WO2025259969A1 - Methods of treating atrial fibrillation and cardiac conduction diseases using retinoids - Google Patents

Abstract

The present technology provides methods for treating, preventing, reversing, or delaying heart conditions or disorders, such as atrial fibrillation (including atrial fibrillation associated with a tyrosine-kinase inhibitor therapy) and/or cardiac conduction diseases, using a pharmaceutical composition comprising or consisting of a retinoid or a derivative thereof. In some embodiments, the pharmaceutical composition comprises or consists of an all-trans retinoic acid (ATRA).

Description

METHODS OF TREATING ATRIAL FIBRILLATION AND CARDIAC

CONDUCTION DISEASES USING RETINOIDS

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/659,621 , filed June 13, 2024, and U.S. Provisional Patent Application No. 63/681 ,410, filed August 9, 2024, the entireties of both of which are incorporated herein by reference.

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under R01 HL165130 and R01 HL171989 awarded by the National Institutes of Health. The government has certain rights in the invention.

BACKGROUND

[0003] Atrial fibrillation (AF) is currently the most common arrhythmia encountered in clinical practice, with an estimated 37.6 million people affected globally. AF negatively impacts most cardiovascular outcomes, increasing stroke risk, heart failure, and death. Current therapeutic options for AF include anti-arrhythmic drugs and catheter ablation. However, recurrence of AF is common even with these therapies, which may result in significant morbidity and/or mortality. Importantly, neither therapy addresses underlying causes of AF, which may be attributed to pathological electrical and structural changes that occur in the left atrium (LA), known as atrial remodeling. As such, more effective AF therapies which address underlying AF causes and prevent AF recurrence are needed.

SUMMARY

[0004] In some embodiments, the present technology comprises methods of treating, preventing, or delaying a cardiotoxicity associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof. [0005] In some embodiments, the present technology comprises a pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof for use in treating, preventing, or delaying a cardiotoxicity associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

[0006] In some embodiments, the present technology comprises methods of treating, preventing, or delaying a cardiotoxicity associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of al l-trans retinoic acid (ATRA) or a pharmaceutically acceptable salt thereof.

[0007] In some embodiments, the present technology comprises a pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof for use in treating, preventing, or delaying a cardiotoxicity associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

[0008] In some embodiments, the present technology comprises methods of preventing atrial fibrosis associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments, the present technology comprises a pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof for use in preventing atrial fibrosis associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

[0010] In some embodiments, the present technology comprises methods of preventing atrial fibrosis associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof. [0011] In some embodiments, the present technology comprises a pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof for use in preventing atrial fibrosis associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

[0012] In some embodiments, the present technology comprises methods of preventing or delaying the onset of atrial arrhythmia in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of pharmaceutical composition comprising or consisting of a retinoid ora pharmaceutically acceptable salt thereof.

[0013] In some embodiments, the present technology comprises a pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof for use in preventing or delaying the onset of atrial arrhythmia in a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

[0014] In some embodiments, the present technology comprises methods of preventing or delaying the onset of atrial arrhythmia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof.

[0015] In some embodiments, the present technology comprises a pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof for use in preventing or delaying the onset of atrial arrhythmia in a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

[0016] In some embodiments, the present technology comprises methods of treating, preventing or delaying a cardiac conduction disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of a retinoid ora pharmaceutically acceptable salt thereof. [0017] In some embodiments, the present technology comprises a pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof for use in treating, preventing or delaying a cardiac conduction disease in a subject in need thereof, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject.

[0018] In some embodiments, the present technology comprises methods of treating, preventing or delaying a cardiac conduction disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof.

[0019] In some embodiments, the present technology comprises a pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof for use in treating, preventing or delaying a cardiac conduction disease in a subject in need thereof, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject.

[0020] In some embodiments, the present technology comprises methods of reducing one or more of a QRS duration, a ventricular fibrosis, or a ventricular mechanical dyssynchrony in a subject in need thereof compared to a control, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of a retinoid ora pharmaceutically acceptable salt thereof.

[0021] In some embodiments, the present technology comprises a pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof for use in method of reducing one or more of a QRS duration, a ventricular fibrosis, or a ventricular mechanical dyssynchrony in a subject in need thereof, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject.

[0022] In some embodiments, the present technology comprises methods of reducing one or more of a QRS duration, a ventricular fibrosis, or a ventricular mechanical dyssynchrony in a subject in need thereof compared to a control, comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of a ATRA or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments, the present technology comprises a pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof for use in method of reducing one or more of a QRS duration, a ventricular fibrosis, or a ventricular mechanical dyssynchrony in a subject in need thereof, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject.

BRIEF DESCRIPTION OF THE DRAWINGS

[0024] FIGS. 1 A-1 D illustrate all-trans retinoic acid (ATRA) prevention of ibrutini b- induced atrial fibrosis in mice. FIG. 1A shows an ibrutinib-ATRA study timeline in mice in accordance with the embodiments of the present technology. FIG. 1 B shows histological sections of left atrium (LA) sections in ATRA-treated mice of FIG. 1A compared to controls. FIG. 1 C shows fibrosis levels for the samples of 1 B. FIG. 1 D shows quantified fibrosis levels of FIG. 1 C. ATRA: All-trans retinoic acid; V: Vehicle. Scale bars 100pm. n=5 per group. Values show mean ± SD. One-way ANOVA with post-hoc Tukey's test was used. *p<0.05, ***p<0.001.

[0025] FIGS. 2A-2E illustrate heart rate, PR Interval, P duration, QRS duration, and QTc Interval, respectively, following ATRA and arsenic trioxide (ATO) induction therapy in human acute promyelocytic leukemia (APL) subjects. N = 25 patients. Paired t-test compares differences between groups. *p <0.05, **p<0.01 , ***p<0.001 , ****p<0.0001.

[0026] FIG. 3 shows P wave duration with ATRA and ATO therapy in human APL subjects at baseline and 3 months. N = 18 patients. Paired t-test compares differences between groups. *p <0.05.

[0027] FIGS. 4A-4L show ECG and histological assessment and left atrial ribonucleic acid sequencing (RNAseq) analysis of an ATRA reversal assessment in mice, in accordance with the embodiments of the present technology. FIG. 4A shows a timeline for assessing ATRA reversal. FIGS. 4B-4F show heart rate, PR Interval, P duration, QRS duration, and QTc interval, respectively, n = 5-8 per group. FIGS. 4G and 4H show LA fibrosis levels for the mice of FIG. 4A. Scale bar 100pm. n=5 per group. Values show mean±SD. One-way ANOVA with post-hoc Tukey's test was used. *p<0.05, ***p<0.001 , ****p<0.0001 . FIG. 4I shows counts of differentially expressed genes. (FDR 0.1 ) in Transverse Aortic Constriction (TAC) vs. Sham mice compared to TAC vs. TAC + dATRA mice. Overlapped genes represent ATRA-responsive genes in the TAC versus Sham mice. FIG. 4J shows a pairwise correlation between log fold change of differential gene expression in TAC vs. Sham compared to treatment condition, TAC vs TAC + dATRA (R=-0.45, P<2.2x10’¹⁶). FIG. 4K shows gene expression levels of metabolic processes in ATRA-treated TAC banded LA. FIG. 4L gene expression levels of fibrotic and inflammatory pathways in the mice of FIG. 4K. Abbreviations: ECG: electrocardiogram; TTE: transthoracic echocardiography; TAC: transverse aortic constriction; dATRA: delayed ATRA treatment; dV: delayed vehicle administration.

[0028] FIGS. 5A-5C illustrate effects of delayed ATRA treatment with withdrawal on mice having TAC-induced left atrial fibrosis. FIG. 5A shows an ATRA reversalwithdrawal study design and timeline in mice. FIG. 5B shows representative images of whole left atria for the mice of FIG. 5A. Arrowheads: Left atrial appendage. Scale bar: 100 pm. FIG. 5C shows quantified analysis of whole left atrial fibrosis by percent area for the mice of FIG. 5B. n = 3-5 per group. Values represent mean ± SEM. One-way ANOVA followed by a Tukey post hoc analysis to determine statistical significance. ****p<0.0001. Abbreviations: dATRA: delayed ATRA treatment; dV: delayed vehicle administration; 2WD: 2-week withdrawal.

[0029] FIGS. 6A-6F illustrate single nuclear RNA-seq (snRNA-seq) analysis in TAC-banded mice administered ATRA. FIG. 6A shows an unsupervised Uniform Manifold Approximation and Projection (UMAP) plot embedding LA snRNA-seq data (N=total of 15,000 nuclei from 15 LA per experimental condition). FIG. 6B shows UMAP plots of each condition of FIG. 6A and compositional changes in LA myocytes, macrophages, fibroblasts, and endocardial cells. FIG. 6C shows violin plots of experimental conditions of FIG. 6A for shifts in pro-inflammatory CCR2+ macrophage proportion in TAC+V LA and reversions to CD163-enriched resident macrophages in TAC+ATRA LA. FIGs. 6D-6F show cell communication circle plots of Platelet-derived growth factor C (Pdgfc) signaling in TAC+V mice (FIG. 6E) and TAC+ATRA mice (FIG. 6F) compared to controls (FIG. 6D). DETAILED DESCRIPTION

[0030] The present technology comprises all-trans retinoic acid (ATRA) for treating, preventing, or otherwise ameliorating, atrial fibrillation (AF), atrial fibrosis, and/or conduction disease. The present technology may prevent or reverse pathological atrial remodeling and improve atrial His-Purkinje system conduction parameters.

Definitions

[0031] To facilitate an understanding of the principles and features of the various embodiments of the technology, various illustrative embodiments are explained below. Although exemplary embodiments of the technology are explained in detail, it is to be understood that other embodiments are contemplated. Accordingly, it is not intended that the technology is limited in its scope to the details of construction and arrangement of components set forth in the following description or examples. The technology is capable of other embodiments and of being practiced or carried out in various ways. Also, in the context of exemplary embodiments, specific terminology will be resorted to for the sake of clarity.

[0032] The term “about” means a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length that varies by acceptable levels in the art. Typically, such variation may be as much 10% above and below a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length and such variation may be influenced by standard applicable measurement practices. When the term “about” is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. The terms "a," "an," and "the" do not denote a limitation of quantity, but rather denote the presence of "at least one" of the referenced item.

[0033] The terms "patient", "individual", "subject", and "animal" are used interchangeably herein and refer to mammals, including, without limitation, human and veterinary animals (e.g., cats, dogs, cows, horses, sheep, pigs, etc.) and experimental animal models.

[0034] The terms "treat" or "treatment" of a state, disorder or condition include: (1 ) preventing or delaying the appearance of at least one clinical or sub-clinical symptom of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; or (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or sub-clinical symptom thereof; or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or sub-clinical symptoms. The benefit to a subject to be treated is either statistically significant or at least perceptible to the patient or to the physician.

[0035] An "effective amount" applied to dose or amount refers to that quantity of a compound or composition that is sufficient to result in a desired activity upon administration to a subject in need thereof. Note that when a combination of active compounds is administered, the effective amount of the combination may or may not include amounts of each ingredient that would have been effective if administered individually. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the condition being treated, the particular drug or drugs employed, the mode of administration, and the like.

[0036] A "therapeutically effective amount" of a compound of the present technology is an amount sufficient to elicit a therapeutic benefit in the treatment of a state, disorder or condition or to delay or minimize one or more symptoms associated with the state, disorder or condition. A therapeutically effective amount of a compound means an amount of therapeutic agent, alone or in combination with other therapies, which elicits a therapeutic benefit in the treatment of the condition. The term "therapeutically effective amount" may encompass an amount that improves overall therapy, reduces or avoids symptoms or causes of the condition, and/or enhances the therapeutic efficacy of another therapeutic agent.

[0037] As used herein, the term "pharmaceutically acceptable salt" means those salts of compounds of the technology that are safe for application in a subject. Pharmaceutically acceptable acid salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., 1 ,11-methylene-bis-(2- hydroxy-3-naphthoate)) salts. Certain compounds of the present disclosure may form pharmaceutically acceptable salts with various amino acids. Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17^th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418 and Berge, SM et al, Journal of Pharmaceutical Science, 1977, 66, 1 , 1-19.

[0038] In the context of the field of medicine, the term "prevent" encompasses any activity which reduces the burden of mortality or morbidity from disease. Prevention may occur at primary, secondary and tertiary prevention levels. While primary prevention avoids the development of a disease, secondary and tertiary levels of prevention encompass activities aimed at preventing the progression of a disease and the emergence of symptoms as well as reducing the negative impact of an already established disease by restoring function and reducing disease-related complications.

[0039] The term “control” as used herein may refer to any means in the art for comparison to assess the pharmaceutical compositions and methods of the present technology. The control may comprise a pharmaceutical composition lacking one or more features or having one or more different features relative to the pharmaceutical compositions of the present technology. With respect to methods, the control may comprise the subject at baseline, a non-treated subject, or a subject subjected to a method lacking one or more features or steps relative to the methods of the present technology or an alternate method thereof.

[0040] The methods and techniques of the present technology are generally performed according to conventional methods well known in the art and as described in various general and more specific references that are cited and discussed throughout the present specification unless otherwise indicated. See, e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual, 2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989) and Ausubel et al., Current Protocols in Molecular Biology, Greene Publishing Associates (1992), and Harlow and Lane Antibodies: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1990), which are incorporated herein by reference. Enzymatic reactions and purification techniques are performed according to manufacturer's specifications, as commonly accomplished in the art or as of the present technology. The nomenclatures used in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry of the present technology are those well-known and commonly used in the art. Standard techniques are used for chemical syntheses, chemical analyses, pharmaceutical preparation, formulation, and delivery, and treatment of patients.

[0041] It is intended that each term contemplates its broadest reasonable meaning as understood by those skilled in the art and includes all technical equivalents which operate in a similar manner to accomplish a similar purpose.

Methods

[0042] The present technology comprises methods of treating, preventing, or otherwise ameliorating atrial arrhythmia, cardiotoxicities (e.g., atrial fibrillation (AF)), such as those induced by an anti-cancer agent, and/or cardiac conduction diseases, in a subject in need thereof. The methods comprise administering to the subject, a pharmaceutical composition comprising, consisting essentially of, or consisting of retinoids or derivatives thereof. In some embodiments, the retinoid or derivative thereof is ATRA. ATRA may reverse, reduce, or prevent pathological atrial remodeling, including electrical, fibrotic, metabolic, and pro-thrombotic effects of diseased LA. Additionally, ATRA may prevent an onset of atrial arrhythmias and/or AF by targeting or affecting underlying atrial myopathies. As such, use of the pharmaceutical compositions comprising, consisting essentially of, or consisting of ATRA may reduce the negative sequelae associated with AF, including heart failure and left atrial thrombus formation. There is currently no disease modifying therapy for atrial myopathies. Therefore, the pharmaceutical compositions of the present technology comprising, consisting essentially of, or consisting of a retinoid or derivative thereof, such as ATRA, may represent a first-in-class therapy for reversing atrial myopathy and may potentially reduce a risk of developing AF, compared to controls.

Methods of treating, preventing or delaying Atrial Fibrillation (AF)

[0043] Current therapies for AF, such as anti-arrhythmic drugs and catheter ablation, are both thought to maintain sinus rhythm but may also be associated with high rates of recurrence and do not address the underlying pathological changes in the left atrium that contribute to disease progression. Therefore, the present technology comprises methods and compositions for treating, preventing, delaying, or otherwise ameliorating AF by administering a therapeutically effective amount of a pharmaceutical composition comprising a retinoid or a derivative thereof (e.g., a pharmaceutically acceptable salt), such as ATRA. In some embodiments, the pharmaceutical composition is orally administered to the subject.

[0044] In some embodiments, the pharmaceutical compositions are administered to the subject to treat, prevent, reduce, or otherwise ameliorate an underlying myopathy or cardiac effect associated with AF, such as atrial remodeling.

Atrial Remodeling:

[0045] The present technology comprises methods of treating, preventing, delaying an onset of, or otherwise ameliorating an atrial arrhythmia in a subject in need thereof by administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising, consisting essentially of, or consisting of a retinoid or a derivative thereof, such as ATRA. In some embodiments, the methods comprise oral administration of the pharmaceutical composition.

[0046] In some embodiments, the atrial arrhythmia is atrial tachycardia, atrial flutter, and/or atrial fibrillation.

[0047] In some embodiments, the atrial arrhythmia is atrial fibrillation.

[0048] In some embodiments, the methods comprise preventing or reversing atrial fibrosis in a subject in need thereof.

[0049] The method comprising an administration of a retinoid or a pharmaceutically acceptable salt thereof (e.g., ATRA) as of the present technology has shown reduction in an electrical, a structural, and/or a functional atrial remodeling in mouse models. The method comprising an administration of a retinoid or a pharmaceutically acceptable salt thereof (e.g., ATRA) as of the present technology has shown reduction in P wave duration of ECG of the patients. In some embodiments, the method for treating, preventing, or delaying the onset of atrial arrhythmia (e.g., atrial fibrillation) characterized by an atrial remodeling as of the present technology may be used to treat subjects who are at risk for AF (stage I) or the subjects with pre-atrial fibrillation (Stage II) according to Atrial Fibrillation Guidelines; and who have an evidence of electrical, structural, and/or functional atrial remodeling, wherein evidence of atrial remodeling is determined by an ECG, a holter, a telemetry, and/or a cardiac imaging. In some embodiments, the method of the present technology may be used to treat the subjects to prevent or reverse atrial remodeling. In some embodiments, the method of the present technology may be used to treat the subjects to prevent the onset of atrial arrhythmia (e.g., atrial fibrillation).

[0050] In some embodiments, the CHARGE-AF risk score (Alonso et al., Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium. J Am Heart Assoc. 2013 Mar 18;2(2):e000102; incorporated herein by reference in its entirety) or the C2HEST risk score (Li et al., A Simple Clinical Risk Score (C2HEST) for Predicting Incident Atrial Fibrillation in Asian Subjects: Derivation in 471,446 Chinese Subjects, With Internal Validation and External Application in 451,199 Korean Subjects. Chest. 2019 Mar; 155(3):510-518; incorporated herein by reference in its entirety) may be used to determine risk of AF and atrial remodeling in the subject.

[0051] In some embodiments, the subject diagnosed with the onset of atrial arrhythmia (e.g., atrial fibrillation) characterized by the atrial remodeling is selected from the subject having hypertension, sleep apnea, paroxysmal atrial fibrillation, diabetes, heart failure, coronary artery disease, and/or is over 60 years old.

[0052] The improvement in the subject diagnosed with the onset of atrial arrhythmia (e.g., atrial fibrillation) characterized by the atrial remodeling results in reduction in P wave duration on ECG after the method of treatment or prevention of the present technology as compared to a control subject or to observation of the subject without the administration of said retinoid or a pharmaceutically acceptable salt thereof. In some embodiments, the P wave duration is less than about 100 milliseconds after administration of the retinoid or pharmaceutically acceptable salt thereof to the subject.

Methods of treating, preventing or delaying a cardiac conduction disease

[0053] The present technology comprises methods of treating, preventing, delaying an onset of, or otherwise ameliorating a cardiac conduction disease in a subject in need thereof. The methods comprise administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising, consisting essentially of, or consisting of a retinoid or a derivative thereof, such as ATRA. In some embodiments, the pharmaceutical composition is orally administered to the subject. The subject have or be at risk of developing the cardiac conduction disease.

[0054] In some embodiments, the cardiac conduction disease is an atrial conduction disease, a His-Purkinje conduction disease, and/or a left bundle branch block (LBBB).

[0055] The cardiac conduction disease may be determined by any methods known to those of ordinary skill in the art. In some embodiments, the cardiac conduction disease is determined by recording an electrical activity of a heart, including, but not limited to, use of an electrocardiogram (ECG). The ECG may be used to measure the electrical activity of the heart. Nonlimiting examples of such measurements include a measurement of P wave duration, PR interval, QRS duration, and/or QTc interval. The cardiac conduction disease may be characterized by one or more of: P wave prolongation, long PR interval, long QRS duration, and long QTc interval on ECG.

[0056] A normal range of ECG parameters for ECG waves and intervals may comprise one or more of the following conduction intervals: P wave: about 80 milliseconds; PR interval: about 120- about 200 milliseconds; PR segment: about 50- about 120 milliseconds; QRS complex: about 80- about 100 milliseconds; and QT interval: about 420 milliseconds or less if heart rate is about 60 beats per minute (bpm). Conduction intervals beyond these ranges may represent conduction abnormalities.

[0057] The methods of the present technology may improve an atrioventricular conduction (analyzed by PR interval on ECG) level and/or improve a His-Purkinje dependent ventricular activation level (analyzed by QRS duration on ECG), relative to a control. In some embodiments, the methods prevent or reduce a need for pacemaker implantation, relative to a control.

[0058] In some embodiments, the methods of the present technology are employed in conjunction with a pacemaker implantation. In some embodiments, the methods minimize a pacing level (i.e., pacing using a pacemaker) to reduce a risk of pacing induced cardiomyopathy. In some embodiments, the methods extend a device battery life of a pacemaker. [0059] In some embodiments, the methods as of the present technology results in an elimination of need of a pacemaker, a reduction in the usage of a pacemaker, and/or an elimination of need of a cardiac resynchronization therapy.

[0060] In some embodiments of the method of treating, preventing or delaying a cardiac conduction disease as of the present technology, the cardiac conduction disease is selected from atrioventricular conduction disease, His-Purkinje conduction disease, LBBB, hear failure, and/or leukemia-associated conduction disease. In some embodiments, leukemia is an acute promyelocytic leukemia.

[0061] In some embodiments, the methods of the present technology improve an atrioventricular conduction, His-Purkinje conduction disease (e.g., a His-Purkinje dependent ventricular activation), and/or a LBBB. In some embodiments, the methods of the present technology comprise reducing one or more of: an atrioventricular conduction, P wave duration, PR interval, QRS duration, and/or QTc interval in the subject, relative to a control. Such reductions may be assessed using ECG techniques after the method of treatment compared to a control. The reduction in PR interval may indicate an improvement in atrioventricular conduction. The reduction in QRS duration may indicate an improvement in His-Purkinje dependent ventricular activation. In some embodiments, the method prevents, reduces, or otherwise ameliorates a ventricular fibrosis or a ventricular mechanical dyssynchrony. The ventricular fibrosis may be assessed by, but is not limited to, a cardiac MRL The ventricular mechanical dyssynchrony may be assessed by, but is not limited to, an echocardiography (EKG) and/or a cardiac magnetic resonance imaging (MRI).

[0062] In some embodiments, the methods improve or delay a worsening of or progression in a New York Heart Association (NYHA) functional class in the subject. The subject may comprise a Class I, Class II, Class III, orClas IV NYHA functional class. The NYHA class may be used to indicate a severity of heart failure symptoms or may be used to assess response to treatment and/or to guide management in clinical research.

[0063] In some embodiments, the methods reduce a level of one or more biomarkers (e.g., a biomarker of heart failure severity), compared to a control. The biomarker may comprise a gene expression level, a protein level, or a protein activity level. Nonlimiting examples of such biomarkers include a B-type natriuretic peptide (BNP) level (National Center for Biotechnology Information (NCBI) Accession: NP_002512.1; NM.002521.3) or a N-terminal (NT)-proBNP level (NCBI Accession(s): P16860.1; P07634.2; P16859.1).

[0064] In some embodiments, the methods maintain or enhance a voltage-gated Na⁺ channels (e.g., SCN5A) (NCBI Accession/Gene ID: AAI44622.1 ; AAH51374.1 ; 6331 ) and/or a gap junction Connexin 43 (GJA1) (NCBI Accession/Gene ID: P18246.2; NP_000156.1 ; AAA52131.1 ; 2697) gene expression level or protein level.

Methods of treating, preventing or delaying cardiotoxicity induced by an anti-cancer agent

[0065] The present technology comprises methods of treating, preventing, delaying an onset of, or otherwise ameliorating a cardiotoxicity (e.g., a cardiac-related adverse event) associated with use of a tyrosine-kinase inhibitor (e.g., an anti-cancer agent comprising or consisting of a tyrosine-kinase inhibitor), in a subject in need thereof, the methods comprising administering to the subject a pharmaceutical composition comprising, consisting essentially of, or consisting of a retinoid or a derivative thereof, such as ATRA. The cardiotoxicity may be induced by the tyrosine- kinase inhibitor. The methods comprise administering to the subject a therapeutically effective amount of the pharmaceutical composition. In some embodiments, the pharmaceutical composition is orally administered to the subject.

[0066] In some embodiments, the methods include treating, preventing ordelaying a cardiotoxicity (e.g., a cardiac-related adverse event) induced by an anti-cancer therapy, in a subject in need thereof, the methods comprising or consisting of administering to the subject a therapeutically effective amount of a retinoid or a pharmaceutically acceptable salt thereof.

[0067] In some embodiments, the cardiotoxicity comprises an atrial arrhythmia. In some embodiments, the atrial arrhythmia is atrial tachycardia, atrial flutter, and/or atrial fibrillation.

[0068] In some embodiments, the subject diagnosed with a cardiotoxicity and the subject diagnosed with a cancer are the same subject. Subjects diagnosed with cancer may have received or is receiving a cancer therapy, such as a cancer therapy that causes cardiotoxicity over a time. Non-limiting examples of cancer therapies include a small molecule anti-cancer agent.

[0069] In some embodiments, the subject is being or has been administered the anti-cancer agent comprising or consisting of the tyrosine-kinase inhibitor. In some embodiments, the tyrosine-kinase inhibitor is a Bruton's tyrosine-kinase (BTK) inhibitor. In some embodiments, the tyrosine-kinase inhibitor is ibrutinib (e.g., IMBRLMCA®).

[0070] In some embodiments, the methods comprise assessing an electrical activity of a heart, and/or conducting a safety assessment. In some embodiments, assessing the electrical activity of the heart comprises a measurement of one or more of a P wave duration, a PR interval, a QRS duration, and/or a QTc interval. Such measurements may be made using an electrocardiogram (ECG).

[0071] The safety assessments may include, but are not limited to, testing of a liver function, a thyroid function, a complete blood count, a coagulation panel, a renal function panel (Chemi 0), a lipid panel, and/or an evaluation of adverse events. The evaluation of adverse events may include, but are not limited to, evaluation of the adverse events of special interest (AESIs), serious adverse events (SAEs), and/or treatment emergent adverse events (TEAE). In some embodiments, the safety assessment comprises clinical laboratory tests, physical examinations, vital signs, and/or ECGs.

[0072] In some embodiments, the methods reduce one or more of: a P wave duration, a PR interval, a QRS duration, and/or a QTc interval in the subject.

[0073] In some embodiments, the P wave duration in the subject is less than about 100 milliseconds after administration of the pharmaceutical composition of the present technology. In some embodiments, the P wave duration in the subject is about 80 milliseconds after administration of the pharmaceutical composition.

[0074] In some embodiments, the P wave duration in the subject is less than 100 milliseconds after administration of the pharmaceutical composition of the present technology. In some embodiments, the P wave duration in the subject is equal to or less than 80 milliseconds after administration of the pharmaceutical composition.

[0075] In some embodiments, the PR interval in the subject is about 120 to about 200 milliseconds after administration of the pharmaceutical composition. [0076] In some embodiments, the PR interval in the subject is at least 120 to at least 200 milliseconds after administration of the pharmaceutical composition.

[0077] In some embodiments, the PR interval in the subject is at least about 120 to at least about 200 milliseconds after administration of the pharmaceutical composition.

[0078] In some embodiments, the QRS duration in the subject is about 80 to about 100 milliseconds after administration of the pharmaceutical composition.

[0079] In some embodiments, the QRS duration in the subject is at least 80 to at least 100 milliseconds after administration of the pharmaceutical composition.

[0080] In some embodiments, the QRS duration in the subject is at least about 80 to at least about 100 milliseconds after administration of the pharmaceutical composition.

[0081] In some embodiments, the QTc interval in the subject is about 420 milliseconds or less after administration of the pharmaceutical composition.

[0082] In some embodiments, the QTc interval in the subject is at least 420 milliseconds or less after administration of the pharmaceutical composition.

[0083] In some embodiments, the QTc interval in the subject is at least about 420 milliseconds or less after administration of the pharmaceutical composition.

[0084] Assessing the electrical activity of the heart may be done up to 15 days, one month, two months, three months, four months, five months, six months or until an improvement in the electrical activity is achieved after administering a pharmaceutical composition of the present technology.

[0085] In some embodiments, P wave duration and/or QRS duration are measured at about 30 days, about 60 days, and/or about 90 days after administering a pharmaceutical composition of the present technology to the subject.

[0086] In some embodiments, P wave duration and/or QRS duration are measured at least 30 days, at least 60 days, and/or at least 90 days after administering a pharmaceutical composition of the present technology to the subject. [0087] In some embodiments, P wave duration and/or QRS duration are measured at least about 30 days, at least about 60 days, and/or at least about 90 days after administering a pharmaceutical composition of the present technology to the subject.

[0088] In some embodiments, the methods comprise assessing one or more of a left atrium (LA) enlargement, left atrial fibrosis burden, left atrial systolic and diastolic function of the subject, and/or a left atrium (LA) strain measurement. Such assessments may be used to determine an efficacy of the methods of the present technology. The LA enlargement assessment and/or LA strain measurement may be done up to 15 days, one month, two months, three months, four months, five months, six months or until the improvement is achieved after administering a pharmaceutical composition of the present technology. In some embodiments, the LA enlargement assessment and/or LA strain measurement is performed at 90 days after administering a pharmaceutical composition of the present technology.

[0089] In some embodiments, the methods reduce a left atrium (LA) enlargement, and/or a left atrium fibrosis (e.g., a scarring) of the subject. In some embodiments, the methods as of the present technology improves left atrium strain parameters and/or left atrium systolic and diastolic function of the subject.

[0090] In some embodiments, the methods of the present technology comprise reduced or no adverse events, such as myocarditis and/or pericarditis, compared to controls.

[0091] In some embodiments, the methods comprise conducting or evaluating an assessment that may be used to predict a heart condition or disorder, such as AF. The assessment may comprise an assessment of a polygenic risk score (Miyazawa et al., Cross-ancestry genome-wide analysis of atrial fibrillation unveils disease biology and enables cardioembolic risk prediction. Nat Genet. 2023 Feb;55(2):187-197; incorporated herein by reference in its entirety), a variation at genetic level, and/or using artificial intelligence (see Harmon DM, Artificial Intelligence for the Detection and Treatment of Atrial Fibrillation, Arrhythm Electrophysiol Rev. 2023 Apr 19;12:e12; incorporated herein by reference in its entirety) in addition to the assessment methods of the present technology. Combination Therapies

[0092] The present technology may include combination therapies, such as, a retinoid or a pharmaceutically acceptable salt thereof and an anti-cancer agent. Use of the retinoid or a pharmaceutically acceptable salt thereof may prevent, delay or treat a cardiotoxicity induced by an anti-cancer therapy as disclosed herein. In some embodiments, the anti-cancer agent comprises a small molecule or a derivative thereof. Exemplary small molecules or derivatives thereof include kinase inhibitors. In some embodiments, the kinase inhibitor is a tyrosine-kinase inhibitor.

[0093] Tyrosine-kinase inhibitors may be associated with cardiovascular toxicities. To treat, prevent, reduce, or otherwise ameliorate unwanted effects, including adverse cardiac events, of tyrosine-kinase inhibitors, pharmaceutical compositions of the present technology comprising, consisting essentially of, or consisting of a retinoid or a derivative thereof, may be administered to a subject. In some embodiments, the retinoid or derivative thereof is ATRA. The pharmaceutical compositions may be administered before, during, or after administration of a tyrosine-kinase inhibitor as a combination therapy. In some embodiments, combination therapies of the present technology comprise administration of a pharmaceutical composition of the present technology and an anti-cancer agent comprising, consisting essentially of, or consisting of a tyrosine- kinase inhibitor.

[0094] The tyrosine-kinase inhibitor may be a Bruton's tyrosine-kinase (BTK) inhibitor. In some embodiments, the tyrosine-kinase inhibitor is ibrutinib. A BTK may encompass Bruton's tyrosine-kinase from Homo sapiens, as described in, U.S. Pat. No. 6,326,469 (Gen Bank Accession No. NP 000052), incorporated herein by reference in its entirety. Ibrutinib may also comprise pharmaceutically acceptable salts, solvates, esters, acids, and prodrugs thereof. In some embodiments, isomer or chemically protected forms of ibrutinib may be used as an anti-cancer agent. [0095] Ibrutinib may be referred to by the molecular formula C25H24NeO2.the chemical name, 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1 H-pyrazolo[3,4-d]pyrimidin- 1 -yl]-1 -piperidinyl]-2-propen-1 -one, or the chemical structure:

[0096] The combination therapies of the present technology may refer to a separate administration of the pharmaceutical composition and the anti-cancer agent comprising the tyrosine-kinase inhibitor, to the subject. The separate administration may comprise a sequential or a simultaneous administration of the pharmaceutical composition and the anti-cancer agent comprising the tyrosine-kinase inhibitor. Each compound (e.g., the pharmaceutical composition and the anti-cancer agent comprising the tyrosine-kinase inhibitor) may be administered via a same route or different route to the subject at the same or different time. In some embodiments, the pharmaceutical composition is administered before the administration of the tyrosine-kinase inhibitor to the subject. In some embodiments, the pharmaceutical composition is administered concurrently with the tyrosine-kinase inhibitor to the subject. In some embodiments, the retinoid or pharmaceutically acceptable salt thereof is administered after the administration of the tyrosine-kinase inhibitor to the subject.

[0097] The administration route for combination therapies of the present technology may be any mode of administration known in the art, including but not limited to injection into involved tissue, intraarterially, intravenously, via an implanted device, parenterally, topically, subcutaneously, intradermally, transdermally (e.g., by transdermal patch), via intracorporal application during surgery, intramuscularly, intraperitoneally, buccally, intrathecally, intracranially, intratracheally, intranasal, intraocular, or orally. In some embodiments, the combination therapy is administered orally. [0098] The dosage administered of both the pharmaceutical compositions of the present technology and the anti-cancer agent comprising the tyrosine kinase inhibitor may be dependent upon the route of administration, age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.

[0099] In some embodiments, the combination therapy treats, prevent or delays cardiotoxicity induced by an anti-cancer agent. For example, if an anti-cancer agent comprising an administration of a kinase inhibitor to the cancer subject leads to one or more cardiotoxicity upon receiving kinase inhibitor in the subject, it may be appropriate to administer the retinoid or a pharmaceutically acceptable salt thereof of the present technology in combination with an anti-cancer agent (e.g., a tyrosine-kinase inhibitor) to treat, prevent or delay cardiotoxicity induced by the anti-cancer agent.

[0100] In some embodiments, the combination therapy treats, prevents, delays, or otherwise ameliorates a cardiotoxicity induced by ibrutinib-based therapies. In some embodiments, the pharmaceutical compositions of the present technology are administered in combination with ibrutinib to treat, prevent, delay, or otherwise ameliorate a cardiotoxicity induced by ibrutinib based therapy.

[0101] Non-limiting examples of cardiotoxicity induced by the anti-cancer agent comprising or consisting of a tyrosine-kinase inhibitor include an atrial flutter, an atrial fibrosis, susceptibility to an atrial arrhythmia (e.g., atrial fibrillation), and/or an atrial arrhythmia (e.g., atrial fibrillation).

[0102] In some embodiments, the combination therapies may reduce or prevent an off-target effect on C-terminal Src kinase (CSK) (NCBI Accession/Gene ID: KAI2575171 .1 ; 6714) that may inhibit CSK gene or protein expression or activity, relative to a control.

[0103] In some embodiments, the combination therapies may treat a cardiotoxicity induced by an anti-cancer agent in a subject having a condition or disorder, such as cancer. In some embodiments, the cancer is a hematological malignancy, such as, but not limited to, a B-cell malignancy. In some embodiments, the condition or disorder is a leukemia. In some embodiments, the leukemia is chronic lymphocytic leukemia (CLL). In other embodiments, the condition or disorder is a lymphoma. In some embodiments, the lymphoma is selected from the group consisting of small lymphocytic lymphoma (SLL), Mantle cell lymphoma (MCL), Marginal zone lymphoma (MZL), and Waldenstrom’s macroglobulinemia (WM).

[0104] In some embodiments, an anti-cancer agent comprising the tyrosine-kinase inhibitor (e.g., ibrutinib) is administered at a dose ranging from about 1 .25 mg/kg/day to about 12.5 mg/kg/day. In some embodiments, the anti-cancer agent (e.g., ibrutinib) is administered at a dose selected from about 1 .25 mg/kg/day, about 2.5 mg/kg/day, about 5 mg/kg/day, about 8.3 mg/kg/day, about 12.5 mg/kg/day and about 25 mg/kg/day.

[0105] In some embodiments, an anti-cancer agent comprising the tyrosine-kinase inhibitor (e.g., ibrutinib) is administered at a dose ranging from at least 1.25 mg/kg/day to at least 12.5 mg/kg/day. In some embodiments, the anti-cancer agent (e.g., ibrutinib) is administered at a dose selected from at least 1 .25 mg/kg/day, at least 2.5 mg/kg/day, at least 5 mg/kg/day, at least 8.3 mg/kg/day, at least 12.5 mg/kg/day and at least 25 mg/kg/day.

[0106] In some embodiments, an anti-cancer agent comprising the tyrosine-kinase inhibitor (e.g., ibrutinib) is administered at a dose ranging from at least about 1.25 mg/kg/day to at least about 12.5 mg/kg/day. In some embodiments, the anti-cancer agent (e.g., ibrutinib) is administered at a dose selected from at least about 1.25 mg/kg/day, at least about 2.5 mg/kg/day, at least about 5 mg/kg/day, at least about 8.3 mg/kg/day, at least about 12.5 mg/kg/day and at least about 25 mg/kg/day.

[0107] In some embodiments, an anti-cancer agent (e.g., ibrutinib) is administered at a dose ranging from about 1 mg to about 1680 mg per day. In some embodiments, an anti-cancer agent (e.g., ibrutinib) is administered at a dose ranging from about 140mg to about 420 mg per day. The anti-cancer agent may be administered as a single dose or as divided doses simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four, five or more sub-doses per day.

[0108] In some embodiments, an effective amount of the anti-cancer agent comprising the tyrosine-kinase inhibitor (e.g., ibrutinib) is administered once or multiple times daily. In some embodiments, the effective amount comprises a single dose. In some embodiments, the effective amount comprises multiple administrations with a time span between multiple administration every 6 hours or every 8 hours. [0109] The pharmaceutical composition of the present technology may be administered fora same duration as a duration of administration of the anti-cancer agent comprising the tyrosine-kinase inhibitor. In some embodiments, the pharmaceutical compositions are administered until no or reduced cardiotoxicity is achieved in the subject. In some embodiments, the subject has a cancer therapy induced cardiac- adverse events.

Subjects

[0110] The subjects in need thereof of the present technology may comprise those at risk of developing atrial fibrillation. In some embodiments, the subject has not yet manifested AF.

[0111] In some embodiments, the subject comprises Stage 1 (at risk for AF) Stage 2 (Pre-AF), Stage 3 (AF; e.g., Stage 3A (paroxysmal AF), or Stage 3B (persistent AF), Stage 3C (long-standing persistent AF), Stage 3D (successful AF ablation)) AF.

[0112] In some embodiments, the subject comprises one or more cardiovascular subject structural or electrical predispositions to AF. Nonlimiting examples of such predispositions include atrial enlargement or conduction disease based on electrocardiography or echocardiography, frequent atrial ectopy, short bursts of atrial tachycardia, atrial flutter, or other high-risk clinical conditions, such as hypertension, diabetes, sleep apnea, heart failure, and coronary artery disease.

[0113] In some embodiments, the subject comprises an electrical, a structural, and/or a functional atrial remodeling. The atrial remodeling may be determined by an ambulatory holter or a telemetry monitoring; or with cardiac imaging. The electrical, structural, and/or functional atrial remodeling may be analyzed using an ECG. The cardiac imaging may include, but are not limited to, an echocardiography, a cardiac CT, and/or a cardiac MRI. Electrical remodeling may comprise increased triggered activity and by abnormalities in conduction and refractoriness and may be evidenced by prolonged P wave duration, such as on ECG, a holter, or a telemetry. The prolonged P wave duration as determined by ECG is more than about 100 milliseconds in the subjects having electrical remodeling. Electrical remodeling may also be evidenced by a frequent atrial ectopy, short runs of atrial tachycardia or an atrial flutter. The structural and functional remodeling may comprise increased fibrosis, altered metabolism, and increased thrombosis, and may be evidenced by atrial enlargement, hypertrophy, and/or abnormal heart muscle contraction or relaxation by analyzing contractile or relaxation parameters, strain imaging, and/or left atrial appendage emptying time.

[0114] In some embodiments, the subject comprises one or more risk factors associated atrial remodeling, including, but not limited to, an age greater than 60, hypertension, diabetes, and/or heart failure.

[0115] In some embodiments, the subjects of the present technology have or have had a cancer. The subjects of the present technology may have a condition or disorder selected from the group consisting of B-cell cancer, chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), Mantle cell lymphoma (MCL), Waldenstrom's macroglobulinemia, Marginal zone lymphoma (MZL), and Waldenstrom's macroglobulinemia (WM).

[0116] In some embodiments, the subject has undergone or is undergoing therapy with an anti-cancer agent including a tyrosine-kinase inhibitor (e.g., ibrutinib).

[0117] In some embodiments, the subject has a symptomatic Mobitz I atrioventricular block, a Mobitz II atrioventricular block, or a third-degree atrioventricular block. In some embodiments, the subject is a subject who qualifies for pacemaker implantation.

[0118] In some embodiments, the method of the present technology is used to treat a subject diagnosed with heart failure. In some embodiments, the method of the present technology is used to treat subject diagnosed with heart failure who qualifies for cardiac resynchronization therapy. The subjects diagnosed with heart failure having prolongation of QRS duration on ECG with LBBB are associated with the increased morbidity and mortality. For every 10 ms (milliseconds) prolongation of QRS duration on ECG with LBBB in the subjects diagnosed with heart failure, there is an associated increase in mortality by 18%. In some embodiments, the method comprising an administration of a retinoid or a pharmaceutically acceptable salt thereof (e.g., ATRA) is used to treat subjects diagnosed with heart failure and who have LBBB to reduce QRS duration on ECG and thereby to prevent the need for cardiac resynchronization therapy. In some embodiments, the method comprising an administration of a retinoid or a pharmaceutically acceptable salt thereof (e.g., ATRA) is used to treat subjects diagnosed with heart failure and atrioventricular block who have an increased burden of ventricular pacing. Ventricular pacing more than 40% is an indication to implant a cardiac resynchronization device.

[0119] In some embodiments, the subject is human.

Pharmaceutical Compositions

[0120] The present technology comprises pharmaceutical compositions comprising, consisting essentially of, or consisting of retinoids or derivatives thereof for use in treating, preventing, or otherwise ameliorating atrial arrhythmia, cardiotoxicities (e.g., AF), such as those induced by an anti-cancer agent, and/or cardiac conduction diseases, in a subject in need thereof. Nonlimiting examples of the retinoids or derivatives thereof include retinol (Vitamin A), retinal (retinaldehyde), retiferol, tretinoin (retinoic acid), isotretinoin, alitretinoin (9-cis-retinoic acid), etretinate, acitretin, adapalene, bexarotene, tazarotene, and trifarotene. In some embodiments, the retinol is a retinol isomer. In some embodiments, the retinol isomer is all-trans-retinol, 13-cis- retinol, 11 -cis-retinol, 9-cis-retinol, 3,4-didehydro-retinol, 3,4-didehydro-13-cis-retinol; 3,4-didehydro-11 -cis-retinol; or 3,4-didehydro-9-cis-retinol. In some embodiments, the derivatives thereof comprises a retinoid metabolite.

[0121] In some embodiments, the retinoid or the derivative thereof is a compound comprising a retinoid structure, a retinoid metabolite, or an agent that may be metabolized into a retinoid or retinoid metabolite. The retinoid may include a compound that is an analog or mimic of a retinoid or a retinoid metabolite, or an agent that may be metabolized into an analog or mimic of a retinoid or a retinoid metabolite. In some embodiments the retinoid may be any retinoid disclosed in U.S. Pat. Nos. 5,648,563; 5,648,385; 5,618,839; 5,559,248; 5,616,712; 5,616,597; 5,602,135; 5,599,819;

5,556,996; 5,534,516; 5,516,904; 5,498,755; 5,470,999; 5,468,879; 5,455,265;

5,451 ,605; 5,426,118; 5,407,937; 5,399,586; 5,399,561 ; 5,391 ,753, each of which is incorporated herein by reference in their entireties.

[0122] In some embodiments, the retinoid is a retinoic acid. In some embodiments, the retinoid is all-trans retinoic acid (ATRA).

[0123] ATRA and tretinoin may be considered chemical compounds of retinoids pharmacological class. Chemical name of ATRA is 3,7-dimethyl-9-(2,6,6- trimethylcyclohex-1 -enyl)nona-2,4,6,8-all-trans-etraenoic acid. [0124] ATRA may be referred to by the formula, C20H28O2, or the chemical structure:

[0125] ATRA may include VESANOID®(tretinoin), which may be present in capsules containing 10 mg tretinoin for the treatment of acute promyelocytic leukemia (APL).

[0126] In some embodiments the retinoid or derivative thereof comprises Alitretinoin (also known as 9-cis-Tretinoin), which may comprise Panretin® (alitretinoin) and may be prepared, for example as described in C. D. Robeson et al., Chemistry of Vitamin A. XXIV. The Synthesis of Geometric Isomers of Vitamin A via Methyl {3- Methylglutaconate-, J. Am. Chem. Soc. 77, 4111 (1955); M. Matsui et al., Synthetic Studies on Vitamin A; J. Vitaminol. 4, 178 (1958); M. F. Boehm et al., Synthesis and structure-activity relationships of novel retinoid X receptor-selective retinoids. J Med Chem. 1994 Sep 2;37(18):2930-41 ; (each of which is incorporated herein by reference in its entirety), or by processes equivalent thereto. In some embodiments, the retinoid or derivative thereof comprises Bexarotene (also known as Targret) or Targretin® (bexarotene) and may be prepared for example as described in M. F. Boehm et al., Int. Pat. Pub. No. WO 1993/021 ,146; M. L. Dawson et al., U.S. Pat. No. 5,466,861 (each of which is incorporated herein by reference in its entirety), or by processes equivalent thereto. ATRA and tretinoin may each be referred to as Aknoten; Retacnyl; or Tretin M. In some embodiments, ATRA includes Vesanoid® (tretinoin) and/or may be prepared as described in Van Dorp DA, Arens JF. The synthesis of “vitamin A acid’’, a biologically active substance. Recueil des Travaux Chimiques des Pays-Bas. 1946;65(5):338-45; C. D. Robeson et al., Chemistry of Vitamin A. XXIV. The Synthesis of Geometric Isomers of Vitamin A via Methyl fi-Methylglutaconate, J. Am. Chem. Soc. 77, 4111 (1955); R. Marbet, DE Patent No. 2,061 ,507; U.S. Pat. No. 3,746,730 (each of which is incorporated herein by reference in its entirety), or by processes equivalent thereto.

[0127] The retinoids and derivatives thereof may be quantified (e.g., for dosing purposes) according to any methods known in the art and as previously described, for example, in Yang, N., et al. Cardiac retinoic acid levels decline in heart failure. JCI Insight. 2021 Apr 22;6(8):e137593; the disclosure of which is incorporated herein by reference in its entirety. In some embodiments, the retinoids may be quantified, for example, by using LC-MRM (liquid chromatography with multiple reaction monitoring), UHPLC-MS/MS (ultra-high-performance liquid chromatography), HPLC/MSⁿ, LC- MS/MS, GC/MS, or LC/diode array detector-atmospheric pressure chemical ionization/MS/MS.

[0128] In some embodiments, the derivative of the retinoid is a pharmaceutically acceptable salt. The pharmaceutically acceptable salts may include salts of acidic or basic groups present in retinoids or compounds thereof of the present technology.

[0129] The pharmaceutical compositions of the present technology may be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions, or solutions.

[0130] The pharmaceutical compositions of the present technology may comprise bulk liquid solutions or suspensions, or bulk powders. In some embodiments, the pharmaceutical compositions are presented in unit dosage forms, which may facilitate accurate dosing. In some embodiments, the pharmaceutical compositions comprise a unit dosage comprising physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient. Nonlimiting examples of unit dosage forms include prefilled, premeasured ampules or syringes of the liquid compositions or pills, tablets, capsules, or the like in the case of solid compositions.

[0131] In some embodiments, the liquid compositions comprise an aqueous or nonaqueous vehicle with buffers, suspending and dispensing agents, colorants, flavors, and the like. Solid compositions may include, for example, any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel (e.g., sodium starch glycolate), or com starch; a lubricant such as magnesium stearate; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring. [0132] In some embodiments, the pharmaceutical compositions of the present technology are formulated for sublingual administration, wherein the unit dosage form is a film including one or more disintegrants (e.g., materials that favor disintegration or fast dissolution by virtue of their solubility in water, such as hydrolyzed starches, sugars, and glycerin, which may play a dual role as a plasticizer and disintegrant) and a plasticizing agent, the film having a first portion including apomorphine hydrochloride, and a second portion including pH neutralizing agent, wherein the unit dosage form includes from 0.5 to 5 mg, from 4 to 10 mg, or from 8 to 20 mg of apomorphine hydrochloride and the pH neutralizing agent is present in an amount sufficient to produce a solution having a pH of between 3.0 and 6.0, such as between 4.5 and 6.5, (e.g., a pH of between 2.5 and 4.5, 3.0 and 6.0, 3.5 and 6.5, 4.5 and 6.5, or 5.0 and 6.0) when the unit dosage form is placed in unbuffered water at pH 7 (e.g., the pH observed within 5 minutes of placing the unit dosage form in 1 , 5, or 10 mL of unbuffered water). The film may include from 1 to 50% (w/w) (e.g., 1 ±0.75%, 2±1 .5%, 3±0.5%, 5±2%, 7.5±2.5%, 10±2%, 14±3%, 18±4%, 22±5%, 25±5%, 30±5%, 35±5%, 40±5%, 45±5%, or 50±5% (w/w)) of the one or more disintegrants.

[0133] In some embodiments, the pharmaceutical compositions are administered by the oral or nasal respiratory route or atrial for local or systemic effect. Compositions in may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device may be attached to a face masks tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered orally or nasally from devices which deliver the formulation in an appropriate manner.

[0134] Injectable compositions may comprise injectable sterile saline or phosphate-buffered saline or other injectable carriers known in the art. The active compound (e.g., a retinoid or a pharmaceutically acceptable salt thereof) in such compositions is typically a minor component, which may be from about 0.05 to 10% by weight with the remainder being the injectable carrier and the like.

[0135] Transdermal compositions may be formulated as a topical ointment or cream containing the active compound(s), generally in an amount ranging from about 0.01 to about 20% by weight, for example, from about 0.1 to about 20% by weight, or from about 0.1 to about 10%) by weight, and from about 0.5 to about 15% by weight. When formulated as an ointment, the active compounds may be combined with either a paraffinic or a water-miscible ointment base. Alternatively, the active compounds may be formulated in a cream with, for example an oil-in-water cream base. Such transdermal formulations may include additional ingredients to enhance the dermal penetration of stability of the active compounds or the formulation.

[0136] The components for orally administrable, injectable, or topically administrable compositions are merely representative. Other materials as well as processing techniques and the like are set forth in Part 8 of Remington's Pharmaceutical Sciences, 17^th edition, 1985, Mack Publishing Company, Easton, Pennsylvania, which is incorporated herein by reference.

[0137] A retinoid or a pharmaceutically acceptable salt thereof of the present technology may be encapsulated or otherwise protected against gastric or other secretions.

[0138] Compositions containing the retinoid or a pharmaceutically acceptable salt thereof may be prepared in combination with one or more pharmaceutically acceptable carriers. In making the pharmaceutical compositions of the technology, the active compound is typically mixed with an excipient, diluted by an excipient, or enclosed within such a carrier in the form of, for example, a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it may be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active compound. Thus, the pharmaceutical compositions may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.

[0139] In some embodiments, the pharmaceutical compositions of the present technology are in liquid form. Nonlimiting examples of liquid forms include emulsions, solutions, suspensions, syrups, slurries, dispersions, colloids, and the like. In some embodiments, the pharmaceutical composition is in liquid, semi-solid or solid (e.g., powder) form. In some embodiments, the pharmaceutical composition is in semi-solid form, e.g., a gel, a gel matrix, a cream, a paste, or the like. In some embodiments, semisolid forms comprise a liquid vehicle. In some embodiments, the pharmaceutical composition is a solid dosage form, such as a tablet, a granule, a sachet, or a powder. In some embodiments, the pharmaceutical compositions are in the form of a dissolving tablet, a dissolving wafer, a capsule, or a gel capsule. In some embodiments, solid dosage forms may comprise a solid vehicle (e.g., as used in a tablet), and/or a gaseous vehicle (e.g., as used in DPI).

[0140] In some embodiments, the pharmaceutical compositions of the present technology are in a unit dose formulation for oral, intravenous, or other administration to a patient. A unit dosage form may comprise physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.

[0141] The active compound e.g., a retinoid or a pharmaceutically acceptable salt thereof) may be effective over a wide dosage range and is generally administered in a pharmaceutically effective amount. It will be understood, however, that the amount of the compound (e.g., a retinoid or a pharmaceutically acceptable salt thereof) actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound (e.g., a retinoid or a pharmaceutically acceptable salt thereof) administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0142] Pharmaceutical compositions of the present technology may be simple aqueous (e.g., saline) solutions. In some embodiments, the pharmaceutical composition comprise one or more additional ingredients which may enhance stability and/or nasal delivery of the compounds of the technology. Such additional ingredients are well known in the art. In some embodiments, the pharmaceutical compositions comprise substantial, cumulative toxicity, nor any permanent deleterious changes induced with long term use.

[0143] In some embodiments, the unit dosage form comprises a high molecular weight polymer having a weight average molecular weight of greater than 60 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose. In other embodiments, the unit dosage form further includes a low molecular weight polymer having a weight average molecular weight of from 5 KDa to 50 KDa selected from hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, and methyl cellulose. The pH neutralizing agent may be an organic base (e.g., pyridoxine, meglumine, or any organic base of the present technology) or an inorganic base (e.g., magnesium hydroxide, sodium bicarbonate, or an inorganic base of the present technology). In particular embodiments, the unit dosage form includes 35±5% (w/w) disintegrant, from 0.5 to 5 mg, from 4 to 10 mg, or from 8 to 20 mg of apomorphine hydrochloride and pyridoxine present in an amount sufficient to produce a solution having a pH of between 4.5 and 6.5 when the unit dosage form is placed in unbuffered water at pH 7. Suitable film for oral administration of the pharmaceutical compositions according to the technology is described in, e.g., U.S. Pat. No. 8,846,074, incorporated herein by reference in its entirety.

[0144] In some embodiments, a pharmaceutical composition of the present technology is formulated as an emulsion, a solution, a suspension, a syrup, a slurry, a dispersion, a colloid, a dissolving tablet, a dissolving wafer, a capsule, a gel capsule, a semi-solid, a solid forma gel, a gel matrix, a cream, a paste, a tablet, a granule, a sachet, a powder, or the like.

[0145] In preparing a formulation, the active compound (e.g., a retinoid or a pharmaceutically acceptable salt thereof) may be milled to generate an appropriate particle size prior to combining with the other ingredients. If the active compound e.g., a retinoid or a pharmaceutically acceptable salt thereof) is substantially insoluble, it may be milled to a particle size of less than 200 mesh. If the active compound (e.g., a retinoid or a pharmaceutically acceptable salt thereof) is substantially water soluble, the particle size may be adjusted by milling to generate a substantially uniform distribution in the formulation, e.g., about 40 mesh. Nonlimiting examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose. The formulations may additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The pharmaceutical compositions of the technology may be formulated so as to include quick, sustained, or delayed release of the active compound after administration to the patient by employing any procedure known in the art. [0146] For preparing solid compositions such as tablets, the pharmaceutical compositions may comprise a pharmaceutical excipient to form a solid pre-formulation composition containing a homogeneous mixture of the active compound (e.g., a retinoid ora pharmaceutically acceptable salt thereof) of the present technology. When referring to these pre-formulation compositions as homogeneous, the active compound (e.g., a retinoid or a pharmaceutically acceptable salt thereof) is typically dispersed evenly throughout the pharmaceutical composition so that the pharmaceutical composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules. This solid pre-formulation is then subdivided into unit dosage forms of the type containing from, for example, about 0.000001 to about 2000 mg of the active compound of the present technology.

[0147] The tablets or pills containing the active compound (e.g., a retinoid or a pharmaceutically acceptable salt thereof) of the present technology may be coated or otherwise compounded to include a dosage form affording the advantage of prolonged action. For example, the tablet or pill may comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components may be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials may be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0148] In some embodiments, the active compound (e.g., a retinoid or a pharmaceutically acceptable salt thereof) of the present technology may be encapsulated in the core of a microcapsule having a shell. In some embodiments, the core comprising the active compound (e.g., a retinoid or a pharmaceutically acceptable salt thereof) coated by a shell, wherein said core is in the solid form and said microcapsules have a size of less than about 100 pm. Thick and dense coating on core/core material, may be prepared using metal oxide nanoparticles in combination with a sol-gel precursor.

[0149] The liquid forms in which the compounds and pharmaceutical compositions of the present technology may comprise one or more aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, soya-bean oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.

[0150] Pharmaceutical compositions may be formulated for inhalation or insufflation. Such compositions include solutions and suspensions in pharmaceutically acceptable, aqueous, or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients.

[0151] In some embodiments, the pharmaceutical compositions of the present technology are lyophilized. Upon mixing of a diluent and a lyophilized formulation, a desired concentration of a reconstituted formulation may be reached.

[0152] The pharmaceutical compositions of the present technology may be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions may be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.

[0153] The pH of a pharmaceutical composition or a formulation thereof may be between 3 and 11. In some embodiments, the pH is between 5 to 9.

[0154] It will be understood that use of certain of the foregoing excipients, carriers, or stabilizers will result in the formation of pharmaceutical salts.

[0155] In some embodiments, the pharmaceutical composition comprises ATRA and a pharmaceutically acceptable excipient selected from yellow beeswax, hydrogenated soya-bean oil, partially hydrogenated soya-bean oil, refined soya-bean oil, and suitable combinations thereof.

[0156] In some embodiments, the pharmaceutical composition comprising ATRA is in the form of a capsule. In some embodiments of the capsule includes a capsule shell comprising a pharmaceutically acceptable excipient selected from the group consisting of gelatin, glycerol (85%), dry substance of Karion 83, titanium dioxide, yellow iron oxide, red iron oxide, monogramming ink, and suitable combinations thereof.

[0157] In some embodiments, the pharmaceutical composition described herein further comprises another active ingredient such as an anti-cancer agent (e.g., a kinase inhibitor) in addition to the active compound (e.g., a retinoid or a pharmaceutically acceptable salt thereof). In some embodiments, the kinase inhibitor is a BTK inhibitor. In some embodiments, the BTK inhibitor is ibrutinib. Dosage and Administration

[0158] Therapeutically effective doses of the pharmaceutical compositions of the present technology may be determined using methods known to one skilled in the art. Effective doses may be determined, for example, in vitro, to identify an optimal dose range using any of the methods of the present technology.

[0159] In some embodiments, an aqueous solution of a pharmaceutical composition of the present technology is administered by an intraperitoneal injection. Each dose may range from about 0.001 pg/kg body weight to about 100 mg/kg body weight, or from about 0.1 pg/kg to about 20 mg/kg body weight.

[0160] In some embodiments, the dose may range from at least 0.001 pg/kg body weight to at least 100 mg/kg body weight, or from at least 0.1 pg/kg to at least 20 mg/kg body weight.

[0161] In some embodiments, the dose may range from at least about 0.001 pg/kg body weight to at least about 100 mg/kg body weight, or from at least about 0.1 pg/kg to at least about 20 mg/kg body weight.

[0162] The dosing schedule may vary from a single one-time dose to once a week or to daily or twice (or more) daily, depending on subject effects.

[0163] A suitable, non-limiting example of a dosage of a pharmaceutical composition of the present technology is from about 1 mg/m²/day to about 80 mg/ m²/day, including from about 10 mg/ m²/day to about 80 mg/ m²/day, from about 10 mg/ m²/day to about 50 mg/ m²/day, or from about 20 mg/ m²/day to about 50 mg/ m²/day.

[0164] In some embodiments, a dosage of a pharmaceutical composition of the present technology is from at least 1 mg/m²/day to at least 80 mg/ m²/day, including from at least 10 mg/ m²/day to at least 80 mg/ m²/day, from at least 10 mg/ m²/day to at least 50 mg/ m²/day, or from at least 20 mg/ m²/day to at least 50 mg/ m²/day.

[0165] In some embodiments, a dosage of a pharmaceutical composition of the present technology is from at least about 1 mg/m²/day to at least about 80 mg/ m²/day, including from at least about 10 mg/ m²/day to at least about 80 mg/ m²/day, from at least about 10 mg/ m²/day to at least about 50 mg/ m²/day, or from at least about 20 mg/ m²/day to at least about 50 mg/ m²/day. [0166] In some embodiments, the dosages of a pharmaceutical composition of the present technology or a retinoid or a pharmaceutically acceptable salt thereof is about 22.5 mg/ m²/day or about 45 mg/ m²/day.

[0167] In some embodiments, the dosages of a pharmaceutical composition of the present technology or a retinoid or a pharmaceutically acceptable salt thereof is at least 22.5 mg/ m²/day or at least 45 mg/ m²/day.

[0168] In some embodiments, the dosages of a pharmaceutical composition of the present technology or a retinoid or a pharmaceutically acceptable salt thereof is at least about 22.5 mg/ m²/day or at least about 45 mg/ m²/day.

[0169] In some embodiments, the retinoid or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising such a retinoid or a pharmaceutically acceptable salt thereof is administered orally.

[0170] A suitable, non-limiting example of a dosage of a retinoid or a pharmaceutically acceptable salt thereof according to the present technology or a pharmaceutical composition comprising such a retinoid or a pharmaceutically acceptable salt thereof, is from about 1 ng/kg to about 1000 mg/kg, such as from about 1 mg/kg to about 100 mg/kg, including from about 5 mg/kg to about 50 mg/kg and about 1 mg/kg to about 10 mg/kg. Other representative dosages of a retinoid or pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present technology include about 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 400 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg, or 1000 mg/kg.

[0171] In some embodiments, a suitable, non-limiting example of a dosage of a retinoid or a pharmaceutically acceptable salt thereof according to the present technology or a pharmaceutical composition comprising such a retinoid or a pharmaceutically acceptable salt thereof, is from at least 1 ng/kg to at least 1000 mg/kg, such as from at least 1 mg/kg to at least 100 mg/kg, including from at least 5 mg/kg to at least 50 mg/kg. Other representative dosages of a retinoid or pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present technology include at least 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 400 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg, or 1000 mg/kg.

[0172] In some embodiments, a suitable, non-limiting example of a dosage of a retinoid or a pharmaceutically acceptable salt thereof according to the present technology or a pharmaceutical composition comprising such a retinoid or a pharmaceutically acceptable salt thereof, is from at least about 1 ng/kg to at least about 1000 mg/kg, such as from at least about 1 mg/kg to at least about 100 mg/kg, including from at least about 5 mg/kg to at least about 50 mg/kg. Other representative dosages of a retinoid or pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present technology include at least about 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg, 200 mg/kg, 250 mg/kg, 300 mg/kg, 400 mg/kg, 500 mg/kg, 600 mg/kg, 700 mg/kg, 800 mg/kg, 900 mg/kg, or 1000 mg/kg.

[0173] The administration route for the retinoid or pharmaceutically acceptable salt thereof or the pharmaceutical composition of the present technology may be any mode of administration known in the art, including but not limited to injection into involved tissue, intraarterially, intravenously, via an implanted device, parenterally, topically, subcutaneously, intradermally, transdermally e.g., by transdermal patch), via intracorporal application during surgery, intramuscularly, intraperitoneally, buccally, intrathecally, intracranially, intratracheally, intranasal, intraocular, or orally. In some embodiments, a retinoid or pharmaceutically acceptable salt thereof or a pharmaceutical composition of the present technology is administered or delivered to the atrium.

[0174] In some embodiments, the pharmaceutical compositions are administered by a transdermal device. Accordingly, transdermal administration may be accomplished using a patch either of the reservoir or porous membrane type, or of a solid matrix variety.

[0175] In some embodiments, the retinoid or pharmaceutically acceptable salt thereof, is administered at a dose of about 2mg/kg, 5mg/kg, 10mg/kg, or 20mg/kg. In some embodiments, the retinoid or pharmaceutically acceptable salt thereof, is administered intraperitoneally.

[0176] In some embodiments, the retinoid or pharmaceutically acceptable salt thereof, is administered at a dose of at least 2mg/kg, 5mg/kg, 10mg/kg, or 20mg/kg. In some embodiments, the retinoid or pharmaceutically acceptable salt thereof, is administered intraperitoneally.

[0177] In some embodiments, the retinoid or pharmaceutically acceptable salt thereof, is administered at a dose of at least about 2mg/kg, 5mg/kg, 10mg/kg, or 20mg/kg. In some embodiments, the retinoid or pharmaceutically acceptable salt thereof, is administered intraperitoneally.

[0178] In some embodiments, the pharmaceutical compositions of the present technology or the retinoid or pharmaceutically acceptable salt thereof is administered at a dose of about 22.5 mg/ m²/day or about 45 mg/ m²/day. In some embodiments, the retinoid or pharmaceutically acceptable salt thereof, is administered orally.

[0179] In some embodiments, the pharmaceutical compositions of the present technology or the retinoid or pharmaceutically acceptable salt thereof is administered at a dose of at least 22.5 mg/ m²/day or at least 45 mg/ m²/day. In some embodiments, the retinoid or pharmaceutically acceptable salt thereof, is administered orally.

[0180] In some embodiments, the pharmaceutical compositions of the present technology or the retinoid or pharmaceutically acceptable salt thereof is administered at a dose of at least about 22.5 mg/ m²/day or at least about 45 mg/ m²/day. In some embodiments, the retinoid or pharmaceutically acceptable salt thereof, is administered orally.

[0181] In some embodiments, from about 1 mg/m²/day to about 80 mg/ m²/day, from about 10 mg/ m²/day to about 80 mg/ m²/day, from about 10 mg/ m²/day to about 50 mg/ m²/day, from about 20 mg/ m²/day to about 50 mg/ m²/day, about 22.5 mg/ m²/day or about 45 mg/ m²/day of retinoid or a pharmaceutically acceptable salt thereof of the present technology is administered to the subject.

[0182] In some embodiments, from at least 1 mg/m²/day to at least 80 mg/ m²/day, from at least 10 mg/ m²/day to at least 80 mg/ m²/day, from at least 10 mg/ m²/day to at least 50 mg/ m²/day, from at least 20 mg/ m²/day to at least 50 mg/ m²/day, at least 22.5 mg/ m²/day or at least 45 mg/ m²/day of retinoid or a pharmaceutically acceptable salt thereof of the present technology is administered to the subject.

[0183] In some embodiments, from at least about 1 mg/m²/day to at least about 80 mg/ m²/day, from at least about 10 mg/ m²/day to at least about 80 mg/ m²/day, from at least about 10 mg/ m²/day to at least about 50 mg/ m²/day, from at least about 20 mg/ m²/day to at least about 50 mg/ m²/day, at least about 22.5 mg/ m²/day or at least about 45 mg/ m²/day of retinoid or a pharmaceutically acceptable salt thereof of the present technology is administered to the subject.

[0184] The therapeutic dosage of the pharmaceutical compositions of the present technology may vary according to, for exam pie, the use for which the treatment is made, the manner of administration of the active compound (e.g., a retinoid or a pharmaceutically acceptable salt thereof), the health and condition of the subject and the judgment of the prescribing physician. The proportion or concentration of the active compounds (e.g., a retinoid or a pharmaceutically acceptable salt thereof) of the present technology may vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound (e.g., a retinoid or a pharmaceutically acceptable salt thereof) selected, formulation of the excipient, and its route of administration. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0185] The pharmaceutical compositions of the present technology may be administered as a single dose or as divided doses simultaneously, such as over a short period of time, or at appropriate intervals, for example as two, three, four, five, or more sub-doses per day.

[0186] In some embodiments, the pharmaceutical compositions of the present technology are administered hourly, daily, weekly, monthly, yearly or as a onetime delivery. In some embodiments, the pharmaceutical compositions are administered daily via intraperitoneal injection over a one-week, two-week, three-week or four-week time period. In some embodiments, the pharmaceutical compositions are administered at a frequency ranging from twice in a day to once in a day. [0187] In some embodiments, the pharmaceutical compositions of the present technology are administered daily. In some embodiments, the pharmaceutical compositions are administered daily via an oral route. In some embodiments, the pharmaceutical compositions are administered daily up to one month.

[0188] In some embodiments, the administration of the pharmaceutical composition is temporarily reduced or suspended. The length of the temporary suspension of administration of the pharmaceutical composition may vary from hourly to yearly. In some embodiments, the pharmaceutical composition is administered daily up to two weeks followed by no administration (e.g., temporarily suspension) for up to two weeks. In some embodiments, the temporary suspension of the pharmaceutical composition is introduced after one month daily administration of the pharmaceutical composition.

[0189] The dosage administered may be dependent upon the route of administration, age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.

[0190] In some embodiments of the present technology, the methods may further comprise administering a pharmaceutically acceptable carrier to the subject during the administration of the pharmaceutical compositions. The pharmaceutically acceptable carrier may be a diluent, an aerosol, a topical carrier, an aqueous solution, a nonaqueous solution or a solid carrier. The pharmaceutically acceptable carrier may encompass any standard pharmaceutically accepted carriers, such as phosphate buffered saline solution, water, emulsions such as an oil/water emulsion or a triglyceride emulsion, various types of wetting agents, tablets, coated tablets, and capsules.

Kits

[0191] In some embodiments, the present technology comprises kits having one or more pharmaceutical compositions of the present technology.

[0192] In some embodiments, the kit comprises (i) a pharmaceutical composition comprising, consisting essentially of, or consisting of a retinoid or a pharmaceutically acceptable salt thereof of the present technology, and (ii) optionally, packaging for the same and/or instructions for use. [0193] In some embodiments, the kit comprises: (a) a container that comprises a pharmaceutical composition of the present technology, for example, a pharmaceutical composition in solution or in lyophilized form; (b) optionally, a second container comprising a diluent or reconstituting solution for the lyophilized formulation; and/or (c) optionally, instructions for (i) use of the solution or (ii) reconstitution and/or use of the lyophilized formulation.

[0194] In some embodiments, the kit may further comprise, one or more of (i) a diluent, (ii) a buffer, (iii) a filter (iv) a syringe, and/or (v) a needle.

[0195] In some embodiments, the kit comprises an anti-cancer agent that is a kinase inhibitor. In some embodiments, the kinase inhibitor is a BTK inhibitor. In some embodiments, the BTK inhibitor is ibrutinib.

[0196] In some embodiments, the components of the kit may be included in one or more liquid solutions, such as a sterile aqueous solution. The components of the kit may also be included as solids, which may be converted into liquids such as by addition of suitable solvents, which may be included in another distinct container.

[0197] In some embodiments, kits may comprise a lyophilized formulation comprising a pharmaceutical composition of the present technology in a suitable container and instructions for its reconstitution and/or use. Non-limiting examples of suitable containers include, e.g., syringes (such as dual chamber syringes), vials (such as dual chamber vials), bottles, and test tubes. In some embodiments, a container may be a multi-use container. The container may be formed from a variety of materials such as plastic or glass. The kit and/or container may contain instructions upon or accompanying the container which may denote directions for reconstitution of, e.g., a lyophilized formulation and/or use of the kit. In some embodiments, a label may denote that the lyophilized formulation is to be reconstituted to an appropriate concentration. The label may denote that the formulation is useful or intended for any route of administration of the present technology.

[0198] The container containing the formulation may be a multi-use vial, which may allow for repeat administrations (e.g., from 2-6 administrations) of a reconstituted formulation. The kit may further comprise a second container comprising a suitable diluent (e.g., sodium bicarbonate solution). [0199] The kit may further include other materials desirable from a commercial and/or user perspective, including, e.g., other filters, needles, syringes, buffers, diluents, and/or package inserts which may comprise, e.g., instructions for use.

[0200] Kits may contain a single container that contains the formulation of the pharmaceutical composition with or without other components (e.g., other compounds or compositions of such other compounds) or may have a separate container for each component.

[0201] In some embodiments, the container of a therapeutic kit may be a vial, flask, test tube, bottle, syringe, or any other means of enclosing a solid or liquid. When there is more than one component, the kit may contain a second vial or other container, which may allow for separate dosing. The kit may also contain another container for a pharmaceutically acceptable liquid. In some embodiments, a kit may contain an apparatus (e.g., syringes, one or more needles, pipettes, eye droppers, etc.) which may permit administration of agents of the disclosure which are components of the kit.

[0202] In some embodiments, kits comprise an agent capable of detecting a biomarker of the present technology, e.g., a biomarker of a heart condition or other disorder, or a biomarker of a BTK-inhibitor mediated off-target signaling pathway. In some embodiments, the biomarker is a protein level or a nucleic acid level. In some embodiments, the kit comprises a means for determining the amount of the biomarker in the sample following incubation of the sample with a pharmaceutical composition of the present technology. Kits may be packaged to allow for detection of multiple biomarkers of interest by including individual labeled compounds or agents capable of detecting each individual biomarker of interest and means for determining the amount of each biomarker in the sample.

EXAMPLES

[0203] The following examples are intended to illustrate various embodiments of the present technology. As such, the specific embodiments discussed are not to be construed as limitations on the scope of the present technology. It will be apparent to one skilled in the art that various equivalents, changes, and modifications may be made without departing from the scope of present technology, and it is understood that such equivalent embodiments, are to be included herein. Further, all references cited herein are hereby incorporated by reference in their entirety, as if fully set forth herein.

Example 1. All-trans retinoic acid (ATRA) prevents ibrutinib-induced atrial fibrosis.

[0204] To investigate whether ATRA may mitigate atrial fibrosis in a known atrial fibrillation (AF) model that does not cause left ventricular (LV) pressure overload, the ibrutinib-induced atrial fibrosis model was used. Ibrutinib is a small molecule therapy may be used to treat chronic lymphocytic leukemia/small lymphocytic lymphoma by inhibiting Bruton's tyrosine-kinase but causes increased atrial fibrosis and AF through off target effects on C-terminal Src kinase. In the ibrutinib-ATRA study (FIG. 1A), male C57BL/6J mice were randomly divided into 3 groups of Control, ibrutinib + Vehicle (ibrutinib + V), and ibrutinib + ATRA (10 mice/group). Mice in the ibrutinib + V arm were treated with ibrutinib (25 mg/kg/d) (MedChemExpress) plus vehicle control (peanut oil) via intraperitoneal (IP) injection daily for 28 days. The mice in ibrutinib + ATRA groups were treated with ibrutinib (25 mg/kg/d) and ATRA (10 mg/kg/d) via IP injection daily for 28 days. The control group was injected with the same volume of vehicle in parallel. Ibrutinib therapy caused increased atrial fibrosis (FIGS. 1 B-1 D), and ATRA therapy prevented ibrutinib-induced atrial fibrosis. This suggests that ATRA prevents atrial fibrosis in a non-pressure overload AF model.

Example 2. ATRA therapy improves atrial and ventricular conduction parameters in humans.

[0205] To further assess ATRA therapies, human electrocardiograms (ECGs) were analyzed at baseline and at one month and three months following treatment with ATRA (45mg/m²/day divided into 2 daily doses) and arsenic trioxide (ATO) (0.15 mg/kg/day intravenous daily) induction therapy (FIGS. 2A-2E and 3). At one month of ATRA therapy, the treatment was given daily. After one month, ATRA was given as a 2-week on and 2-week off alternating cycle therapy. Therefore, at 3 months, all patients were on ATRA on a 2-week on and 2-week off alternating cycle. Frequent ECGs were acquired during induction and consolidation/maintenance phases not due to ATRA, but rather due to ATO's known effect of prolonging the QTc interval. ECGs were anonymized and analyzed by two blinded interpreters. ATRA therapy was associated with significant reduction in PR interval, P wave duration, and QRS duration (FIGS. 2B- 2D). As expected with ATO, QTc interval prolongation was observed (FIG. 2E). Importantly, ATRA therapy is associated with significant reduction in QRS wave duration, which may be used as a measure of His-Purkinje system dependent ventricular activation time. These results show that ATRA therapy may improve atrial, AV nodal, and His-Purkinje dependent ventricular conduction parameters in humans. The improvement in QRS duration with ATRA therapy may be related to reduced ventricular fibrosis, human-specific response in Purkinje cells, or enhanced SCN5A or GJA1 expression. Notably, no patients exhibited major adverse events, including myocarditis nor pericarditis, in this cohort. ATRA therapy was shown to be associated with improved atrial and ventricular conduction parameters in humans at one month of treatment. P wave duration was improved at 3 months of ATRA therapy given in alternating 2-week cycles.

Example 3. ATRA therapy reverse pathological atrial remodeling (ATRA reversal study).

[0206] To further assess ATRA effects on pathological atrial remodeling, an ATRA reversal study was performed in mice (FIG. 4A). ECG and histological assessments were performed at 2 weeks and 4 weeks. ECG assessment included heart rate (FIG. 4B), PR Interval (FIG. 4C), P duration (FIG. 4D), QRS duration (FIG. 4E), and QTc interval (FIG. 4F). Masson's trichrome staining of LA sections is shown in FIG. 4G and analysis of the LA fibrosis % is shown in FIG. 4H.

[0207] To assess biological functions through which ATRA may exert therapeutic effects, RNA-seq analysis was performed. Data of left atrial RNAseq analysis of ATRA reversal experiment are shown in FIG. 4I-4L. Counts of differentially expressed genes (FDR 0.1 ) in TAC vs Sham treatment groups were assessed, which overlapped with TAC vs TAC + dATRA groups (FIG. 4I). Overlapped genes were considered to represent ATRA responsive genes in the TAC versus Sham dataset. A pairwise correlation between log fold change of differential gene expression in TAC vs Sham compared to treatment condition, TAC vs TAC + dATRA (R=-0.45, P<2.2x10^-16) was also assessed (FIG. 4J). This assessment also demonstrated that ATRA treatment reverses metabolic biological processes in TAC banded LA (FIG. 4K) and that ATRA treatment reverses fibrotic and inflammatory biological processes in TAC banded LA (FIG. 4K). [0208] These data indicate that short duration ATRA therapy may partially reverse left atrial remodeling in transverse aortic constriction banded mice with 2 weeks of treatment and that that ATRA therapy may protect against pressure-induced changes on metabolism, cardiac conduction, inflammation, and fibrosis.

Example 4. ATRA therapy continues to reverse pathological atrial remodeling even after therapy withdrawal.

[0209] As shown in Examples 1 and 2, ATRA treatment may prevent atrial fibrosis in I brutinib-treated mice and may improve atrial conduction parameters in humans. This suggests that ATRA may be used for atrial remodeling therapy. Therefore, to test the durability of the ATRA therapeutic response, an ATRA Reversal-Withdrawal Study was designed (FIG. 5, panel A). Mice underwent Sham or TAC surgery and were left untreated for 2 weeks. Then all mice were administrated ATRA (10mg/kg/day) or egual volume vehicle control by intraperitoneal injection daily for 2 weeks followed by therapy discontinuation for an additional 2 weeks. The total study duration was 6 weeks after TAC or Sham surgery. The 4 groups were designated: i) Sham + delayed vehicle followed by 2-week withdrawal (Sham+dV 2WD), ii) Sham + delayed ATRA followed by 2-week withdrawal (Sham+dATRA 2WD), iii) TAC + delayed vehicle followed by 2-week withdrawal (TAC+dV 2WD), and iv) TAC + delayed ATRA followed by 2-week withdrawal (TAC+dATRA 2WD). At the end of the study, hearts were collected for histological examination by Masson's trichrome staining and fibrosis was quantified.

[0210] As shown in FIG. 5, panels B and C, TAC+dV 2WD left atria showed marked fibrosis (24.99% ± 3.10%) and left atrial appendage thrombus formation (red arrowheads), similar to that observed in human left atrial myopathy. Moreover, TAC+dATRA 2WD hearts showed continued improvement in left atrial fibrosis with normalization of fibrosis levels compared to sham groups. In addition, ATRA treatment prevented left atrial appendage thrombus formation. In the TAC+dATRA 2WD cohort, fibrosis fraction was 8.01 % ± 0.42% compared to 7.70% ± 0.07% in Sham+dV 2WD control, representing a non-statistically significant difference. There were no differences in fibrosis levels measured between Sham+dV 2WD and Sham+dATRA 2WD groups.

[0211] This assessment demonstrated that ATRA treatment may have a lasting, restorative effect on atrial structural remodeling beyond its initial administration. Example 5. Assessing effects of ATRA on left atrial remodeling and AF susceptibility and minimizing side effects.

[0212] To assess whether longer duration of ATRA therapy may reverse pathological remodeling to normalize atrial conduction and functional parameters and thereby reduce susceptibility to atrial arrhythmias, an additional ATRA assessment will be conducted. To assess the maximal therapeutic benefit achievable with the lowest effective dose of ATRA to minimize side effects, the ATRA Reversal Study of Example 3 will be extended and ATRA will be administered at different doses for 6 weeks. Multi- omics analyses will also be employed to indicate whether ATRA may be shifting LA responses from a pathological remodeling response to one that is more physiologic, which may create a more durable therapeutic effect. This will be tested using ATRA therapy withdrawal experiments to determine if the beneficial effects of ATRA may persist. Lastly, the ECG analysis of ATRA treated APL patients will be expanded to determine the time course of atrial conduction improvement and whether the conduction benefits are maintained even with intermittent dosing cycles of ATRA after the first month. The results of these experiments may yield important information that will help guide ATRA therapeutic dosing and duration strategies that maximize benefit and minimize harm. This will inform whether extended ATRA therapy may reverse pathological atrial remodeling to restore normal conduction and functional parameters. It is expected that the therapeutic benefit of ATRA on atrial remodeling may be maintained after therapy withdrawal.

Example 6. Single nuclear RNA-seg (snRNA-seg) analysis with ATRA treatment.

[0213] Single nuclear RNA-seg (snRNA-seq) analysis was conducted on ATRA- treated mice to assess transcriptional changes that may occur with use of ATRA. Groups assessed included sham surgery plus vehicle-treated mice (Sham + V), transverse aortic constriction (TAG) pressure overload plus vehicle treated mice (TAC+V) and TAC mice administered ATRA (TAC+ATRA). This analysis revealed that ATRA attenuated large transcriptomic shifts in left atrial myocytes, macrophages, and fibroblasts induced by pressure overload (FIG. 6A and 6B). In the macrophage cluster, trajectory analysis (FIG. 6C) showed that ATRA treatment inhibits the shift toward pro- inflammatory macrophages (C-C motif chemokine receptor 2 (CCR2 (NCBI Accession/Gene ID: P41597.1 ; 729230)+) and enhances the expansion of anti- inflammatory, resident macrophages (CCR2-) that may promote tissue regeneration and recovery. Platelet derived growth factor C (Pdgfc) (NCBI Accession/Gene ID: Q9NRA1.2; 56034) signaling from resident macrophages is disrupted in TAC+V (FIG. 6E) condition and re-established in TAC+ATRA (FIG. 6F) condition compared to control (FIG. 6D).

Example 7. Analysis of cell-type specific anti-remodeling mechanisms of ATRA.

[0214] To assess cell-type specific anti-remodeling mechanisms of ATRA, LA myocytes, macrophages, and fibroblasts, and study of crosstalk signaling between target cells will be assessed, based on multi-omics data. The activation states of LA myocytes, macrophages, and fibroblasts will be defined by expanding the snRNA-seq datasets of Example 6. Differential gene expression analysis and cell trajectory algorithms were employed to delineate state transitions of left atrial myocytes, macrophages, and fibroblasts during pressure overload and ATRA therapy. CellChat analysis will be extended to quantitatively infer and analyze intercellular communication networks to understand how pressure overload and ATRA therapy modulate myocyte: macrophage:fibroblast crosstalk to create a pro- vs anti-inflammatory environment. LA myocytes, macrophages, and fibroblasts will also be isolated to define their transcriptom ic and chromatin regulatory landscapes to identify enhancer regions modulated by pressure overload and ATRA therapy. Discoveries from these experiments may help to define signaling pathways downstream of ATRA that may yield novel druggable targets. It is expected that ATRA therapy may prevent pathological state transition of left atrial myocytes, macrophages, and fibroblasts via specific downstream signaling pathways that may be therapeutically targeted.

Example 8. A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial with an Open-Label Extension to Determine Safety and Efficacy of Full and Half dose of ATRA in Patients with Hypertension and Atrial Remodeling.

[0215] The purpose of the current clinical study is to evaluate effect of ATRA to prevent atrial remodeling that may give rise to AF and stroke risk.

Predinical studies

[0216] ATRA prevents and reverses atrial remodeling and improves conduction parameters in mouse models of cardiac pressure overload. As proof of concept in human, ATRA treatment in APL patients improves atrial conduction parameters (P- wave duration) when measured at one month of therapy. The clinical indications to be assessed will include hypertension and atrial remodeling

Dose and mode of administration: Full dose of ATRA: 45mg/m²/day or half dose of ATRA: 22.5mg/m²/day or placebo, via an oral administration. Oral placebo is a concurrent control of the study.

Target patient population: Hypertensive patients

[0217] Patients who have hypertension will be enrolled to study effect of full dose and half dose ATRA treatment on atrial electrical and structural remodeling by electrocardiography, cardiac rhythm monitoring, and echocardiography.

Study population: Hypertensive patients

[0218] Rationale for open-label extension (OLE) phase: To assess longer term safety (3-6 months total).

[0219] Rationale for selection of full dose to treat atrial remodeling: To assess efficacy of full dose ATRA to treat atrial remodeling similar to observations in APL patients.

[0220] Rationale for selection of half dose to treat atrial remodeling: To assess efficacy of half-dose ATRA to treat atrial remodeling similar to observations in APL patients.

Objectives:

[0221] Primary objectives:

• To assess the effect of full dose of ATRA on P wave duration at 30, 60, and 90 days after treatment;

• To assess the effect of half dose of ATRA on P wave duration at 30, 60, and 90 days after treatment; and

• To assess the safety and tolerability of full and half dose of ATRA for 90-day treatment.

[0222] Secondary objectives: To assess the effect of full and half dose of ATRA on QRS at 30, 60, and 90 days after treatment.; and

• To assess the effect of full and half dose of ATRA on LA enlargement and LA strain measurements at 90 days after treatment.

[0223] Safety objectives:

• To assess the effect of full and half dose of ATRA on CBC, Chem 10, liver function tests;

• To assess the effect of full and half dose of ATRA on thyroid function studies;

• To assess the effect of full and half dose of ATRA on coagulation panel; and

• To assess the effect of full and half dose of ATRA on lipid panel.

[0224] The study design of the present clinical study encompasses three-arm parallel group.

[0225] The number of subjects planned for this study includes randomize 108 participants with 1 :1 : 1 ratio to the 3 groups, 36 per group. Accounting for -20% dropout, 30 subjects per group are expected to complete 90-day treatment and assessments.

[0226] The duration of the randomized phase is 90 days. OLE may continue from three to six months. Randomization will be stratified by age (below 70 years old and those >70). Block randomization with random block size with 1 :1 :1 ratio to full:half:placebo dose groups are used.

Sample size calculations

[0227] P-wave duration: A sample size of 22 in each group have 85% power to detect a difference in means of -10.36 (a change of -10.36 in the ATRA group versus a 0 change in the placebo group), assuming that the common standard deviation is 11.14 using a two group t-test with a 5% two-sided significance level.

[0228] QRS duration: A sample size of 28 in each group have 85% powerto detect a difference in means of -6.5 (a change of -6.5 in the ATRA group versus a 0 change in the placebo group), assuming that the common standard deviation is 7.9 using a two group t-test with a 5% two-sided significance level. [0229] P-wave duration will be measured at day 30, 60, and 90 as a primary endpoint.

[0230] QRS duration will be measured as a secondary endpoint. LA enlargement and LA strain measurements will be performed on transthoracic echocardiography (TTE) every three (q3) months as secondary endpoints.

[0231] Complete blood count (CBC), a renal function panel (Chem 10), liver function tests, thyroid function studies, a coagulation panel, and a lipid panel will be performed as exploratory endpoints.

[0232] Safety is evaluated via spontaneous reports of adverse events (AEs), including adverse events of special interest (AESIs), serious adverse events (SAEs), treatment emergent adverse events (TEAE). Clinical laboratory tests, physical examinations, vital signs, and ECGs will be used to conduct safety assessments.

[0233] Additional assessments will include clinical laboratory tests, physical examinations, vital signs, and ECGs.

Statistical methods

[0234] Efficacy analysis: For continuous endpoints (primary, secondary), independent sample T-test or Wilcoxon rank sum test will be initially used to compare them between control group to the two dose groups at each time point. For repeatedly measured continuous endpoints, mixed effect models will be used to analyze the data with a random subject effect (random intercept) and with the treatment (full dose, half dose, placebo) and the time trend (30, 60, 90 days) as fixed effects. The analysis will initiate with an unstructured covariance matrix for the errors in the model, then the covariance matrix will be tested for first-order autoregressive for more parsimonious models through examining Akaike-Information-Criterion. Covariate effects to be evaluated in the model include age, gender, BMI.

[0235] Safety analysis: All safety data will be recorded and summarized by treatment groups. All adverse events (AEs) will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and tabulated by System Organ Class (SOC) and Preferred Term (PT). Incidence of AEs, serious AEs (SAEs), and treatment-emergent AEs (TEAEs) leading to study treatment discontinuation, AE of special interest will be summarized and compared by treatment groups. Laboratory parameters will be summarized by treatment groups at each scheduled assessment timepoint using descriptive statistics. Individual subject values will be listed and values outside of the standard reference range will be noted. The change from Baseline for each of the vital signs and electrocardiogram (ECG) parameters will be summarized. Incidence of abnormal vital signs parameters, abnormal laboratory parameters, and outlier ECG results will be tabulated. Biomarker analysis may also be employed.

Example 9. A Randomized, Double-Blind, Placebo-Controlled, Phase 2 Trial with an Open-Label Extension to Determine Safety and Efficacy of Full and Half dose of ATRA in Patients with AF.

[0236] An investigator led study will be designed that directly quantifies the impact of ATRA at full dose (45mg/m²/day) and half dose (22.5mg/m²/day) compared to placebo on human atrial conduction parameters by electrocardiography and atrial function by echocardiography in patients with hypertension and without prior history of atrial fibrillation. The burden of new onset atrial fibrillation will be measured in ATRA treated patients using wearable technology. The effect of ATRA will be studied on these parameters on a monthly basis for up to 3 months with an option to extend up to 6 months.

[0237] The purpose of the current clinical study will be to evaluate effect of ATRA to treat AF.

[0238] Dose and mode of administration: Full dose of ATRA: 45mg/m²/day or half dose of ATRA: 22.5mg/m²/day or placebo, via oral administration. Oral placebo is a concurrent control of the study.

[0239] Target patient population: AF. Patients who have paroxysmal AF will be enrolled to study effect of full dose and half dose ATRA treatment on atrial electrical and structural remodeling by electrocardiography, cardiac rhythm monitoring, and echocardiography.

[0240] Study population: Paroxysmal AF patients

[0241] Rationale for open-label extension (OLE) phase: To assess longer term safety (3-6 months total).

[0242] Rationale for selection of full dose to treat AF: To assess efficacy of full dose ATRA to treat atrial remodeling and AF similar to observations in APL patients. [0243] Rationale for selection of half dose to treat AF: To assess efficacy of halfdose ATRA to treat atrial remodeling and AF similar to observations in APL patients.

Objectives:

[0244] Primary objectives:

• To assess the effect of full dose of ATRA on P wave duration at 30, 60, and 90 days after treatment;

• To assess the effect of half dose of ATRA on P wave duration at 30, 60, and 90 days after treatment; and

• To assess the safety and tolerability of full and half dose of ATRA for 90-day treatment.

[0245] Secondary objectives:

• To assess the effect of full and half dose of ATRA on QRS at 30, 60, and 90 days after treatment.;

• To assess the effect of full and half dose of ATRA on AF recurrence and AF burden using wearable ECG monitoring at 90 days after treatment; and

• To assess the effect of full and half dose of ATRA on LA enlargement and LA strain measurements at 90 days after treatment.

[0246] Safety Objectives:

• To assess the effect of full and half dose of ATRA on CBC, Chem 10, liver function tests;

• To assess the effect of full and half dose of ATRA on thyroid function studies;

• To assess the effect of full and half dose of ATRA on coagulation panel;

• To assess the effect of full and half dose of ATRA on lipid panel; and

• To assess major bleeding, according to the criteria of the International Society on Thrombosis and Haemostasis (ISTH).

[0247] The study design of the present clinical study encompasses three-arm parallel groups. [0248] The number of subjects planned for this study includes randomized 108 participants with 1 :1 : 1 ratio to the 3 groups, 36 per group. Accounting for -20% dropout, 30 subjects per group are expected to complete 90-day treatment and assessments.

Sample Size Calculations

[0249] P-wave duration: A sample size of 22 in each group have 85% power to detect a difference in means of -10.36 (a change of -10.36 in the ATRA group versus a 0 change in the placebo group), assuming that the common standard deviation is 11.14 using a two group t-test with a 5% two-sided significance level.

[0250] QRS duration: A sample size of 28 in each group have 85% powerto detect a difference in means of -6.5 (a change of -6.5 in the ATRA group versus a 0 change in the placebo group), assuming that the common standard deviation is 7.9 using a two group t-test with a 5% two-sided significance level.

[0251] P-wave duration will be measured at day 30, 60, and 90 as a primary endpoint.

[0252] QRS duration, AF recurrence, and total burden of AF (percent time in sinus rhythm) will be measured as secondary endpoints. LA enlargement and LA strain measurements will be performed on transthoracic echocardiography (TTE) every three (q3) months as secondary endpoints.

[0253] Complete blood count (CBC), a renal function panel (Chem 10), liver function tests, thyroid function studies, a coagulation panel, and a lipid panel will be performed as exploratory endpoints.

[0254] Safety will be evaluated via spontaneous reports of adverse events (AEs), including adverse events of special interest (AESIs), serious adverse events (SAEs), Treatment emergent adverse events (TEAE). Clinical laboratory tests, physical examinations, vital signs, and electrocardiograms (ECGs) will be used to conduct safety assessments.

[0255] Efficacy analysis and safety analysis will be conducted using statistical methods of Example 5 under 'Statistical methods'. Biomarker analysis may also be employed.

Additional Embodiments [0256] Various embodiments of the present technology are set forth below in paragraphs [0257] to [0335]:

[0257] Embodiment 1. A method of treating, preventing, or delaying a cardiotoxicity associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof.

[0258] Embodiment 2. A pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof for use in treating, preventing, or delaying a cardiotoxicity associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

[0259] Embodiment 3. A method of treating, preventing, or delaying a cardiotoxicity associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of all-trans retinoic acid (ATRA) or a pharmaceutically acceptable salt thereof.

[0260] Embodiment 4. A pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof for use in treating, preventing, or delaying a cardiotoxicity associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

[0261] Embodiment 5. The method or the pharmaceutical composition of any one of embodiments 1 -4, wherein the cardiotoxicity comprises an atrial arrhythmia.

[0262] Embodiment 6. The method or the pharmaceutical composition of embodiment s, wherein the atrial arrhythmia is an atrial tachycardia, atrial flutter, and/or atrial fibrillation.

[0263] Embodiment 7. A method of preventing atrial fibrosis associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof.

[0264] Embodiment 8. A pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof for use in preventing atrial fibrosis associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

[0265] Embodiment 9. A method of preventing atrial fibrosis associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof.

[0266] Embodiment 10. A pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof for use in preventing atrial fibrosis associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

[0267] Embodiment 11. The method or the pharmaceutical composition of any one of embodiments 1-10, wherein the tyrosine-kinase inhibitor inhibits C-terminal Src kinase (CSK).

[0268] Embodiment 12. The method or the pharmaceutical composition of any one of embodiments 1-11 , wherein the tyrosine-kinase inhibitor is a Bruton's tyrosine-kinase inhibitor.

[0269] Embodiment 13. The method or the pharmaceutical composition of embodiment 12, wherein the Bruton's tyrosine-kinase inhibitor is ibrutinib.

[0270] Embodiment 14. The method or the pharmaceutical composition of embodiment 13, wherein ibrutinib is administered at a dose in the range from about 1 mg/day to about 1680 mg/day.

[0271] Embodiment 15. The method or the pharmaceutical composition of embodiment 14, wherein ibrutinib is administered at a dose in the range from about 140mg/day to about 420 mg/day. [0272] Embodiment 16. The method or the pharmaceutical composition of any one of embodiments 1-15, wherein the pharmaceutical composition is administered before the administration of the tyrosine-kinase inhibitor to the subject.

[0273] Embodiment 17. The method or the pharmaceutical composition of any one of embodiments 1-15, wherein the pharmaceutical composition is administered concurrently with the tyrosine-kinase inhibitor to the subject.

[0274] Embodiment 18. The method or the pharmaceutical composition of any one of embodiments 1-15, wherein the pharmaceutical composition is administered after the administration of the tyrosine-kinase inhibitor to the subject.

[0275] Embodiment 19. The method or the pharmaceutical composition of any one of embodiments 1-18, wherein the subject has a B-cell cancer.

[0276] Embodiment 20. The method or the pharmaceutical composition of embodiment 19, wherein the B-cell cancer is selected from chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), Mantle cell lymphoma (MCL), Marginal zone lymphoma (MZL), and Waldenstrom's macroglobulinemia (WM).

[0277] Embodiment 21 . A method of preventing or delaying the onset of atrial arrhythmia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof.

[0278] Embodiment 22. A pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof for use in preventing or delaying the onset of atrial arrhythmia in a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

[0279] Embodiment 23. A method of preventing or delaying the onset of atrial arrhythmia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof.

[0280] Embodiment 24. A pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof for use in preventing or delaying the onset of atrial arrhythmia in a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

[0281] Embodiment 25. The method or the pharmaceutical composition of any one of embodiments 21-24, wherein the atrial arrhythmia is an atrial tachycardia, atrial flutter, and/or atrial fibrillation.

[0282] Embodiment 26. The method or the pharmaceutical composition of any one of embodiments 21-25, wherein the subject is a subject at risk for atrial fibrillation (Stage I) or a subject with pre-atrial fibrillation (Stage II) according to Atrial Fibrillation Guidelines.

[0283] Embodiment 27. The method or the pharmaceutical composition of any one of embodiments 21-26, wherein the subject presents evidence of electrical, structural, and/or functional atrial remodeling.

[0284] Embodiment 28. The method or the pharmaceutical composition of embodiment 27, wherein the electrical, structural, and/or functional atrial remodeling is determined by an electrocardiography (ECG), an echocardiography (EKG), a cardiac CT, or a cardiac MRI, a holter monitoring, and/or a telemetry monitoring.

[0285] Embodiment 29. The method or the pharmaceutical composition of embodiment 27 or 28, wherein the electrical atrial remodeling comprises a prolonged P wave duration.

[0286] Embodiment 30. The method or the pharmaceutical composition of embodiment 29, wherein the prolonged P wave duration is determined by one or more of an ECG, a holter monitoring, or a telemetry monitoring.

[0287] Embodiment 31. The method or the pharmaceutical composition of embodiment 30, wherein the prolonged P wave duration determined by ECG is more than about 100 milliseconds.

[0288] Embodiment 32. The method or the pharmaceutical composition of embodiment 29 or 31 , wherein the electrical remodeling comprises one or more of an atrial ectopy, an atrial tachycardia, and/or atrial flutter.

[0289] Embodiment 33. The method or the pharmaceutical composition of embodiment 27 or 28, wherein the structural and functional remodeling comprises one or more of an atrial enlargement, an atrial hypertrophy, or an abnormal heart muscle contraction or relaxation.

[0290] Embodiment 34. The method or the pharmaceutical composition of embodiment 33, wherein the structural and functional remodeling is assessed by analyzing one or more of a contractile or a relaxation parameter, a strain imaging, and/or a left atrial appendage emptying time.

[0291] Embodiment 35. The method or the pharmaceutical composition of any one of embodiments 21-34, wherein the subject has one or more of hypertension, sleep apnea, paroxysmal atrial fibrillation, diabetes, heart failure, coronary artery disease, or is over 60 years old.

[0292] Embodiment 36. The method or the pharmaceutical composition of any one of embodiments 21-35, wherein the administration of the pharmaceutical composition prevents or reverses atrial remodeling.

[0293] Embodiment 37. The method of embodiment 36, wherein the atrial myopathy comprises atrial myopathy.

[0294] Embodiment 38. The method or the pharmaceutical composition of any one of embodiments 21-37, wherein the administration of the pharmaceutical composition reduces a P wave duration in the subject compared to a control.

[0295] Embodiment 39. The method or the pharmaceutical composition of embodiment 38, wherein the P wave duration is less than about 100 milliseconds after administration of the pharmaceutical composition to the subject.

[0296] Embodiment 40. The method or the pharmaceutical composition of any one of embodiments 21-39, wherein the administration of the pharmaceutical composition reduces a left atrium (LA) enlargement or a LA fibrosis in the subject, compared to a control.

[0297] Embodiment 41. The method or the pharmaceutical composition of any one of embodiments 21-40, wherein the administration of the pharmaceutical composition improves a LA strain or a LA systolic or diastolic function in the subject, compared to a control.

[0298] Embodiment 42. A method of treating, preventing or delaying a cardiac conduction disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof.

[0299] Embodiment 43. A pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof for use in treating, preventing or delaying a cardiac conduction disease in a subject in need thereof, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject.

[0300] Embodiment 44. A method of treating, preventing or delaying a cardiac conduction disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof.

[0301] Embodiment 45. A pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof for use in treating, preventing or delaying a cardiac conduction disease in a subject in need thereof, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject.

[0302] Embodiment 46. A method of reducing one or more of a QRS duration, a ventricular fibrosis, or a ventricular mechanical dyssynchrony in a subject in need thereof compared to a control, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof.

[0303] Embodiment 47. A pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof for use in method of reducing one or more of a QRS duration, a ventricular fibrosis, or a ventricular mechanical dyssynchrony in a subject in need thereof, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject.

[0304] Embodiment 48. A method of reducing one or more of a QRS duration, a ventricular fibrosis, or a ventricular mechanical dyssynchrony in a subject in need thereof compared to a control, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of a ATRA or a pharmaceutically acceptable salt thereof. [0305] Embodiment 49. A pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof for use in method of reducing one or more of a QRS duration, a ventricular fibrosis, or a ventricular mechanical dyssynchrony in a subject in need thereof, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject.

[0306] Embodiment 50. The method or the pharmaceutical composition of any one of embodiments 45-48, wherein the subject has or is at risk of developing a cardiac conduction disease.

[0307] Embodiment 51. The method or the pharmaceutical composition of any one of embodiments 42-45 or 50, wherein the cardiac conduction disease comprises an atrioventricular conduction disease, a His-Purkinje system conduction disease, or a left bundle branch block (LBBB).

[0308] Embodiment 52. The method or the pharmaceutical composition of any one of embodiments 42-51 , wherein the subject has symptomatic Mobitz I atrioventricular block, Mobitz II atrioventricular block, or a third-degree atrioventricular block.

[0309] Embodiment 53. The method or the pharmaceutical composition of embodiment 52, wherein the subject qualifies for or has received a pacemaker implantation.

[0310] Embodiment 54. The method or the pharmaceutical composition of embodiment 53, wherein the pharmaceutical composition is administered before the pacemaker implantation.

[0311] Embodiment 55. The method or the pharmaceutical composition of embodiment 53 or 54, wherein the pharmaceutical composition is administered while the subject is using the pacemaker.

[0312] Embodiment 56. The method or the pharmaceutical composition of any one of embodiments 42-55, wherein the subject has heart failure.

[0313] Embodiment 57. The method or the pharmaceutical composition of embodiment 56, wherein the subject has a left bundle branch block. [0314] Embodiment 58. The method or the pharmaceutical composition of embodiment 56 or 57, wherein the subject qualifies for or has a cardiac resynchronization therapy.

[0315] Embodiment 59. The method or the pharmaceutical composition of embodiment 56, wherein the subject has an atrioventricular block.

[0316] Embodiment 60. The method or the pharmaceutical composition of embodiment 59, wherein the subject has an increased burden of ventricular pacing.

[0317] Embodiment 61. The method or the pharmaceutical composition of any one of embodiments 42-60, wherein the administration of the pharmaceutical composition improves atrioventricular conduction in the subject, compared to a control.

[0318] Embodiment 62. The method or the pharmaceutical composition of embodiment 61 , wherein the administration of the pharmaceutical composition reduces PR interval in the subject, compared to a control.

[0319] Embodiment 63. The method or the pharmaceutical composition of embodiment 62, wherein the PR interval is about 120 to about 200 milliseconds after administration of the pharmaceutical composition to the subject.

[0320] Embodiment 64. The method or the pharmaceutical composition of any one of embodiments 42-63, wherein the administration of the pharmaceutical composition reduces one or more of a QRS duration, a ventricular fibrosis, or a ventricular mechanical dyssynchrony in the subject, compared to a control.

[0321] Embodiment 65. The method or the pharmaceutical composition of embodiment 64, wherein the QRS duration is about 80 to about 100 milliseconds after administration of the pharmaceutical composition to the subject.

[0322] Embodiment 66. The method or the pharmaceutical composition of any one of embodiments 42-65, wherein the administration of the pharmaceutical composition (i) improves a New York Heart Association (NYHA) functional class or (ii) reduces a level of heart failure biomarker in the subject, compared to a control.

[0323] Embodiment 67. The method or the pharmaceutical composition of embodiment 66, wherein the heart failure biomarker is selected from B-type natriuretic peptide (BNP) or N-terminal (NT)-proBNP. [0324] Embodiment 68. The method or the pharmaceutical composition of any one of embodiments 1-67, wherein the pharmaceutical composition is administered at a dose in the range from about 1 mg/m²/day to about 80 mg/m²/day.

[0325] Embodiment 69. The method or the pharmaceutical composition of any one of embodiments 1-68, wherein the pharmaceutical composition is administered at a dose in the range from about 10 mg/m²/day to about 80 mg/m²/day.

[0326] Embodiment 70. The method or the pharmaceutical composition of any one of embodiments 1-69, wherein the pharmaceutical composition is administered at a dose in the range from about 10 mg/m²/day to about 50 mg/m²/day.

[0327] Embodiment 71. The method or the pharmaceutical composition of any one of embodiments 1-70, wherein the pharmaceutical composition is administered at a dose in the range from about 20 mg/m²/day to about 50 mg/m²/day.

[0328] Embodiment 72. The method or the pharmaceutical composition of any one of embodiments 1-71 , wherein the pharmaceutical composition is administered at a dose of about 22.5 mg/m²/day or of about 45 mg/m²/day.

[0329] Embodiment 73. The method or the pharmaceutical composition of any one of embodiments 1-72, wherein the pharmaceutical composition is administered at a frequency from twice in a day to once in a day.

[0330] Embodiment 74. The method or the pharmaceutical composition of any one of embodiments 1-73, wherein the pharmaceutical composition is administered via an oral, an intravenous, a subcutaneous, or an intramuscular route.

[0331] Embodiment 75. The method or the pharmaceutical composition of any one of embodiments 1-74, wherein the pharmaceutical composition is administered via an oral route.

[0332] Embodiment 76. The method or the pharmaceutical composition of any one of embodiments 1 -75, wherein the pharmaceutical composition is encapsulated.

[0333] Embodiment 77. The method or the pharmaceutical composition of any one of embodiments 1 , 2, 5-8, 11-22, 25-43, 46, 47, or 50-75, wherein the retinoid is a retinoic acid. [0334] Embodiment 78. The method or the pharmaceutical composition of embodiment 77, wherein the retinoic acid is all-trans retinoic acid (ATRA).

[0335] Embodiment 79. The method or the pharmaceutical composition of any one of embodiments 1-78, wherein the subject is human.

[0336] From the foregoing, it will be appreciated that specific embodiments of the present technology have been of the present technology for purposes of illustration, but that various modifications may be made without deviating from the scope of the present technology. Accordingly, the present technology is not limited except as by the appended claims.

[0337] All patents, applications, publications, test methods, literature, and other materials cited herein are hereby incorporated by reference in their entirety as if physically present in this specification.

Claims

1. A method of treating, preventing, or delaying a cardiotoxicity associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof.

2. A pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof for use in treating, preventing, or delaying a cardiotoxicity associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

3. A method of treating, preventing, or delaying a cardiotoxicity associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of all-trans retinoic acid (ATRA) or a pharmaceutically acceptable salt thereof.

4. A pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof for use in treating, preventing, or delaying a cardiotoxicity associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

5. The method or the pharmaceutical composition of any one of claims 1-4, wherein the cardiotoxicity comprises an atrial arrhythmia.

6. The method or the pharmaceutical composition of claim 5, wherein the atrial arrhythmia is an atrial tachycardia, atrial flutter, and/or atrial fibrillation.

7. A method of preventing atrial fibrosis associated with use of a tyrosinekinase inhibitor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof for use in preventing atrial fibrosis associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

9. A method of preventing atrial fibrosis associated with use of a tyrosinekinase inhibitor in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof for use in preventing atrial fibrosis associated with use of a tyrosine-kinase inhibitor in a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

11 . The method or the pharmaceutical composition of any one of claims 1-10, wherein the tyrosine-kinase inhibitor inhibits C-terminal Src kinase (CSK).

12. The method or the pharmaceutical composition of any one of claims 1-11 , wherein the tyrosine-kinase inhibitor is a Bruton's tyrosine-kinase inhibitor.

13. The method or the pharmaceutical composition of claim 12, wherein the Bruton's tyrosine-kinase inhibitor is ibrutinib.

14. The method or the pharmaceutical composition of claim 13, wherein ibrutinib is administered at a dose in the range from about 1 mg/day to about 1680 mg/day.

15. The method or the pharmaceutical composition of claim 14, wherein ibrutinib is administered at a dose in the range from about 140mg/day to about 420 mg/day.

16. The method or the pharmaceutical composition of any one of claims 1-15, wherein the pharmaceutical composition is administered before the administration of the tyrosine-kinase inhibitor to the subject.

17. The method or the pharmaceutical composition of any one of claims 1-15, wherein the pharmaceutical composition is administered concurrently with the tyrosinekinase inhibitor to the subject.

18. The method or the pharmaceutical composition of any one of claims 1-15, wherein the pharmaceutical composition is administered after the administration of the tyrosine-kinase inhibitor to the subject.

19. The method or the pharmaceutical composition of any one of claims 1-18, wherein the subject has a B-cell cancer.

20. The method or the pharmaceutical composition of claim 19, wherein the B-cell cancer is selected from chronic lymphocytic leukemia (CLL)Zsmall lymphocytic lymphoma (SLL), Mantle cell lymphoma (MCL), Marginal zone lymphoma (MZL), and Waldenstrom's macroglobulinemia (WM).

21. A method of preventing or delaying the onset of atrial arrhythmia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof for use in preventing or delaying the onset of atrial arrhythmia in a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

23. A method of preventing or delaying the onset of atrial arrhythmia in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof.

24. A pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof for use in preventing or delaying the onset of atrial arrhythmia in a subject in need thereof, wherein the pharmaceutical composition is administered to the subject in a therapeutically effective amount.

25. The method or the pharmaceutical composition of any one of claims 21-

24, wherein the atrial arrhythmia is an atrial tachycardia, atrial flutter, and/or atrial fibrillation.

26. The method or the pharmaceutical composition of any one of claims 21-

25, wherein the subject is a subject at risk for atrial fibrillation (Stage I) or a subject with pre-atrial fibrillation (Stage II) according to Atrial Fibrillation Guidelines.

27. The method or the pharmaceutical composition of any one of claims 21-

26, wherein the subject presents evidence of electrical, structural, and/or functional atrial remodeling.

28. The method or the pharmaceutical composition of claim 27, wherein the electrical, structural, and/or functional atrial remodeling is determined by an electrocardiography (ECG), an echocardiography (EKG), a cardiac CT, or a cardiac MRI, a holter monitoring, and/or a telemetry monitoring.

29. The method or the pharmaceutical composition of claim 27 or 28, wherein the electrical atrial remodeling comprises a prolonged P wave duration.

30. The method or the pharmaceutical composition of claim 29, wherein the prolonged P wave duration is determined by one or more of an ECG, a ho Iter monitoring, or a telemetry monitoring.

31. The method or the pharmaceutical composition of claim 30, wherein the prolonged P wave duration determined by ECG is more than about 100 milliseconds.

32. The method or the pharmaceutical composition of claim 29 or 31 , wherein the electrical remodeling comprises one or more of an atrial ectopy, an atrial tachycardia, and/or atrial flutter.

33. The method or the pharmaceutical composition of claim 27 or 28, wherein the structural and functional remodeling comprises one or more of an atrial enlargement, an atrial hypertrophy, or an abnormal heart muscle contraction or relaxation.

34. The method or the pharmaceutical composition of claim 33, wherein the structural and functional remodeling is assessed by analyzing one or more of a contractile or a relaxation parameter, a strain imaging, and/or a left atrial appendage emptying time.

35. The method or the pharmaceutical composition of any one of claims 21-

34, wherein the subject has one or more of hypertension, sleep apnea, paroxysmal atrial fibrillation, diabetes, heart failure, coronary artery disease, or is over 60 years old.

36. The method or the pharmaceutical composition of any one of claims 21-

35, wherein the administration of the pharmaceutical composition prevents or reverses atrial remodeling.

37. The method of claim 36, wherein the atrial myopathy comprises atrial myopathy.

38. The method or the pharmaceutical composition of any one of claims 21- 37, wherein the administration of the pharmaceutical composition reduces a P wave duration in the subject compared to a control.

39. The method or the pharmaceutical composition of claim 38, wherein the P wave duration is less than about 100 milliseconds after administration of the pharmaceutical composition to the subject.

40. The method or the pharmaceutical composition of any one of claims 21-

39, wherein the administration of the pharmaceutical composition reduces a left atrium (LA) enlargement or a LA fibrosis in the subject, compared to a control.

41. The method or the pharmaceutical composition of any one of claims 21-

40, wherein the administration of the pharmaceutical composition improves a LA strain or a LA systolic or diastolic function in the subject, compared to a control.

42. A method of treating, preventing or delaying a cardiac conduction disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof.

43. A pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof for use in treating, preventing or delaying a cardiac conduction disease in a subject in need thereof, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject.

44. A method of treating, preventing or delaying a cardiac conduction disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof.

45. A pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof for use in treating, preventing or delaying a cardiac conduction disease in a subject in need thereof, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject.

46. A method of reducing one or more of a QRS duration, a ventricular fibrosis, or a ventricular mechanical dyssynchrony in a subject in need thereof compared to a control, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof.

47. A pharmaceutical composition comprising or consisting of a retinoid or a pharmaceutically acceptable salt thereof for use in method of reducing one or more of a QRS duration, a ventricular fibrosis, or a ventricular mechanical dyssynchrony in a subject in need thereof, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject.

48. A method of reducing one or more of a QRS duration, a ventricular fibrosis, or a ventricular mechanical dyssynchrony in a subject in need thereof compared to a control, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising or consisting of a ATRA or a pharmaceutically acceptable salt thereof.

49. A pharmaceutical composition comprising or consisting of ATRA or a pharmaceutically acceptable salt thereof for use in method of reducing one or more of a QRS duration, a ventricular fibrosis, or a ventricular mechanical dyssynchrony in a subject in need thereof, wherein the therapeutically effective amount of the pharmaceutical composition is administered to the subject.

50. The method or the pharmaceutical composition of any one of claims 45- 48, wherein the subject has or is at risk of developing a cardiac conduction disease.

51. The method or the pharmaceutical composition of any one of claims 42- 45 or 50, wherein the cardiac conduction disease comprises an atrioventricular conduction disease, a His-Purkinje system conduction disease, or a left bundle branch block (LBBB).

52. The method or the pharmaceutical composition of any one of claims 42- 51 , wherein the subject has symptomatic Mobitz I atrioventricular block, Mobitz II atrioventricular block, or a third-degree atrioventricular block.

53. The method or the pharmaceutical composition of claim 52, wherein the subject qualifies for or has received a pacemaker implantation.

54. The method or the pharmaceutical composition of claim 53, wherein the pharmaceutical composition is administered before the pacemaker implantation.

55. The method or the pharmaceutical composition of claim 53 or 54, wherein the pharmaceutical composition is administered while the subject is using the pacemaker.

56. The method or the pharmaceutical composition of any one of claims 42- 55, wherein the subject has heart failure.

57. The method or the pharmaceutical composition of claim 56, wherein the subject has a left bundle branch block.

58. The method or the pharmaceutical composition of claim 56 or 57, wherein the subject qualifies for or has a cardiac resynchronization therapy.

59. The method or the pharmaceutical composition of claim 56, wherein the subject has an atrioventricular block.

60. The method or the pharmaceutical composition of claim 59, wherein the subject has an increased burden of ventricular pacing.

61. The method or the pharmaceutical composition of any one of claims 42- 60, wherein the administration of the pharmaceutical composition improves atrioventricular conduction in the subject, compared to a control.

62. The method or the pharmaceutical composition of claim 61 , wherein the administration of the pharmaceutical composition reduces PR interval in the subject, compared to a control.

63. The method or the pharmaceutical composition of claim 62, wherein the PR interval is about 120 to about 200 milliseconds after administration of the pharmaceutical composition to the subject.

64. The method or the pharmaceutical composition of any one of claims 42- 63, wherein the administration of the pharmaceutical composition reduces one or more of a QRS duration, a ventricular fibrosis, or a ventricular mechanical dyssynchrony in the subject, compared to a control.

65. The method or the pharmaceutical composition of claim 64, wherein the QRS duration is about 80 to about 100 milliseconds after administration of the pharmaceutical composition to the subject.

66. The method or the pharmaceutical composition of any one of claims 42- 65, wherein the administration of the pharmaceutical composition (i) improves a New York Heart Association (NYHA) functional class or (ii) reduces a level of heart failure biomarker in the subject, compared to a control.

67. The method or the pharmaceutical composition of claim 66, wherein the heart failure biomarker is selected from B-type natriuretic peptide (BNP) or N-terminal (NT)-proBNP.

68. The method or the pharmaceutical composition of any one of claims 1 -67, wherein the pharmaceutical composition is administered at a dose in the range from about 1 mg/m²/day to about 80 mg/m²/day.

69. The method or the pharmaceutical composition of any one of claims 1 -68, wherein the pharmaceutical composition is administered at a dose in the range from about 10 mg/m²/day to about 80 mg/m²/day.

70. The method or the pharmaceutical composition of any one of claims 1 -69, wherein the pharmaceutical composition is administered at a dose in the range from about 10 mg/m²/day to about 50 mg/m²/day.

71. The method or the pharmaceutical composition of any one of claims 1-70, wherein the pharmaceutical composition is administered at a dose in the range from about 20 mg/m²/day to about 50 mg/m²/day.

72. The method or the pharmaceutical composition of any one of claims 1-71 , wherein the pharmaceutical composition is administered at a dose of about 22.5 mg/m²/day or of about 45 mg/m²/day.

73. The method or the pharmaceutical composition of any one of claims 1 -72, wherein the pharmaceutical composition is administered at a frequency from twice in a day to once in a day.

74. The method or the pharmaceutical composition of any one of claims 1 -73, wherein the pharmaceutical composition is administered via an oral, an intravenous, a subcutaneous, or an intramuscular route.

75. The method or the pharmaceutical composition of any one of claims 1 -74, wherein the pharmaceutical composition is administered via an oral route.

76. The method or the pharmaceutical composition of any one of claims 1-75, wherein the pharmaceutical composition is encapsulated.

77. The method or the pharmaceutical composition of any one of claims 1 , 2, 5-8, 11-22, 25-43, 46, 47, or 50-76, wherein the retinoid is a retinoic acid.

78. The method or the pharmaceutical composition of claim 77, wherein the retinoic acid is all-trans retinoic acid (ATRA).

79. The method or the pharmaceutical composition of any one of claims 1 -78, wherein the subject is human.