2′F-ANA-LET7 mediated utrophin upregulation for DMD therapy

Patent metadata

Field	Value
Publication number	US-12104152-B2
Application number	US-201916982467-A
Country	US
Kind code	B2
Filing date	Mar 18, 2019
Priority date	Mar 19, 2018
Publication date	Oct 1, 2024
Grant date	Oct 1, 2024

Abstract

The invention relates to compositions and methods for enhancing or upregulating utrophin protein production and methods for treating myopathies, such as Duchenne Muscular Dystrophy (DMD). Specifically, the invention relates to compositions, such as oligonucleotides, and methods for enhancing or upregulating utrophin in a subject by blocking binding of let-7c miRNA to the utrophin mRNA 3 untranslated region (UTR).

First claim

The invention claimed is:

1. An oligonucleotide comprising one or more arabinonucleotides, wherein the oligonucleotide specifically hybridizes to a Let-7c microRNA binding sequence in a utrophin mRNA 3′ untranslated region (UTR) and inhibits the binding of the Let-7c microRNA to the utrophin mRNA 3′-UTR, wherein said Let-7c microRNA binding sequence is SEQ ID NO:62, and the oligonucleotide comprises a nucleic acid sequence that is complementary to a contiguous sequence of at least 20 nucleotides of SEQ ID NO:62, wherein the oligonucleotide has a nucleic acid sequence set forth in SEQ ID NOs:64-75.

2. The oligonucleotide of claim 1 wherein the oligonucleotide comprises alternating segments or units of arabinonucleotides and 2′-deoxynucleotides, wherein the segments or units each independently comprise at least one arabinonucleotide or 2′deoxynucleotide.

3. The oligonucleotide of claim 1 , wherein a heteroduplex formed by the oligonucleotide and the binding sequence is resistant to cleavage by RNase H.

4. The oligonucleotide of claim 1 , wherein the arabinonucleotides are 2′-deoxy-2′-fluoro-P-D-arabinonucleoside.

5. The oligonucleotide of claim 1 , wherein the oligonucleotide comprises one or more phosphorothioate internucleotide linkages.

6. A pharmaceutical composition comprising the oligonucleotide of claim 1 and at least one pharmaceutically acceptable excipient.

7. A method for enhancing utrophin production in a subject, the method comprising: administering to the subject an effective amount of the oligonucleotide according to claim 1 .

8. A method of treating Duchenne Muscular Dystrophy (DMD) in a human subject, the method comprising: administering to the subject an effective amount of an oligonucleotide according to claim 1 .

9. The method of claim 8 , wherein the oligonucleotide comprises alternating segments or units of arabinonucleotides and 2′-deoxynucleotides, wherein the segments or units each independently comprise at least one arabinonucleotide or 2′-deoxynucleotide.

10. The method of claim 8 , wherein a heteroduplex formed by the oligonucleotide and the binding sequence is resistant to cleavage by RNase H.

11. The method of claim 8 , wherein the arabinonucleotides are 2′-deoxy-2′fluoro-P-D-arabinonucleoside.

12. The method of claim 8 , wherein the oligonucleotide comprises one or more phosphorothioate internucleotide linkages.

13. The method of claim 8 , wherein the oligonucleotide has a nucleic acid sequence set forth in SEQ ID NOs: 26-55 and 64-75.

14. The method of claim 8 , wherein the oligonucleotide is between 20 and 32 nucleotides long.

15. The method of claim 8 , wherein the oligonucleotide is administered systemically or wherein administration of the oligonucleotide is gymnotic.

Assignees

• Univ Pennsylvania
• Aum Lifetech Inc

Inventors

• Khurana Tejvir S
• Mishra Manoj Kumar
• Aishwarya Veenu

Classifications

• A61P21/00

  Drugs for disorders of the muscular or neuromuscular system · CPC title

• A61K31/712

  Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose · CPC title

• C12N2320/30

  Special therapeutic applications · CPC title

• C12N2310/323

  modified ring structure · CPC title

• C12N2310/315

  Phosphorothioates · CPC title