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CN-122029280-A - Oligonucleotide with glycol modification

CN122029280ACN 122029280 ACN122029280 ACN 122029280ACN-122029280-A

Abstract

The present disclosure relates to compositions, systems, and methods comprising ethylene glycol chemical modifications to oligonucleotides to modulate silencing activity and improve stability.

Inventors

  • Anastasia Hervorova
  • Vignash Narayan Harihalan
  • Raymond Vogel
  • Catherine Gross
  • Daniel. O'Reilly

Assignees

  • 马萨诸塞大学

Dates

Publication Date
20260512
Application Date
20241017
Priority Date
20231018

Claims (20)

  1. 1. An RNA molecule comprising a 5 'end and a 3' end, wherein the RNA molecule comprises at least one ethylene glycol modification to one or both of the 5 'end and the 3' end, wherein the at least one ethylene glycol modification comprises 1-20 ethylene glycol units.
  2. 2. The RNA molecule of claim 1, wherein the at least one ethylene glycol modification comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ethylene glycol units.
  3. 3. The RNA molecule of claim 1 or 2, wherein the RNA molecule comprises 2-5 ethylene glycol modifications.
  4. 4. The RNA molecule of claim 3, wherein the RNA molecule comprises 2 ethylene glycol modifications.
  5. 5. The RNA molecule of claim 3, wherein the RNA molecule comprises 3 ethylene glycol modifications.
  6. 6. The RNA molecule of claim 3, wherein the RNA molecule comprises 4 ethylene glycol modifications.
  7. 7. The RNA molecule of claim 3, wherein the RNA molecule comprises 5 ethylene glycol modifications.
  8. 8. The RNA molecule of any one of claims 1-7, wherein the at least one ethylene glycol modification is positioned between two adjacent nucleotides.
  9. 9. The RNA molecule of any one of claims 1-8, wherein the at least one ethylene glycol modification does not replace a nucleotide at the position within the RNA molecule relative to an RNA molecule that does not contain the at least one ethylene glycol modification at the same position within the RNA molecule.
  10. 10. The RNA molecule of any one of claims 1-9, wherein the at least one ethylene glycol modification replaces a nucleotide at the position within the RNA molecule relative to an RNA molecule that does not contain the at least one ethylene glycol modification at the same position within the RNA molecule.
  11. 11. The RNA molecule of any one of claims 1-10, wherein the RNA molecule further comprises at least one alkyl modification to one or both of the 5 'end and the 3' end.
  12. 12. The RNA molecule of claim 11, wherein the at least one alkyl modification comprises a C 1 -C 10 alkyl group.
  13. 13. The RNA molecule of claim 11 or 12, wherein the at least one alkyl modification comprises a C 4 alkyl group.
  14. 14. The RNA molecule of any one of claims 11-13, wherein the RNA molecule comprises 2-5 alkyl modifications.
  15. 15. The RNA molecule of claim 14, wherein the RNA molecule comprises 2 alkyl modifications.
  16. 16. The RNA molecule of claim 14, wherein the RNA molecule comprises 3 alkyl modifications.
  17. 17. The RNA molecule of claim 14, wherein the RNA molecule comprises 4 alkyl modifications.
  18. 18. The RNA molecule of claim 14, wherein the RNA molecule comprises 5 alkyl modifications.
  19. 19. The RNA molecule of any one of claims 11-18, wherein the at least one alkyl modification is positioned between two adjacent nucleotides.
  20. 20. The RNA molecule of any one of claims 11-19, wherein the at least one alkyl modification does not replace a nucleotide at the position within the RNA molecule relative to an RNA molecule that does not contain the at least one alkyl modification at the same position within the RNA molecule.

Description

Oligonucleotide with glycol modification Cross Reference to Related Applications The present application claims the benefit of U.S. provisional patent application Ser. No. 63/591,271, filed 10/18 of 2023. The entire contents of the above-mentioned patent application are incorporated herein by reference in their entirety. Technical Field The present disclosure relates to the use of ethylene glycol chemical modifications to modified oligonucleotides to modulate silencing activity and improve stability. Background Chemically modified siRNA is at the forefront of oligonucleotide therapeutics. Exemplary chemical modifications include, for example, but are not limited to, 2 'fluoro RNA (2' frna), 2 '-O-methyl RNA (2' ome RNA), phosphorothioates, vinylphosphonate modifications, alkyl modifications, locked Nucleic Acid (LNA) modifications, unlocked Nucleic Acid (UNA) modifications, 2 '-O-methoxy-ethyl (2' -MOE) modifications, and DNA modifications, and these modifications may enhance the efficacy, stability, and duration of treatment of the oligonucleotide. However, existing modification modes may result in non-silencing or excessive silencing of the target mRNA. Excessive silencing of the target may result in unwanted side effects, while insufficient silencing of the target may result in no therapeutic benefit. Existing modification modes may also hinder long-term in vivo silencing of mRNA by reducing the period of time that the therapeutic oligonucleotide remains active. Thus, there is a need in the art for optimized chemical modifications to oligonucleotides to modulate silencing activity and improve stability. Disclosure of Invention Provided herein are modified oligonucleotides with ethylene glycol chemical modifications that can be used to modulate the activity level of the modified oligonucleotides, enabling robust silencing (e.g., about 75% or more silenced) or moderate silencing (e.g., about 25% to about 50% silenced) over a short period of time (i.e., less than 6 months) or a long period of time (i.e., 6 months or more), and improving the stability of the oligonucleotides. In one aspect, the present disclosure provides an RNA molecule comprising a5 'end and a 3' end, wherein the RNA molecule comprises at least one ethylene glycol modification to one or both of the 5 'end and the 3' end, wherein the at least one ethylene glycol modification comprises 1-20 ethylene glycol units. In certain embodiments, the at least one ethylene glycol modification comprises 1,2, 3, 4,5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 ethylene glycol units. In certain embodiments, the RNA molecule comprises 2-5 ethylene glycol modifications. In certain embodiments, the RNA molecule comprises 2 ethylene glycol modifications. In certain embodiments, the RNA molecule comprises 3 ethylene glycol modifications. In certain embodiments, the RNA molecule comprises 4 ethylene glycol modifications. In certain embodiments, the RNA molecule comprises 5 ethylene glycol modifications. In certain embodiments, the at least one ethylene glycol modification is positioned between two adjacent nucleotides. In certain embodiments, the at least one ethylene glycol modification does not replace a nucleotide at the position within the RNA molecule relative to an RNA molecule that does not contain the at least one ethylene glycol modification at the same position within the RNA molecule. In certain embodiments, the at least one ethylene glycol modification replaces a nucleotide at a position within the RNA molecule relative to an RNA molecule that does not contain at least one ethylene glycol modification at the same position within the RNA molecule. In certain embodiments, the RNA molecule further comprises at least one alkyl modification to one or both of the 5 'and 3' ends. In certain embodiments, the at least one alkyl modification comprises a C 1-C10 alkyl group. In certain embodiments, the at least one alkyl modification comprises a C 4 alkyl group. In certain embodiments, the RNA molecule comprises 2-5 alkyl modifications. In certain embodiments, the RNA molecule comprises 2 alkyl modifications. In certain embodiments, the RNA molecule comprises 3 alkyl modifications. In certain embodiments, the RNA molecule comprises 4 alkyl modifications. In certain embodiments, the RNA molecule comprises 5 alkyl modifications. In certain embodiments, the at least one alkyl modification is positioned between two adjacent nucleotides. In certain embodiments, the at least one alkyl modification does not replace a nucleotide at the position within the RNA molecule relative to an RNA molecule that does not contain the at least one alkyl modification at the same position within the RNA molecule. In certain embodiments, the at least one alkyl modification replaces a nucleotide at the position within the RNA molecule relative to an RNA molecule that does not contain the at least one alkyl modification at the same position within the RNA molecule. In cert