecule;

b) administering said inducer to said patient;
c) hyperactivating said p38 mitogen activated protein kinase immune response pathway; and
d) killing at least a portion of said nematodes.

9. The method of claim 8 , wherein said p38 mitogen activated protein kinase immune response pathway activates an immune response.

10. The method of claim 8 , wherein said p38 mitogen activated protein kinase immune response pathway inducer has specific affinity for a cell surface G protein-coupled receptor.

11. The method of claim 10 , wherein said cell surface G protein-coupled receptor is an OLRN-1 receptor.

12. The method of claim 8 , wherein said cell surface G protein-coupled receptor RNAi molecule targets a gene selected from the group consisting of orln, nsy, pmk, tir, sek and vhp.

13. The method of claim 8 , wherein said hyperactivating produces a nematode-toxic immune response.

14. The method of claim 8 , wherein said method further comprises inducing a nematode endoplasmic reticulum unfolded protein response following administration of the p38 pathway inducer.

15. The method of claim 8 , wherein said nematode is an adult nematode.

16. The method of claim 8 , wherein said nematode is selected from the group consisting of C. elegans, Ascaris lumbricoides, Necator americanus, Ancylostoma duodenale, Trichuris trichiura, Strongyloides stercoralis, Onchocera, Wucheria bancrofti and Loa loa.

Assignees

• Univ Massachusetts

Inventors

• Pukkila-Worley Read

Classifications

• A01K67/64

  Genetically modified nematodes · CPC title

• A01K2217/03

  Animals modified by random mutagenesis, e.g. using ENU, chemicals · CPC title

• C12N15/1137

  against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138) · CPC title

• C12Y207/11001

  Non-specific serine/threonine protein kinase (2.7.11.1), i.e. casein kinase or checkpoint kinase · CPC title

• A01K2207/05

  Animals modified by non-integrating nucleic acids, e.g. antisense, RNAi, morpholino, episomal vector, for non-therapeutic purpose · CPC title