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JP-7855616-B2 - PIKFYVE Antisense Oligonucleotides

JP7855616B2JP 7855616 B2JP7855616 B2JP 7855616B2JP-7855616-B2

Inventors

  • チャン， ウェン－スアン
  • リー， エミリー エリザベス

Assignees

  • アキュラステム インコーポレイテッド

Dates

Publication Date
20260508
Application Date
20220622
Priority Date
20210622

Claims (20)

  1. A single-stranded antisense oligonucleotide that suppresses the expression of PIKFYVE, comprising the nucleic acid base sequence described in Sequence ID No. 20 , wherein the antisense oligonucleotide has a length of 20 nucleotides .
  2. The antisense oligonucleotide according to claim 1 , wherein at least one nucleoside bond is a modified nucleoside bond.
  3. The antisense oligonucleotide according to claim 2 , wherein at least one modified nucleoside bond is a phosphorothioate nucleoside bond or a phosphodiester nucleoside bond .
  4. The antisense oligonucleotide according to claim 2 , wherein at least one nucleoside bond is a phosphorothioate bond and at least one nucleoside bond is a phosphodiester bond.
  5. The antisense oligonucleotide according to claim 1 , wherein at least one nucleoside comprises a modified nucleic acid base.
  6. The antisense oligonucleotide according to claim 5 , wherein the modified nucleic acid base is 5-methylcytosine.
  7. The antisense oligonucleotide according to claim 1 , wherein at least one nucleoside of the antisense oligonucleotide comprises a modified sugar moiety.
  8. The antisense oligonucleotide according to claim 7 , wherein the modified sugar moiety comprises a 2'-O-methoxyethyl group.
  9. The antisense oligonucleotide according to claim 1 , wherein the antisense oligonucleotide is a gapmer.
  10. The antisense oligonucleotide is A gap segment consisting of 10 to 12 linked deoxynucleosides, A 5' wing segment consisting of 4 to 5 linked nucleosides, It contains a 3' wing segment consisting of 4 to 5 linked nucleosides, The antisense oligonucleotide according to claim 1 , wherein the gap segment is located between the 5' wing segment and the 3' wing segment, and each wing segment comprises a sugar moiety modified with a nucleoside.
  11. The antisense oligonucleotide according to claim 10 , wherein each nucleoside in each wing segment comprises a modified sugar moiety.
  12. The antisense oligonucleotide according to claim 10 , wherein each nucleoside constituting a wing segment comprises at least two different modified sugar moieties.
  13. The antisense oligonucleotide according to claim 10 , wherein each nucleoside constituting a wing segment contains the same modified sugar moiety.
  14. The antisense oligonucleotide according to claim 13 , wherein the modified sugar moiety comprises a 2'-O-methoxyethyl group.
  15. The antisense oligonucleotide according to claim 1, wherein the antisense oligonucleotide suppresses the expression of PIKFYVE by at least 80%.
  16. A composition comprising the antisense oligonucleotide described in claim 1 and a pharmaceutically acceptable carrier, diluent, and/or excipient.
  17. A single-stranded antisense oligonucleotide having a length of 20 nucleotides for suppressing the expression of PIKFYVE, wherein the antisense oligonucleotide has the nucleic acid base sequence described in Sequence ID No. 20, the first 3 to 5 nucleotides at the 5' end ("5' wing segment") contain a modified sugar, the last 3 to 5 nucleotides at the 3' end ("3' wing segment") contain a modified sugar, and the remaining nucleotides contain an unmodified gap segment.
  18. The antisense oligonucleotide according to claim 17, wherein the modified sugar comprises 2'-OMe, 2'-MOE, LNA, or any combination thereof.
  19. The antisense oligonucleotide according to claim 17, wherein the skeletal bonds of the 5' wing segment, the 3' wing segment, and the gap segment comprise a mixture of phosphorothioate bonds and phosphodiester bonds.
  20. The antisense oligonucleotide according to claim 17, wherein the antisense oligonucleotide includes a portion that neutralizes the charge on the antisense oligonucleotide.

Description

This application claims the benefit of U.S. Patent Application No. 63/202,717, filed on 22 June 2021, which is incorporated herein by reference. This disclosure relates to PIKFYVE antisense oligonucleotides (ASOs), pharmaceutical compositions containing the same, and methods for treating, inhibiting, suppressing, and preventing neurological or neurodegenerative diseases using the same. Many neurodegenerative disorders in patients are difficult to treat effectively, especially when the pathology of the neurodegenerative disorder in a particular patient is not fully understood. International Publication No. 2016/210372 discloses a method for treating neurodegenerative diseases by administering PIKFYVE inhibitors. Effective treatments for many neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), remain in need. International Publication No. 2016/210372 This invention relates to PIKFYVE antisense oligonucleotides (ASOs), pharmaceutical compositions containing them, and their use in the treatment of neurodegenerative disorders. One embodiment is a single-stranded ASO that suppresses PIKFYVE expression, wherein the ASO has a nucleic acid sequence containing at least 12 or 15 consecutive nucleic acid bases from any of the nucleic acid base sequences of SEQ ID NOs. 1 to 500. The nucleic acid sequence of the ASO may contain 30, 25, 24, 23, 22, 21, or 20 consecutive nucleic acid bases from any of the nucleic acid base sequences of SEQ ID NOs. 1 to 500. The ASO may be any of SEQ ID NOs. 1 to 500. Another embodiment is an oligonucleotide comprising 12 to 30 linked nucleosides and having a nucleic acid base sequence containing at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 consecutive nucleic acid bases from any of the nucleic acid base sequences of SEQ ID NOs. The oligonucleotide may contain 25, 24, 23, 22, 21, or 20 consecutive nucleic acid bases from any of the nucleic acid base sequences of SEQ ID NOs. In certain embodiments, at least one nucleoside bond is a modified nucleoside bond, which may be a phosphorothioate nucleoside bond or a phosphodiester nucleoside bond. At least one of the nucleosides may be a modified nucleic acid base. In other embodiments, at least one nucleoside of the ASO may be a modified sugar moiety, which may be a bicyclic sugar moiety or may contain a 2'-O-methoxyethyl group. In certain embodiments, the bicyclic sugar moiety contains a 4'-CH(R)-O-2' bridge, where the R group is independently H, C1-12 alkyl, or a protecting group. In further embodiments, the ASO is a gapmer (e.g., an MOE gapmer), where the gap segment may consist of 8 to 12 bonded deoxynucleosides, a 5'-wing segment comprising 3 to 5 bonded nucleosides, and a 3'-wing segment comprising 3 to 5 bonded nucleosides. In certain embodiments, the gap segment may be positioned between the 5'-wing segment and the 3'-wing segment, and each wing segment's nucleosides contain a modified sugar moiety (e.g., a sugar moiety having a 2'-O-methoxyethyl group). In other embodiments, the oligonucleotide consists of 12 to 30 linked nucleosides and has a nucleic acid base sequence containing at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 consecutive nucleic acid bases from any of the nucleic acid base sequences of SEQ ID NOs. 1 to 500. Another embodiment is a pharmaceutical composition comprising PIKFYVE ASO of the present invention and one or more pharmaceutically acceptable carriers, diluents, and/or excipients. In one embodiment, the pharmaceutical composition is suitable for parenteral administration, for example, intraventricular injection or intrathecal administration. Another embodiment is a method for inhibiting, suppressing, or preventing the expression of PIKFYVE in a patient (e.g., a patient with a neurological or neurodegenerative disease) by administering PIKFYVE ASO or the pharmaceutical composition described herein (e.g., an effective amount thereof) to the patient (e.g., by intraventricular injection or intrathecal administration). A further embodiment is a method for treating a subject with a neurological or neurodegenerative disease by administering a therapeutically effective amount of PIKFYVE ASO or a pharmaceutical composition described herein. In one embodiment, the disease is amyotrophic lateral sclerosis (ALS) (e.g., C9orf72-associated ALS). In another embodiment, the disease is frontotemporal dementia (FTD), such as FTD with TDP-43 pathology or FTD with tau pathology. In yet another embodiment, the disease is C9orf72-associated FTD (C9-FTD). In yet another embodiment, the disease is microtubule-associated protein tau (MAPT)-associated FTD (MAPT-FTD), e.g., FTD with the V337M MAPT mutation. Another embodiment is a method for trea