Methods and compositions for inhibiting detoxification response

Patent metadata

Field	Value
Publication number	US-12065648-B2
Application number	US-202117208504-A
Country	US
Kind code	B2
Filing date	Mar 22, 2021
Priority date	Aug 27, 2015
Publication date	Aug 20, 2024
Grant date	Aug 20, 2024

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 administering a pharmaceutical compound that induces a detoxification response in a subject in need of treatment by said pharmaceutical compound, the method comprising:
co-administering to the subject (1) said pharmaceutical compound and (2) an inhibitor of expression of a daf-22 gene or its human homolog, SCPx,
wherein administering the pharmaceutical compound with the inhibitor increases the bioavailability of the pharmaceutical compound as compared to the bioavailability of the pharmaceutical compound when administered without the inhibitor.

2. The method of claim 1 , wherein said inhibitor is present in an amount sufficient to increase the bioavailability of said pharmaceutical compound compared to the bioavailability of said pharmaceutical compound in the absence of said inhibitor.

3. The method of claim 2 , wherein bioavailability of the pharmaceutical compound in the presence of the inhibitor is greater than bioavailability of the compound in the absence of the inhibitor by at least 10% of the difference between bioavailability in the absence of the inhibitor and complete bioavailability.

4. The method of claim 2 , wherein bioavailability of the pharmaceutical compound in the presence of the inhibitor is greater than bioavailability of the compound in the absence of the inhibitor by at least 50% of the difference between bioavailability in the absence of the inhibitor and complete bioavailability.

5. The method of claim 2 , wherein bioavailability of the pharmaceutical compound in the presence of the inhibitor is greater than bioavailability of the compound in the absence of the inhibitor by at least 75% of the difference between bioavailability in the absence of the inhibitor and complete oral bioavailability.

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

7. The method of claim 1 , wherein the subject is a mammal.

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

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

10. The method of claim 9 , 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.

11. The method of claim 9 , wherein the pharmaceutical compound induced the translation defect in the subject.

12. The method of claim 11 , wherein said pharmaceutical compound is G418 or hygromycin.

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

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

15. The method of claim 14 , wherein the xenobiotic is selected from the group consisting of: a toxin, a drug, and a pathogenic microorganism.

16. The method of claim 1 , wherein the subject is not exposed to a xenobiotic and has a translation defect.

17. The method of claim 6 , wherein the microorganism is Kocuria rhizophila or homolog thereof.

18. The method of claim 1 , wherein the inhibitor is formulated for oral administration.

Assignees

• Massachusetts Gen Hospital

Inventors

• Ruvkun Gary
• Govindan J Amaranath

Classifications

• C12N2320/31

  Combination therapy · CPC title

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/702

  Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages · CPC title

• A61P39/00

  General protective or antinoxious agents · CPC title

• C12N2310/11

  Antisense · CPC title