US-12617818-B2 - Compositions and methods for modulating myosin subfragment-2 coiled coil stability and methods for using them

Abstract

In alternative embodiments, provided are peptides and peptide-comprising compositions, including products of manufacture and kits, and methods, for modulating myosin subfragment-2 coiled coil stability. In alternative embodiments, a peptide modulator of myosin subfragment-2 coiled coil stability as provided herein is administered to an individual in need thereof for: increasing exercise tolerance in a subject with heart failure; reducing hospitalization in a subject with heart failure; improving quality of life in a subject with heart failure; decreasing morbidity in a subject with heart failure; decreasing mortality in a subject with heart failure; modulating skeletal muscle activity for purposes of impacting patient weight; and/or, modulating skeletal muscle activity for purposes of ameliorating consequences of skeletal muscle diseases such as sarcopenia, muscular dystrophies, muscle cramps, and nemaline myopathies.

Inventors

• Douglas ROOT

Assignees

• UNIVERSITY OF NORTH TEXAS

Dates

Publication Date

20260505

Application Date

20210325

Claims (18)

1. 1 . A method for: treating, ameliorating or protecting, slowing the progress of, abating or decreasing one or more symptoms of heart failure, optionally chronic congestive heart failure (CHF)) in an individual or a patient in need thereof, the method comprising administering a peptide modulator of myosin subfragment-2 coiled coil stability, or a nucleic acid encoding the peptide modulator, to the individual or patient in need thereof, wherein the peptide modulator of myosin subfragment-2 coiled coil stability comprises a peptide or polypeptide comprising: (a) an amino acid sequence EMNERLEDEREMKAELTAK (SEQ ID NO: 1); or (b) an amino acid sequence KKKKKKKKFKAKKKKKK (SEQ ID NO: 3).
2. 2 . The method of claim 1 , wherein the nucleic acid encoding the peptide modulator of myosin subfragment-2 coiled coil stability is operatively linked to a transcriptional regulatory sequence.
3. 3 . The method of claim 2 , wherein an expression vehicle, a vector or a recombinant virus having the nucleic acid encoding the peptide modulator of myosin subfragment-2 coiled coil stability contained therein is administered to the individual or patient in need thereof.
4. 4 . The method of claim 3 , wherein the expression vehicle, vector, recombinant virus, or equivalent is or comprises: an adeno-associated virus (AAV), a lentiviral vector or an adenovirus vector, an AAV serotype AAV5, AAV6, AAV8 or AAV9, a rhesus-derived AAV, or the rhesus-derived AAV AAVrh.10hCLN2, an AAV capsid mutant or AAV hybrid serotype, an organ-tropic AAV, optionally, cardiac or skeletal muscle-tropic, wherein optionally the AAV is engineered to increase efficiency in targeting a specific cell type that is non-permissive to a wild type (wt) AAV and/or to improve efficacy in infecting only a cell type of interest, and optionally the hybrid AAV is retargeted or engineered as a hybrid serotype by one or more modifications comprising: 1) a transcapsidation, 2) adsorption of a bi-specific antibody to a capsid surface, 3) engineering a mosaic capsid, and/or 4) engineering a chimeric capsid.
5. 5 . The method of claim 3 , wherein a cell having the expression vehicle, a vector or a recombinant virus contained therein is administered to the individual or patient in need thereof.
6. 6 . The method of claim 2 , wherein a cell having the nucleic acid encoding the peptide modulator of myosin subfragment-2 coiled coil stability contained therein is administered to the individual or patient in need thereof.
7. 7 . The method of claim 1 , wherein: the peptide modulator or nucleic acid encoding the peptide modulator is administered or delivered to the individual or the patient in need thereof, by oral, intramuscular (IM) injection, by intravenous (IV) injection, by subcutaneous (SC) or intradermal injection, by intrathecal injection, by intra-arterial (IA) injection, by intracoronary injection, by inhalation, by aerosol, or by a biolistic particle delivery system, or by using a “gene gun”, air pistol or by a gene gun.
8. 8 . The method of claim 1 , wherein: (a) the individual or patient in need thereof is administered the nucleic acid encoding the peptide modulator and a stimulus or signal that activates or induces expression of the peptide modulator, wherein the administered nucleic acid comprises and is operative linked to a promoter that is activated or induced by the stimulus or signal; (b) the method of (a), wherein the promoter is a cardiac cell-specific promoter; (c) the individual, patient or subject is administered a stimulus or signal that induces synthesis of a natural or a synthetic activator of the peptide modulator, wherein optionally the natural activator is an endogenous transcription factor; (d) the method of (c), wherein the synthetic activator is a zinc-finger DNA binding protein designed to specifically and selectively turn on an endogenous or exogenous target gene, wherein optionally the endogenous target is a gene peptide modulator of myosin subfragment-2 coiled coil stability expressing nucleic acid or gene or an activator of a peptide modulator of myosin subfragment-2 coiled coil stability expressing nucleic acid or gene, or an activator of a promoter operatively linked to a peptide modulator of myosin subfragment-2 coiled coil stability-expressing nucleic acid or gene; (e) the method of any of (a) to (c), wherein the stimulus or signal comprises a biologic, a light, a chemical or a pharmaceutical stimulus or signal; (f) the individual or patient in need thereof is administered a stimulus or signal that stimulates or induces expression of a post-transcriptional activator of a peptide modulator of myosin subfragment-2 coiled coil stability-expressing nucleic acid or gene, or an activator of a promoter operatively linked to a peptide modulator of myosin subfragment-2 coiled coil stability-expressing nucleic acid or gene, or (g) the individual or patient in need thereof is administered a stimulus or signal that inhibits or induces inhibition of a transcriptional repressor or a post-transcriptional repressor of a peptide modulator of myosin subfragment-2 coiled coil stability expressing nucleic acid or gene.
9. 9 . The method of claim 1 , wherein the individual or patient in need thereof is administered a chemical or a pharmaceutical that induces expression of the peptide modulator, or induces expression of a regulated or inducible promoter operatively linked to the nucleic acid encoding the peptide modulator, and the chemical or pharmaceutical comprises: an oral antibiotic, a doxycycline, a rapamycin; or a tet-regulation system using doxycycline to induce expression of the peptide modulator of a myosin subfragment-2 coiled coil stability-expressing nucleic acid or gene.
10. 10 . The method of claim 1 , wherein the peptide modulator is formulated in a liquid, a gel, a hydrogel, a powder or an aqueous or a saline formulation.
11. 11 . The method of claim 1 , wherein the peptide modulator or the nucleic acid encoding the peptide modulator is formulated in a vesicle, liposome, nanoparticle or nanolipid particle (NLP).
12. 12 . The method of claim 1 , wherein the nucleic acid encoding the peptide modulator is contained in an expression vehicle, a vector, or a recombinant virus, which is formulated in an isolated or cultured cell.
13. 13 . The method of claim 12 , wherein the cell is a mammalian cell, a cardiac cell, or a human cell, a non-human primate cell, a monkey cell, a mouse cell, a rat cell, a guinea pig cell, a rabbit cell, a hamster cell, a goat cell, a bovine cell, an equine cell, an ovine cell, a canine cell or a feline cell.
14. 14 . The method of claim 1 , wherein the peptide modulator or the nucleic acid encoding the peptide modulator is formulated as a pharmaceutical or sterile formulation.
15. 15 . The method of claim 1 , wherein the peptide modulator or the nucleic acid encoding the peptide modulator is formulated or delivered with, on, or in conjunction with a product of manufacture, an artificial organ or an implant.
16. 16 . The method of claim 1 , wherein the peptide modulator of myosin subfragment-2 coiled coil stability comprises a peptide or polypeptide consists of: (a) an amino acid sequence EMNERLEDEREMKAELTAK (SEQ ID NO:1), with L or D amino acid isomers; or (b) an amino acid sequence KKKKKKKKFKAKKKKKK (SEQ ID NO:3), with L or D amino acid isomers.
17. 17 . The method of claim 1 , wherein the peptide modulator of myosin subfragment-2 coiled coil stability comprises a peptide or polypeptide comprising an amino acid sequence EMNERLEDEREMKAELTAK (SEQ ID NO:1).
18. 18 . The method of claim 1 , wherein the peptide modulator of myosin subfragment-2 coiled coil stability comprises a peptide or polypeptide comprising an amino acid sequence KKKKKKKKFKAKKKKKK (SEQ ID NO:3).

Description

RELATED APPLICATIONS This U.S. National Phase Patent Applications claims benefit of priority under 35 U.S.C. § 371 to Patent Convention Treaty (PCT) International Application PCT/US2021/024503, filed Mar. 26, 2021, which claims the benefit of priority under 35 U.S.C. § 119 (e) of U.S. Provisional Patent Application Ser. No. 63/994,723, filed Mar. 25, 2020. The aforementioned applications are expressly incorporated herein by reference in their entirety and for all purposes. REFERENCE TO SEQUENCE LISTING This application includes an electronically submitted sequence listing in .txt format. The .txt file contains a sequence listing entitled “6343.140271_ST25.txt” created on Nov. 10, 2025 and is 5,272 bytes in size. The sequence listing contained in this .txt file is part of the specification and is hereby incorporated by reference herein in its entirety. TECHNICAL FIELD This invention generally relates to cell biology and medicine. In alternative embodiments, provided are peptides and peptide-comprising compositions, including products of manufacture and kits, and methods, for modulating myosin subfragment-2 coiled coil stability. In alternative embodiments, a peptide modulator of myosin subfragment-2 coiled coil stability as provided herein is administered to an individual in need thereof for: increasing exercise tolerance in a subject with heart failure; reducing hospitalization in a subject with heart failure; improving quality of life in a subject with heart failure; decreasing morbidity in a subject with heart failure; decreasing mortality in a subject with heart failure; modulating skeletal muscle activity for purposes of impacting patient weight; and/or, modulating skeletal muscle activity for purposes of ameliorating consequences of skeletal muscle diseases such as sarcopenia, muscular dystrophies, muscle cramps, and nemaline myopathies. BACKGROUND Every day, approximately 2200 Americans die of cardiovascular disease. In fact, cardiovascular disease is the leading global cause of death, representing 31 percent of deaths around the world (Roger et al., 2012). Many types of heart disease contribute to these staggering/appalling statistics, and among them are hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), and chronic congestive heart failure (CHF). Although these diseases all are caused by different genetic mutations in the affected individual, they all render the heart incapable of effectively pumping blood to the body, leading to arrhythmia and cardiac failure (Miller et al., 2015; Reed & Sueta, 2015; Choudhry et al., 2019). The most prevalent methods of treating arrhythmias and conduction defects involve implantation of a pacemaker or an implantable cardioverter-defibrillator (ICD) (Miller et al., 2015). While such methods are largely effective, they require invasive surgery to perform their function, which may lead to complications. Other popular methods of treatment for heart failures include angiotensin-converting enzyme (ACE) inhibitors, beta-blocking agents, diuretics, and digoxin (Reed & Sueta, 2015). However, these drug treatments lose potency as a patient acquires drug tolerance and requires higher doses, increasing the chance of side effects (Rickenbacher, P., 2011). A non-invasive and novel treatment for HCM, DCM, and CHF that directly affects the actin-myosin interaction at a biochemical level could alleviate these problems. SUMMARY In alternative embodiments, provided are synthetic or recombinant peptides comprising or consisting of an amino acid sequence: (a) EMNERLEDEREMKAELTAK (SEQ ID NO:1), with L or D amino acid isomers;(b) having the formula: (K)x-FKA-(K)y, or (Lys)x-Phe-Lys-Ala-(Lys)y (SEQ ID NO: 2) wherein x and y are independently integers between 5 and 20, or x and y are independently 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, with L or D amino acid isomers,wherein optionally the peptide comprises or consists of an amino acid sequence: KKKKKKKKFKAKKKKKK (SEQ ID NO:3), with L or D amino acid isomers; or(c) a mimetic or peptidomimetic of (a) or (b), or a peptide of (a) or (b) having at least one, or comprising 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 or more conservative amino acid substitutions. In alternative embodiments, provided are synthetic or recombinant nucleic acids encoding a synthetic or recombinant peptide as provided herein. In alternative embodiments, provided are expression vehicles comprising the synthetic or recombinant nucleic acid as provided herein. In alternative embodiments, provided are isolated or recombinant cells comprising the synthetic or recombinant peptide as provided herein, or the synthetic or recombinant nucleic acid as provided herein, or the expression vehicle as provided herein. In alternative embodiments, provided are products of manufacture comprising: the synthetic or recombinant peptide as provided herein, or the synthetic or recombinant nucleic acid as provided herein, or the expression vehicle as provided her