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KR-20260064686-A - Oligonucleotide composition and method thereof

KR20260064686AKR 20260064686 AKR20260064686 AKR 20260064686AKR-20260064686-A

Abstract

In particular, the present disclosure provides various techniques including chiral-controlled oligonucleotide compositions and techniques for preparing and using such oligonucleotide compositions. In some embodiments, the present disclosure provides techniques useful for allele-specific knockdown of mutant huntingtin transcripts. In some embodiments, the present disclosure provides techniques useful for reducing the expression, level, amount, and/or activity of mutant huntingtin transcripts or their products. In some embodiments, the present disclosure provides methods for treating Huntington's disease.

Inventors

  • 레이크 스티븐 리스터
  • 라모어 사라 다이앤
  • 판자라 마이클 안젤로
  • 알람 모하메드 로우숀
  • 장 현경
  • 반다라 아셀라 칼리야나프리야
  • 헤겔 조셉 앤드류
  • 허트 마크 리차드
  • 고엘 바룬
  • 나라야난 파드마쿠마르
  • 리-콰이-청 앤-매리
  • 후 샤오 셸리
  • 카락타 신시아 파하르도
  • 트롬비노 앤서니
  • 가오 ?캭?
  • 장 이린
  • 로스 필립
  • 아두다 빈센트
  • 시미즈 마모루
  • 수 단린
  • 바우먼 키스 앤드류

Assignees

  • 웨이브 라이프 사이언시스 리미티드

Dates

Publication Date
20260507
Application Date
20240802
Priority Date
20230803

Claims (20)

  1. As a method, the method includes the step of administering or delivering WVE-003 to a subject, wherein: A set of two or more doses is administered or delivered approximately every 8 weeks or less frequently, and each dose of the set is independently equivalent to approximately 30 mg of the free acid form of WVE-003; The above subject has a mutant HTT gene containing a mutation capable of allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * Steo, where: m represents a 2'-Ome modification for a nucleoside; *S represents the Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxyethyl C; n001R represents the Rp n001 connection, where the n001 connection is It has the structure of; eo represents a 2'- OCH2CH2OCH3 modification to the nucleoside; and *R is a method representing the Rp phosphothioate linkage.
  2. A method for selectively reducing the level of mutant HTT protein relative to wild-type HTT protein in a subject, for selectively reducing the level of mutant HTT protein relative to wild-type HTT protein in the subject's cerebrospinal fluid (CSF), for slowing caudate nucleus atrophy, and/or reducing the Total Motor Score (TMS) of a subject with Huntington's disease, comprising the step of administering or delivering WVE-003 to said subject, wherein: A set of two or more doses is administered or delivered approximately every 8 weeks or less frequently, and each dose of the set is independently equivalent to approximately 30 mg of the free acid form of WVE-003; The subject has a mutant HTT gene encoding a mutant HTT protein and including a mutation capable of allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, where: m represents the 2'-OMe modification for the nucleoside; *S represents the Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxyethyl C; n001R represents the Rp n001 connection, where the n001 connection is It has the structure of; eo represents a 2'- OCH2CH2OCH3 modification to the nucleoside; and *R is a method representing the Rp phosphothioate linkage.
  3. As a method, the method includes the step of administering or delivering WVE-003 to a subject, wherein: Each dose of WVE-003 independently corresponds to approximately 30 mg of the free acid form of WVE-003; A set of two or more doses is administered or delivered approximately every 8 weeks or less frequently; The above subject has a mutant HTT gene containing a mutation capable of allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * Steo, where: m represents a 2'-Ome modification for a nucleoside; *S represents the Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxyethyl C; n001R represents the Rp n001 connection, where the n001 connection is It has the structure of; eo represents a 2'- OCH2CH2OCH3 modification to the nucleoside; and *R is a method representing the Rp phosphothioate linkage.
  4. A method for selectively reducing the level of mutant HTT protein relative to wild-type HTT protein in a subject, for selectively reducing the level of mutant HTT protein relative to wild-type HTT protein in the subject's cerebrospinal fluid (CSF), for slowing caudate nucleus atrophy, and/or reducing the Total Motor Score (TMS) of a subject with Huntington's disease, comprising the step of administering or delivering WVE-003 to said subject, wherein: Each dose of WVE-003 independently corresponds to approximately 30 mg of the free acid form of WVE-003; A set of two or more doses is administered or delivered approximately every 8 weeks or less frequently; The subject has a mutant HTT gene encoding a mutant HTT protein and including a mutation capable of allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, where: m represents the 2'-OMe modification for the nucleoside; *S represents the Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxyethyl C; n001R represents the Rp n001 connection, where the n001 connection is It has the structure of; eo represents a 2'- OCH2CH2OCH3 modification to the nucleoside; and *R is a method representing the Rp phosphothioate linkage.
  5. A method according to any one of claims 1 to 4, wherein the subject has a variant A of rs362273 and the variant A exists on the same chromosome as the extended CAG repeat region in the HTT gene.
  6. A method according to any one of claims 1 to 4, wherein the subject has an A variant of rs362273 on the same allele as the extended CAG repeat region in the HTT gene and does not exhibit Huntington's disease.
  7. A method according to any one of claims 1 to 4, wherein the subject has Huntington's disease and has variant A of rs362273 on the same allele as the extended CAG repeat region in the HTT gene.
  8. A method according to any one of claims 1 to 4, wherein the subject has an A variant of rs362273 on the same allele as the extended CAG repeat region in the HTT gene and is in stage 3 of HD-ISS.
  9. A method for delaying the onset of one or more symptoms of Huntington's disease in a subject, comprising the step of administering or delivering WVE-003 to said subject, wherein: A set of two or more doses is administered or delivered approximately every 8 weeks or less frequently, and each dose of the set is independently equivalent to approximately 30 mg of the free acid form of WVE-003; The subject has a mutant HTT gene encoding a mutant HTT protein and including a mutation capable of allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, where: *S represents the Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxyethyl C; n001R represents the Rp n001 connection, where the n001 connection is It has the structure of; eo represents a 2'- OCH2CH2OCH3 modification to the nucleoside; and *R is a method representing the Rp phosphothioate linkage.
  10. A method for delaying the onset of one or more symptoms of Huntington's disease in a subject, comprising the step of administering or delivering WVE-003 to said subject, wherein: Each dose of WVE-003 independently corresponds to approximately 30 mg of the free acid form of WVE-003; A set of two or more doses is administered or delivered approximately every 8 weeks or less frequently; The subject has a mutant HTT gene encoding a mutant HTT protein and including a mutation capable of allele-specific knockdown of the mutant HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, where: *S represents the Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxyethyl C; n001R represents the Rp n001 connection, where the n001 connection is It has the structure of; eo represents a 2'- OCH2CH2OCH3 modification to the nucleoside; and *R is a method representing the Rp phosphothioate linkage.
  11. A method according to any one of claims 9 to 10, wherein the subject has an A variant of rs362273 on the same allele as the extended CAG repeat region in the HTT gene and does not exhibit Huntington's disease.
  12. A method according to any one of claims 9 to 10, wherein the subject has an A variant of rs362273 on the same allele as the extended CAG repeat region in the HTT gene and is in stage 0, 1, or 2 of HD-ISS.
  13. A method in which, in any one of paragraphs 1 to 12, two or more doses are administered or delivered approximately every 8 weeks, approximately every 3 months, or less frequently.
  14. As a method, the method includes the step of administering or delivering WVE-003 to a subject, wherein: A set of three or more doses is administered or delivered approximately every eight weeks or less frequently, and each dose of the set is independently equivalent to approximately 30 mg of the free acid form of WVE-003; The subject has Huntington's disease and has the A variant of rs362273 on the same allele as the extended CAG repeat region in the HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, where: m represents the 2'-OMe modification for the nucleoside; *S represents the Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxyethyl C; n001R represents the Rp n001 connection, where the n001 connection is It has the structure of; eo represents a 2'- OCH2CH2OCH3 modification to the nucleoside; and *R is a method representing the Rp phosphothioate linkage.
  15. As a method, the method includes the step of administering or delivering WVE-003 to a subject, wherein: Each dose of WVE-003 independently corresponds to approximately 30 mg of the free acid form of WVE-003; A set of three or more doses is administered or delivered approximately every eight weeks or less frequently; The subject has Huntington's disease and has the A variant of rs362273 on the same allele as the extended CAG repeat region in the HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, where: m represents the 2'-OMe modification for the nucleoside; *S represents the Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxyethyl C; n001R represents the Rp n001 connection, where the n001 connection is It has the structure of; eo represents a 2'- OCH2CH2OCH3 modification to the nucleoside; and *R is a method representing the Rp phosphothioate linkage.
  16. A method according to any one of claims 14 to 15, wherein the subject has an A variant of rs362273 on the same allele as the extended CAG repeat region in the HTT gene and is in stage 3 of HD-ISS.
  17. As a method, the method includes the step of administering or delivering WVE-003 to a subject, wherein: A set of three or more doses is administered or delivered approximately every eight weeks or less frequently, and each dose of the set is independently equivalent to approximately 30 mg of the free acid form of WVE-003; The above subject has variant A of rs362273 on the same allele as the extended CAG repeat region in the HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, where: m represents the 2'-OMe modification for the nucleoside; *S represents the Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxyethyl C; n001R represents the Rp n001 connection, where the n001 connection is It has the structure of; eo represents a 2'- OCH2CH2OCH3 modification to the nucleoside; and *R is a method representing the Rp phosphothioate linkage.
  18. As a method, the method includes the step of administering or delivering WVE-003 to a subject, wherein: Each dose of WVE-003 independently corresponds to approximately 30 mg of the free acid form of WVE-003; A set of three or more doses is administered or delivered approximately every eight weeks or less frequently; The above subject has variant A of rs362273 on the same allele as the extended CAG repeat region in the HTT gene; WVE-003 is mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, where: m represents the 2'-OMe modification for the nucleoside; *S represents the Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxyethyl C; n001R represents the Rp n001 connection, where the n001 connection is It has the structure of; eo represents a 2'- OCH2CH2OCH3 modification to the nucleoside; and *R is a method representing the Rp phosphothioate linkage.
  19. A method according to any one of claims 17 to 18, wherein the subject has an A variant of rs362273 on the same allele as the extended CAG repeat region in the HTT gene and is in stage 0, 1, 2 or 3 of HD-ISS.
  20. A method in which, in any one of paragraphs 1 to 19, three or more doses are administered or delivered approximately every 8 weeks, approximately every 3 months, or less frequently.

Description

Oligonucleotide composition and method thereof Cross-reference regarding related applications The present application claims priority to U.S. Provisional Patent Application No. 63/517,529, filed August 3, 2023 and U.S. Provisional Patent Application No. 63/664,150, filed June 25, 2024 and PCT International Application No. PCT/US2023/030103, filed August 11, 2023 and published as WO/2024/035946 on February 15, 2024, the full text of which is incorporated herein by reference. In particular, the present disclosure provides a technique for treating Huntington's disease. In some embodiments, a method of administering WVE-003 to improve Huntington's disease, reduce mHTT RNA, or reduce mHTT protein in a human subject who needs to improve Huntington's disease or reduce mHTT RNA or reduce mHTT protein is provided herein. In certain cases, the method is useful for improving at least one symptom of Huntington's disease. Such symptoms of Huntington's disease include, but are not limited to, brain atrophy, muscle atrophy, neurodegeneration, uncontrolled movement, dysphagia, dysarthria, anxiety, and depression. Oligonucleotides are useful in therapeutic, diagnostic, research, and nanomaterial applications. The use of naturally occurring nucleic acids (e.g., unmodified DNA or RNA) for therapeutic purposes may be limited due to instability to, for example, extracellular and intracellular nucleases and/or poor cellular permeability and distribution. Currently, there is a lack of acceptable options for treating neurodegenerative diseases such as Huntington's disease. The objective of this invention is to provide a method for treating these diseases. In particular, the present disclosure provides a technique for preventing or treating Huntington's disease, comprising the step of administering or delivering WVE-003 to a subject who is susceptible to or has Huntington's disease according to the dosage or dosing regimen described herein. For example, in some embodiments, the present disclosure provides a technique for preventing or treating Huntington's disease, comprising the step of administering or delivering WVE-003 equivalent to about 30 mg of the free acid form of WVE-003 to a subject who is susceptible to or has Huntington's disease at about 8 weeks or more (e.g., at about 8 weeks, at about 3 months, etc.). In some embodiments, the present disclosure provides a technique for preventing or treating Huntington's disease, which comprises the step of independently administering or delivering multiple doses of WVE-003 (e.g., three or more times) of WVE-003 in the form of about 30 mg of WVE-003 free acid to a subject who is susceptible to or suffering from Huntington's disease, at intervals of about 8 weeks or more (e.g., every 8 weeks, every 3 months, etc.). In particular, the present disclosure provides the first clinical demonstration of allele-selective silencing of any disease target. In some embodiments, the present disclosure demonstrates a 46% reduction in mutant huntingtin (mHTT) protein while preserving wild-type huntingtin (wtHTT) protein. For example, statistically significant, potent, and sustained allele-selective silencing was demonstrated in the 30 mg multiple dose WVE-003 cohort: a 46% mean reduction in CSF mHTT protein compared to placebo, preservation of wtHTT protein, and a generally safe and well-tolerated profile were achieved in the 30 mg multiple dose WVE-003 cohort. Additionally, in some embodiments, the present disclosure demonstrates that a decrease in mHTT is significantly correlated with a slowing of caudate nucleus atrophy (e.g., after only 28 weeks), which is an imaging biomarker predicting clinical outcomes. In some embodiments, the present disclosure provides caudate nucleus volume as a biomarker for clinical development, considering its association with clinical outcomes. Further results are provided in the examples. WVE-003 (also referred to as WV-21405) has the structure mG * S mUn001R mU mGn001R mA * ST * SC * ST * SG * ST * RA * SG * SC * SA * SG * R m5Ceon001RAeoGeon001R m5Ceo * STeo, where: m represents the 2’-OMe modification for the nucleoside; *S represents the Sp phosphorothioate linkage; m5Ceo represents 5-methyl 2'-O-methoxyethyl C; n001R represents the Rp n001 connection, where the n001 connection is It has the structure of; eo represents a 2’-OCH2CH2OCH3 modification to a nucleoside; and *R represents the Rp phosphothioate link. As is typically used in descriptions of oligonucleotides, unless specifically stated otherwise, the nucleoside is a DNA nucleoside and the linkage is a natural phosphate linkage. As described herein, WVE-003 may be provided in various forms, including pharmaceutically acceptable salt forms such as sodium salts. In particular, the present disclosure encompasses the recognition that structural elements of HTT (huntingtin) oligonucleotides, e.g., base sequence, chemical modifications (e.g., modifications of sugars, bases and/or nucleotide-linkings and pattern