Granted Patent
B2
US 12,364,707 · App. 17/159,288 · Granted Jul 22, 2025
Manipulation of eIF3 to modulate repeat associated non-ATG (RAN) translation
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Abstract
Methods and compositions for modulating repeat non-ATG protein (RAN protein) translation are provided. In some aspects, the disclosure relates to methods for treating a subject having a disease associated with RAN protein translation by administering the subject a modulator of eIF3 or an eIF3 subunit, or an antibody that bind to a RAN protein.
Claims (21)
1. A method of modulating repeat-associated non-ATG protein (RAN protein) translation, the method comprising contacting a cell expressing a RAN protein with an effective amount of a selective modulator of eukaryotic initiation factor 3 subunit f (eIF3f),
wherein the selective modulator of eIF3f is a protein, a small molecule, or an inhibitory nucleic acid selected from the group consisting of dsRNA, siRNA, shRNA, miRNA, artificial miRNA (amiRNA), and an antisense oligonucleotide (ASO).
2. The method of claim 1 , wherein the selective modulator of eIF3f directly or indirectly inhibits a gene encoding eIF3f (eIF3F) and/or reduces expression of eIF3f.
3. The method of claim 1 , further comprising contacting the cell with a selective modulator of eukaryotic initiation factor 3 subunit m (eIF3m).
4. The method of claim 3 , wherein the selective modulator of eIF3m directly or indirectly inhibits a gene encoding eIF3m (eIF3M) and/or reduces expression of eIF3m.
5. The method of claim 1 , wherein the cell is located in a subject, optionally wherein the cell is located in the brain of the subject.
6. The method of claim 1 , wherein the RAN protein is a poly-Alanine, poly-Leucine, poly-Serine, poly-Cysteine, poly-Glutamine, poly-Leu-Pro-Ala-Cys (SEQ ID NO: 6), poly-Gln-Ala-Gly-Arg (SEQ ID NO: 5), poly-Gly-Pro, poly-Gly-Arg, poly-Gly-Ala, poly-Pro-Ala, or poly-Pro-Arg.
7. The method of claim 1 , wherein the RAN protein is not poly-Glutamine.
8. The method of claim 1 , wherein the RAN protein is encoded by a gene associated with Huntington's disease (HD, HDL2), Fragile X Tremor Ataxia Syndrome (FXTAS), Spinal Bulbar Muscular Atrophy (SBMA), Dentatorubropallidoluysian Atrophy (DRPLA), Spinocerebellar Ataxia 1 (SCA1), Spinocerebellar Ataxia 2 (SCA2), Spinocerebellar Ataxia 3 (SCA3), Spinocerebellar Ataxia 6 (SCA6), Spinocerebellar Ataxia 7 (SCA7), Spinocerebellar Ataxia 8 (SCA8), Spinocerebellar Ataxia 12 (SCA12), or Spinocerebellar Ataxia 17 (SCA17), amyotrophic lateral sclerosis (ALS), Spinocerebellar ataxia type 36 (SCA36), Spinocerebellar ataxia type 29 (SCA29), Spinocerebellar ataxia type 10 (SCA10), myotonic dystrophy type 1 (DM1), myotonic dystrophy type 2 (DM2), or Fuchs' Corneal Dystrophy (CTG181).
9. The method of claim 1 , wherein the RAN protein is a poly-Alanine, poly-Leucine, poly-Serine, poly-Cysteine, or poly-Glutamine.
10. The method of claim 1 , wherein the RAN protein is encoded by a gene comprising CAG, CAGG, GGGGCC, or CCTG expansion repeats.
11. The method of claim 1 , wherein the selective modulator of eIF3f is an siRNA.
12. The method of claim 1 , wherein the selective modulator of eIF3f is an shRNA.
13. The method of claim 3 , wherein the selective modulator of eIF3m is an inhibitory nucleic acid selected from the group consisting of dsRNA, siRNA, shRNA, miRNA, artificial miRNA (amiRNA), and an antisense oligonucleotide (ASO).
14. The method of claim 13 , wherein the selective modulator of eIF3m is an siRNA or an shRNA.
15. The method of claim 1 , wherein the method further comprises contacting the cell with an additional therapeutic agent for a disease associated with RAN protein translation.
16. The method of claim 15 , wherein the additional therapeutic agent is an antibody.
17. The method of claim 16 , wherein the antibody binds specifically to a RAN repeat expansion.
18. The method of claim 16 , wherein the antibody binds specifically to a unique region of a RAN protein that is C-terminal to the repeat expansion.
19. The method of claim 5 , wherein the subject has a disease associated with RAN protein translation.
20. The method of claim 19 , wherein the disease is Huntington's disease (HD, HDL2), Fragile X Tremor Ataxia Syndrome (FXTAS), Spinal Bulbar Muscular Atrophy (SBMA), Dentatorubropallidoluysian Atrophy (DRPLA), Spinocerebellar Ataxia 1 (SCA1), Spinocerebellar Ataxia 2 (SCA2), Spinocerebellar Ataxia 3 (SCA3), Spinocerebellar Ataxia 6 (SCA6), Spinocerebellar Ataxia 7 (SCA7), Spinocerebellar Ataxia 8 (SCA8), Spinocerebellar Ataxia 12 (SCA12), or Spinocerebellar Ataxia 17 (SCA17), amyotrophic lateral sclerosis (ALS), Spinocerebellar ataxia type 36 (SCA36), Spinocerebellar ataxia type 29 (SCA29), Spinocerebellar ataxia type 10 (SCA10), myotonic dystrophy type 1 (DM1), myotonic dystrophy type 2 (DM2), or Fuchs' Corneal Dystrophy (CTG181).
Assignments (2)
CONFIRMATORY LICENSE
Recorded Nov 2, 2023
From: UNIVERSITY OF FLORIDA
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 065431/0132 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded May 2, 2021
From: RANUM, LAURA; AYHAN, FATMA; ZU, TAO
To: UNIVERSITY OF FLORIDA RESEARCH FOUNDATION, INCORPORATED
Reel/Frame 056108/0435 →
Continuity (3)
Division
16091444
Provisional Application
62318200
· Apr 4, 2016
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