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US-12624358-B2 - Compounds and methods for reducing PLN expression

US12624358B2US 12624358 B2US12624358 B2US 12624358B2US-12624358-B2

Abstract

Provided are oligomeric compounds, methods, and pharmaceutical compositions for reducing the amount or activity of PLN RNA in a cell or animal, and in certain instances reducing the amount of phospholamban protein in a cell or animal. Such oligomeric compounds, methods, and pharmaceutical compositions are useful to treat cardiomyopathy, heart failure, or arrhythmia.

Inventors

  • Dieter A. KUBLI
  • Brooke A. Anderson
  • Adam Mullick
  • Eric E. Swayze

Assignees

  • IONIS PHARMACEUTICALS, INC.

Dates

Publication Date
20260512
Application Date
20250714

Claims (10)

  1. 1 . An oligomeric duplex comprising: i) a modified oligonucleotide according to the following chemical notation: (SEQ ID NO: 1255) vPT es A fs U yo A yo A yo A yo U yo A yo G yo A yo U yo U yo C yo U fo G yo U fo A yo G yo C yo U yo U ys A e sA e ; wherein: A=an adenine nucleobase, C=a cytosine nucleobase, G=a guanine nucleobase, T=a thymine nucleobase, U=a uracil nucleobase, e=a 2′-MOE sugar moiety, f=a 2′-fluoro sugar moiety, y=a 2′-OMe sugar moiety, o=a phosphodiester internucleoside linkage, s=a phosphorothioate internucleoside linkage, and vP=a 5′ vinyl phosphonate group; and ii) a conjugated modified oligonucleotide according to the following chemical notation: (SEQ ID NO: 1041) [X] 1 - A es A es G yo C yo U yo A yo C yo A yo G yo A fo A fo U yo C yo U yo A yo U yo U yo U yo A ys T es A e, wherein: C=a cytosine nucleobase, A=an adenine nucleobase, G=a guanine nucleobase, U=a uracil nucleobase, T=a thymine nucleobase, e=a 2′-MOE sugar moiety, f=a 2′-fluoro sugar moiety, y=a 2′-OMe sugar moiety, o=a phosphodiester internucleoside linkage, s=a phosphorothioate internucleoside linkage, [X] 1 =a conjugate group having the following structure (SEQ ID NO: 1301): or a pharmaceutically acceptable salt thereof.
  2. 2 . The oligomeric duplex of claim 1 , wherein the pharmaceutically acceptable salt is a sodium salt.
  3. 3 . The oligomeric duplex of claim 1 , wherein the pharmaceutically acceptable salt is a potassium salt.
  4. 4 . A pharmaceutical composition comprising the oligomeric duplex of claim 1 and a pharmaceutically acceptable diluent or carrier.
  5. 5 . An oligomeric duplex according to the following chemical structure: or a pharmaceutically acceptable salt thereof.
  6. 6 . The oligomeric duplex of claim 5 , wherein the pharmaceutically acceptable salt is a sodium salt.
  7. 7 . The oligomeric duplex of claim 5 , wherein the pharmaceutically acceptable salt is a potassium salt.
  8. 8 . A pharmaceutical composition comprising the oligomeric duplex of claim 5 and a pharmaceutically acceptable diluent or carrier.
  9. 9 . An oligomeric duplex according to the following chemical structure:
  10. 10 . A pharmaceutical composition comprising the oligomeric duplex of claim 9 and a pharmaceutically acceptable diluent or carrier.

Description

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS This specification claims the benefit of priority to U.S. patent application Ser. No. 18/626,889 (filed 4 Apr. 2024), U.S. Provisional Patent Application No. 63/494,415 (filed 5 Apr. 2023), U.S. Provisional Patent Application No. 63/508,453 (filed 15 Jun. 2023) and U.S. Provisional Patent Application No. 63/561,700 (filed 5 Mar. 2024). The entire text of the above-referenced patent applications is incorporated by reference into this specification. SEQUENCE LISTING The present application is being filed concurrently with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled 201366-US01-NP-CON_SL.xml, created on Nov. 24, 2025, which is 1,598,369 bytes in size. The contents of the electronic format of the sequence listing are incorporated herein by reference in their entirety. FIELD The present invention relates to compounds, compositions, and uses therefor, including methods for decreasing the levels of PLN expression, PLN RNA, and/or the levels (and/or activity) of phospholamban protein, as well as to methods for preventing, treating, and/or ameliorating at least one symptom of, a cardiac disease, disorder or condition, such as, for example, cardiomyopathy, heart failure, or arrhythmia. BACKGROUND Heart pumping action, which forces blood throughout the body, is generated by the repetitive contraction of cardiac muscle (i.e., myocardium). The rhythmic contraction process of cardiac muscle is regulated by changes in cytosolic calcium ion concentration in cardiac muscle cells (referred to as cardiomyocytes). Increases in cytosolic calcium ion concentration are associated with myocardial contraction (during systole), whereas decreases in cytosolic calcium ion concentration are associated with heart muscle relaxation (during diastole). The sarcoplasmic reticulum, a membranous intracellular tubular structure within cardiac and skeletal muscle cells, is responsible for contractile calcium handling (i.e., uptake and storage of calcium ions from the cytosol during relaxation and release of sequestered calcium ions into the cytosol for muscle contraction); and is associated with multiple proteins that facilitate and regulate its uptake and release of calcium ions. One such protein is sarco(endo) plasmic reticulum calcium ATPase (SERCA), which functions to pump cytosolic calcium into the sarcoplasmic reticulum during relaxation of cardiac muscle. SERCA is regulated by phospholamban (encoded by PLN), a phosphoprotein which inhibits SERCA activity in its dephosphorylated state by decreasing affinity of SERCA for calcium ions. This in turn attenuates filling the sarcoplasmic reticulum calcium store and diminishes contractile force development. Phospholamban phosphorylation reverses its inhibition of SERCA. Heart failure, a condition wherein the heart is not able to provide sufficient blood flow to the body, is a leading cause of death worldwide. Heart failure can be chronic, developing gradually over time, or acute, which is a more sudden, rapid decline in heart functioning. Heart failure may be caused by conditions that damage, weaken and/or overwork the heart, including cardiomyopathy. Cardiomyopathy refers to heart muscle diseases, disorders and conditions that weaken the heart, eventually resulting in inability to pump effectively. As the heart weakens, normal heart muscle can thicken, stiffen, or thin out, impairing its ability to pump blood which can lead to heart failure. Arrhythmia is an irregular or abnormal heartbeat and the leading cause of sudden cardiac deaths. Arrhythmia originating in the ventricles (lower chambers of the heart) is particularly dangerous and cause the heart to beat too fast, which impairs blood circulation and can result in cardiac arrest. Ventricular fibrillation (vfib) is a rapid uncoordinated heart rhythm in which the heart's electrical signals often lack a normal and repetitive pattern. Ventricular tachycardia (vtac) is a rapid heart rhythm, which if too fast, can prevent the heart from effectively beating or pumping blood to the entire body and cause loss of consciousness. Effective management of intracellular calcium is a significant factor in regulation of contractile force in cardiac muscle. Symptoms of heart failure include reduced contractile function, which can appear as blunted, slowed, dysynchronous contraction, and impaired relaxation of the heart. Aberrant calcium cycling and defective intracellular calcium ion homeostasis within cardiac muscle cells are associated with contractile dysfunction and arrhythmias in failing myocardium. There remains a need for therapies targeting cardiac dysfunction in heart failure and conditions associated with heart failure. Therapeutics targeting cardiac calcium regulation may provide a new class of compounds for effective management of contractile function and therapy for subjects at risk of cardiomyopathy and heart failure. SUMMARY Provided herein are comp