METHODS AND COMPOSITIONS OF BIOLOGICALLY ACTIVE AGENTS

• US 20190249173A1
• Filed: 05/03/2017
• Published: 08/15/2019
• Est. Priority Date: 05/04/2016
• Status: Abandoned Application

• Current Assignee: WAVE Life Sciences Ltd.
• Original Assignee: Chandra Vargeese, David Charles Donnell Butler, Genliang Lu, Hailin Yang, Jason Jingxin Zhang, Maria David Frank-Kamenetsky, Naoki Iwamoto, Sethumadhavan Divakaramenon, Subramanian Marappan, WAVE Life Sciences Ltd.
• Inventors: Vargeese, Chandra, Zhang, Jason Jingxin, Divakaramenon, Sethumadhavan, Butler, David Charles Donnell, Lu, Genliang, Iwamoto, Naoki, Yang, Hailin, Frank-Kamenetsky, Maria David, Marappan, Subramanian
• Application Number:
  US16/098,658
• Publication Number:
  US 20190249173A1
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/7088 Compounds having three or more nucleosides or nucleotides
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C12N 15/111 General methods applicable to biologically active non-coding nucleic acids
• CPC Class Codes: C12N 2310/11 Antisense
• CPC Class Codes: C12N 2310/14 interfering N.A.
• CPC Class Codes: C12N 2310/141 MicroRNAs, miRNAs
• CPC Class Codes: C12N 2310/16 Aptamers
• CPC Class Codes: C12N 2310/20 involving clustered regularly interspaced short palindromic repeats [CRISPRs]
• CPC Class Codes: C12N 2310/315 Phosphorothioates
• CPC Class Codes: C12N 2310/3515 Lipophilic moiety, e.g. cholesterol
• CPC Class Codes: C12N 2320/32 Special delivery means, e.g. tissue-specific

Abstract

In some embodiments, the present disclosure pertains to compositions and methods related to delivery of a biologically active agent, wherein the compositions comprise a biologically active agent and a lipid. In various embodiments, the lipid is selected from: lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, alpha-linolenic acid, gamma-linolenic acid, docosa-hexaenoic acid (cis-DHA), turbinaric acid and dilinoleyl. In some embodiments, a composition and method are useful for delivery of a biologically active agent to a particular cell or tissue, e.g., a muscle cell or tissue.

Claims

1-5. -5. (canceled)

6. A chirally controlled oligonucleotide composition comprising a lipid and a plurality of oligonucleotides, which oligonucleotides of the plurality share:

1) a common base sequence;

2) a common pattern of backbone linkages; and

3) a common pattern of backbone phosphorus modifications;

wherein;

b. the composition is chirally controlled in that the plurality of oligonucleotides share the same stereochemistry at one or more chiral internucleotidic linkages;

c. one or more oligonucleotides of the plurality are individually conjugated to a lipid; and

d. one or more oligonucleotides of the plurality are optionally and individually conjugated to a targeting compound or moiety.

7. The composition of claim 6, wherein the oligonucleotide comprises a sequence which is substantially complementary to that of a targeted element in a nucleic acid in a muscle cell in a subject, wherein the targeted element is associated with a muscle disease, disorder, or condition.

8. The composition of claim 7, wherein a muscle disease, disorder, or condition is DMD.

9. The composition of claim 8, wherein the oligonucleotides in the composition provide exon skipping of exon 51 of dystrophin.

10. The composition of claim 6, wherein the plurality of oligonucleotides share the same stereochemistry at five or more chiral internucleotidic linkages.

11. The composition of claim 10, wherein the plurality of oligonucleotides share a common pattern of sugar modification, which comprises 3, 4, 5, 6, 7, 8, 9 or more 2′

-F.

12. The composition of claim 10, wherein the plurality of oligonucleotides share a common pattern of sugar modification, which comprises 3, 4, 5, 6, 7, 8, 9 or more consecutive 2′

-F.

14. The composition of claim 12, wherein the plurality of oligonucleotides have the structure of:

A^c-[-L^LD-(R^LD)_a]_b or [(A^c)_a-L^LD]_b—

R^LD, or a salt thereof,

wherein;

A^c is an oligonucleotide chain ([H]_b—

A^c is an oligonucleotide);

a is 1-1000;

b is 1-1000;

each L^LD is independently a covalent bond or an optionally substituted, C₁-C₈₀ saturated or partially unsaturated aliphatic group, wherein one or more methylene units are optionally and independently replaced by T^LD or an optionally substituted group selected from C₁-C₆ alkylene, C₁-C₆ alkenylene, —

C≡

C—

, a C₁-C₆ heteroaliphatic moiety, —

C(R′

)₂—

, -Cy-, —

O—

, —

S—

, —

S—

S—

, —

N(R′

)—

, —

C(O)—

, —

C(S)—

, —

C(NR′

)—

, —

C(O)N(R′

)—

, —

N(R′

)C(O)N(R′

)—

, —

N(R′

)C(O)—

, —

N(R′

)C(O)O—

, —

OC(O)N(R′

)—

, —

S(O)—

, —

S(O)₂—

, —

S(O)₂N(R′

)—

, —

N(R′

)S(O)₂—

, —

SC(O)—

, —

C(O)S—

, —

OC(O)—

, and —

C(O)O—

;

each R^LD is independently an optionally substituted, C₁-C₈₀ saturated or partially unsaturated aliphatic group, wherein one or more methylene units are optionally and independently replaced by an optionally substituted group selected from C₁-C₆ alkylene, C₁-C₆ alkenylene, —

C≡

C—

, a C₁-C₆ heteroaliphatic moiety, —

C(R′

)₂—

, -Cy-, —

O—

, —

S—

, —

S—

S—

, —

N(R′

)—

, —

C(O)—

, —

C(S)—

, —

C(NR′

)—

, —

C(O)N(R′

)—

, —

N(R′

)C(O)N(R′

)—

, —

N(R′

)C(O)—

, —

N(R′

)C(O)O—

, —

OC(O)N(R′

)—

, —

S(O)—

, —

S(O)₂—

, —

S(O)₂N(R′

)—

, —

N(R′

)S(O)₂—

, —

SC(O)—

, —

C(O)S—

, —

OC(O)—

, and —

C(O)O—

;

T^LD has the structure of;

15. The composition of claim 14, wherein the oligonucleotide comprises at least one phosphorothioate internucleotidic linkage.

16. A method of delivering an oligonucleotide to a muscle cell or tissue in a human subject, comprising:

(a) providing a composition of claim 6; and

(b) administering the composition to the human subject such that the oligonucleotide is delivered to a muscle cell or tissue in the subject.

17. A method of modulating the level of a transcript or gene product of a gene in a cell, the method comprising the step of contacting the cell with a composition of claim 6, wherein the oligonucleotides are capable of modulating the level of the transcript or gene product.

18. A method for treating a sign and/or symptom of a disease, disorder, or condition in a subject selected from cancer, a proliferative disease, disorder, or condition, a metabolic disease, disorder, or condition, an inflammatory disease, disorder, or condition, and a viral infection by providing and administering a composition of claim 6 to the subject.

19. A method of modulating the amount of exon skipping in a cell, the method comprising contacting the cell with a composition of claim 6, wherein the oligonucleotides are capable of modulating the amount of exon skipping.

20. A method of modulating the amount of exon skipping in a cell, the method comprising contacting the cell with a composition of claim 6, wherein the oligonucleotides are capable of modulating the amount of exon skipping of exon 51 of DMD.

13. (canceled)

21. (canceled)