Agents for reversing toxic proteinopathies

Patent metadata

Field	Value
Publication number	US-11207278-B2
Application number	US-202117161431-A
Country	US
Kind code	B2
Filing date	Jan 28, 2021
Priority date	Jun 21, 2019
Publication date	Dec 28, 2021
Grant date	Dec 28, 2021

Abstract

The present disclosure relates to compositions and methods for the diagnosis and treatment or prevention of proteinopathies, particularly MUC1-associated kidney disease (ADTKD-MUC1 or MKD), Retinitis Pigmentosa (e.g., due to rhodopsin mutations), autosomal dominant tubulo-interstitial kidney disease due to UMOD mutation(s) (ADTKD-UMOD), and other forms of toxic proteinopathies resulting from mutant protein accumulation in the ER or other secretory pathway compartments and/or vesicles, among others. The disclosure also identifies and provides TMED9-binding agents as capable of treating or preventing proteinopathies of the secretory pathway, and further provides methods for identifying additional TMED9-binding agents.

First claim

We claim:

1. A method of treating MUC1-associated kidney disease in a subject, the method comprising administering to the subject 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane or a pharmaceutically acceptable salt thereof in an amount effective to treat MUC1-associated kidney disease, thereby treating MUC1-associated kidney disease in the subject.

2. The method of claim 1 , wherein the 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane is racemic (±) 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane.

3. The method of claim 1 , wherein the 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane is (+) 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane.

4. The method of claim 1 , wherein the 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane is (−) 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane.

5. The method of claim 1 , wherein the 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane is a hydrochloride salt of 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane.

6. A method for selecting a composition comprising 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane for administration to a subject for treating MUC1-associated kidney disease in the subject, the method comprising:
(a) identifying the subject as having MUC1-associated kidney disease; and
(b) selecting a composition comprising 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane for administration to the subject in an amount effective to treat MUC1-associated kidney disease,
thereby selecting the composition comprising 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane for administration to the subject for treating MUC1-associated kidney disease in the subject.

7. The method of claim 6 , wherein step (a) comprises identifying the presence in the subject of a mutation in MUC1.

8. The method of claim 6 , wherein the subject has one or more of the following: end-stage renal disease, urinalysis revealing minimal protein and no blood, slowly progressive kidney failure, hyperglycemia and/or gout.

9. The method of claim 6 , wherein the subject has been identified to be in need of dialysis or kidney transplantation.

10. The method of claim 6 , wherein step (a) comprises identifying the presence in the subject of a MUC1 frameshift mutation.

11. The method of claim 6 , further comprising: (c) administering the selected 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane to the subject.

12. The method of claim 6 , wherein identifying step (a) comprises use of a kit consisting essentially of (i) an oligonucleotide for detection of a MUC1 frameshift mutant or (ii) an antibody capable of binding a MUC1 frameshift mutant protein, and instructions for its use.

13. The method of claim 6 , wherein the subject is human.

14. A method for treating MUC1-associated kidney disease in a subject, the method comprising:
identifying a subject as having MUC1-associated kidney disease; and
administering 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane or a pharmaceutically acceptable salt thereof, to the subject in an amount effective to cause reduction or improvement of a symptom of MUC1-associated kidney disease in the subject,
thereby treating MUC1-associated kidney disease in the subject.

15. The method of claim 14 , wherein said compound causes release of MUC1, from an early secretory compartment.

16. The method of claim 14 , wherein the subject has a mutation in MUC1.

17. The method of claim 14 , wherein the symptom of MUC1-associated kidney disease is selected from the group consisting of slowly progressive tubulointerstitial disease, end-stage renal disease, and a need for dialysis or kidney transplantation.

18. The method of claim 14 , wherein the subject has a MUC1 frameshift mutation.

19. The method of claim 14 , wherein the 2 endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane or a pharmaceutically acceptable salt thereof is administered to the subject via the oral route.

20. The method of claim 14 , wherein the 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane or pharmaceutically acceptable salt thereof comprises a pharmaceutically-acceptable carrier or excipient.

Assignees

• Broad Inst Inc
• Brigham & Womens Hospital Inc
• Dana Farber Cancer Inst Inc
• Inst Carlos Slim De La Salud A C
• Brigham & Womens Hospital Inc

Inventors

• Greka Anna
• Dvela-Levitt Moran
• Alimova Maria
• Lander Eric
• Golub Todd R
• Wagner Florence
• Chamberlain Brian
• Padovano Valeria
• Growney Joseph

Classifications

• G01N33/6893

  related to diseases not provided for elsewhere · CPC title

• G01N33/502 Primary

  for testing non-proliferative effects · CPC title

• A61K31/13 Primary

  Amines {(A61K31/04 takes precedence)} · CPC title

• A61P13/12

  of the kidneys · CPC title

• C12Q1/6883

  for diseases caused by alterations of genetic material · CPC title