Methods and compositions for inhibiting detoxification response

Patent metadata

Field	Value
Publication number	US-10988765-B2
Application number	US-201615755777-A
Country	US
Kind code	B2
Filing date	Aug 29, 2016
Priority date	Aug 27, 2015
Publication date	Apr 27, 2021
Grant date	Apr 27, 2021

Abstract

Disclosed herein are compositions and methods for attenuating detoxification response and related symptoms thereof induced by translation defect. The compositions and methods herein are useful for attenuating detoxification response and/or treat related symptoms thereof in subjects comprising translation defect. The composition and methods herein are also useful for improving pharmacokinetics of a pharmaceutical compound.

First claim

What is claimed is:

1. A method of attenuating a detoxification response and/or treating related symptoms in a subject in need of such treatment, the method comprising administering an inhibitor of expression of a daf-22 gene or its human homolog, SCPx.

2. The method of claim 1 , wherein the step of comprises administering the inhibitor in an amount sufficient to inhibit expression of the daf-22 gene or its human homolog, SCPx.

3. The method of claim 1 , wherein the related symptoms are selected from the group consisting of: nausea, headaches, fatigue, anorexia nervosa, migraine, depression, vomiting or bowel disturbances, constipation, and diarrhea.

4. The method of claim 1 , wherein the inhibitor comprises a small molecule, siRNA, shRNA, double-stranded RNA, micro-RNA, aptamers, morpholinos, single-stranded oligonucleotides, or antisense oligonucleotide.

5. The method of claim 1 , wherein the subject is a human.

6. The method of claim 1 , wherein the subject has a translation defect.

7. The method of claim 1 , wherein the subject is exposed to a xenobiotic, wherein the xenobiotic causes a translation defect.

8. The method of claim 7 , wherein the xenobiotic is selected from the group consisting of: a toxin, a drug, and a pathogenic microorganism.

9. The method of claim 6 , wherein the subject is not exposed to a xenobiotic and has a translation defect.

10. The method of claim 6 , wherein the translation defect is caused by a germline mutation, wherein the germline mutation is in a gene expressing a translation component.

11. The method of claim 1 , wherein the subject has ribosomopathy.

12. A method of reducing toxicity of a pharmaceutical compound in a subject, the method comprising:
co-administering to the subject, (1) said pharmaceutical compound, and (2) an effective amount of an inhibitor of expression of a daf-22 gene or its human homolog, SCPx, wherein the toxicity of the pharmaceutical compound is reduced in the presence of the inhibitor compared to the toxicity of the pharmaceutical compound administered in the absence of the inhibitor.

13. The method of claim 12 , wherein the toxicity of the pharmaceutical compound in the presence of the inhibitor is at least 10% lower than the toxicity of the pharmaceutical compound in the absence of the inhibitor.

14. A method of increasing efficacy of a pharmaceutical compound in a subject, the method comprising:
co-administering to the subject, (1) said pharmaceutical compound, and (2) an effective amount of an inhibitor of expression of a daf-22 gene or its homolog SCPx thereof, wherein the efficacy of said pharmaceutical compound is increased in the presence of the inhibitor compared to the efficacy of said pharmaceutical compound in the absence of said inhibitor.

15. The method of claim 14 , wherein efficacy of the pharmaceutical compound in the presence of the inhibitor is greater than efficacy of the pharmaceutical compound in the absence of the inhibitor by at least 10%.

16. The method of claim 14 , wherein the subject is a human.

17. The method of claim 14 , wherein the subject has a translation defect.

18. The method of claim 17 , wherein the translation defect is caused by a germline mutation in the subject, wherein the germline mutation is in a gene expressing a translation component.

19. The method of claim 17 , wherein the pharmaceutical compound induced the translation defect in the subject.

20. The method of claim 19 , wherein said pharmaceutical compound is G418 or hygromycin.

Assignees

• Massachusetts Gen Hospital

Inventors

• Ruvkun Gary
• Govindan J Amaranath

Classifications

• C12N2310/3233

  Morpholino-type ring · CPC title

• C12N2310/531

  Stem-loop; Hairpin · CPC title

• C12N2310/141

  MicroRNAs, miRNAs · CPC title

• C12N2310/11

  Antisense · CPC title

• C12N2320/30

  Special therapeutic applications · CPC title