Compositions and methods for treating infections in cystic fibrosis patients with senolytic agents

Abstract

Compositions, kits, and systems are disclosed that contain at least one senolytic agent. The compositions, kits, and systems may be utilized, for example, in a method of treating at least one lung infection in a patient. In a particular (but non-limiting) embodiment, the compositions, kits, and systems may be utilized in a method of treating at least one infection in a cystic fibrosis patient.

Description

ELECTRONICALLY TRANSMITTED: AUGUST 29, 2025COMPOSITIONS AND METHODS FOR TREATING INFECTIONS IN CYSTIC FIBROSIS PATIENTS WITH SENOLYTIC AGENTSCROSS REFERENCE TO RELATED APPLICATIONS

[0001] The subject application claims benefit under 35 USC § 119(e) of US Provisional Application No. 63 / 688,358, filed August 29, 2024. The entire contents of the above- referenced patent a ppi ication (s) are hereby expressly incorporated herein by reference.STATEMENT OF GOVERNMENT SUPPORT

[0002] This invention was made with government support under National Institutes of Health Grant No. P20GM103648. The government has certain rights in the invention.BACKGROUND

[0003] Nontuberculous Mycobacteria (NTM) are environmental organisms that can be found, for example, in soil, dust, and water, including natural water sources (such as lakes, rivers, and streams) and municipal water sources (including drinking and bathing water sources). Nontuberculous Mycobacteria (NTM), such as Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex, are a group of opportunistic bacterial pathogens which can cause severe pulmonary infections in people with immunocompromised conditions such as cystic fibrosis (CF), bronchiectasis, or chronic obstructive pulmonary disease (COPD). However, little is known about the mechanism that drives host susceptibility to NTM pulmonary infection in CF patients.

[0004] Cystic Fibrosis (CF) is an inherited genetic disorder in humans and affects approximately 100,000 children and adults in the world (Veit et al., 2016; Shteinberg et al., 2021). CF is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes a cell-surface chloride ion channel. Six classes (I— VI) of more than 2000 CFTR mutations have been identified in CF patients based on the protein production process (Zielenski and Tsui, 1995; Ratjen et al., 2015; Veit et al., 2016; Shteinberg et al., 2021). These mutations cause no / low protein synthesis, defective processing, low chloride ion channel activity, or decreased protein stability. Among those, Phe508Del, also known as AF508, is themost common CFTR mutation, which leads to a misfolded protein that is improperly glycosylated and is targeted for protein degradation (Cohen and Prince, 2012; Shteinberg et al., 2021). The CFTR protein transporter regulates the flow of chloride and bicarbonate across cytoplasmic membrane in different tissues including airway, sweat gland, gastrointestinal tract and pancreas (Shteinberg et al., 2021). In the airway, defective CFTR protein has no or minimal ability to release intracellular chloride and transport bicarbonate, which results in airway surface liquid dehydration and build-up of thick mucus, a hallmark of CF-associated pathogenesis.

[0005] Microbial lung infections are currently a main cause of mortality and morbidity in CF patients. A number of bacterial pathogens have been detected in the airway of CF patients with lung infections, including Staphylococcus aureus, Haemophilus influenzae, Pseudomonas aeruginosa, and Burkholderia cepacia Complex (Lyczak et al., 2002; Hauser et al., 2011; Chiappini et al., 2014; Filkins and O'Toole, 2015). More recently, a couple of emerging bacterial pathogens were discovered in CF patients, including Streptococcus milleri group and non-tuberculous mycobacteria (NTM) (Filkins and O'Toole, 2015; Floto and Haworth, 2015; Park and Olivier, 2015; Martiniano et al., 2019; Yan et al., 2020). According to the data from the CF foundation (CFF 2018 Patient Registry Annual Data Report), NTM infections are mainly observed in the airway of CF patients. In 2018, approximately 13.6% of CF patients tested positive for NTM in the United States.

[0006] Ninety five percent of NTM strains isolated from CF patient lungs belong to the Mycobacterium avium complex (MAC) (M. avium and M. intracellulare) or Mycobacterium abscessus complex (MABSC) (M. abscessus (M. ab), M. massiUense, and M. bolletii). Based on a 2018 study in the United States, each of these two NTM groups accounts for approximately 50% of the NTM infections in CF patients. Compared to MAC, MABSC is more likely to lead to accelerated pulmonary deterioration and lung function decline. CF patients with MABSC lung infection may require lung transplantation for survival (Esther et al., 2010; Skolnik et al., 2016). A study in Scandinavia indicated that about 25% of CF patients with MABSC lung infection from 2000 to the end of 2012 required lung transplantation or died despite antibiotic treatment (Qvist et al., 2015a). It remains unclear why patients with CF are more susceptible to NTM infections, a group of environmental mycobacteria which are typically non- pathogenic. One possible mechanism is ineffective airway clearance that facilitates NTM biofilm formation resulting in a protective environment for the bacteria (Rose and Bermudez, 2014; Rose et al., 2015; Qvist et al., 2015b; Gannon and Darch, 2021).

[0007] Bacterial lung infections result in an exaggerated inflammatory response in CF patients, which are detrimental to the host defense. For example, P. aeruginosa and S. aureus infections induce an exaggerated pulmonary infiltration of immune cells including neutrophils, macrophages, and dendritic cells, which causes an aberrant inflammatory environment in the lungs of CF patients.

[0008] In CF patients as well as in CF mouse models, this dysregulated response is characterized by a robust production of proinflammatory cytokines such as TNF-a, IL- la, IL-6, IL- 10 and granulocyte colony-stimulating factor (G-CSF), and an increased secretion of antimicrobial molecules in the airway including granule-derived proteases and reactive oxygen species (ROS) (Bruscia et al., 2009). The dysregulated inflammatory response in CF patients with lung infections interferes with efficient bacterial clearance, and compromises lung tissue integrity. In addition to innate immune cells, dysregulated lymphocyte responses, such as Th2, Thl7, and regulatory T cells (Tregs), have also been observed in CF patients as well as in mouse models post microbial infections. Previous studies have shown that infection with P. aeruginosa induces an exacerbated Th2 and Thl7, and impaired Treg response in CF patients (Hartl et al., 2006; Tan et al., 2011; Tiringer et al., 2013; Hector et al., 2015). Relative to other microbial pathogens, the current understanding of host immunity in response to NTM infection in CF patients is limited. However, published studies suggest that, similar to other bacterial pathogens, NTM infection also induces an exacerbated production of TNF-a, IL-ip, and IL-6, as well as changes in Thl7 T cell activation in CF patients (Becker et al., 2016; Hayes et al., 2022).BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIGS. 1-4 illustrate that M. abscessus (M. ab) infection induces senescence-like macrophages in Cftr^ mice and AM culture ex vivo. FIG. 1: UMAP (uniform manifold approximation and projection) of alveolar macrophages (AMs) colored by cluster (cell type) identity with Seurat clustering. FIG. 2: Violin plot showing combined expression score of cellular senescence marker genes by cluster. FIG. 3: qRT-PCR analysis for pl6INK4aand p21CIP1in Cftr+ / +and Cftr ' AMs that were uninfected with infected M. ab clinical isolate #1 (Cl#l, MOI=10) ex vitro for 72 hours in cell culture. The mRNA level was normalized to Gapdh, and expressed as fold change relative to M. ab-infected Cftr^ AMs. ND, not detected. FIG. 4: Representative images of SA-3-galactosidase activity staining for Cftr+ / +and Cftr^ AMs that were uninfected or infected with M. ab ( MOI= 10) for 72 hours. Scale bars, 125 pm. In (C), the data are presented as the mean ± SD. n = 3. ***p < 0.001 by two-way ANOVA, followed by Tukey's post-hoc test.

[0010] FIGS. 5-7 illustrate that senolytic agents rescue M. ab killing in the lungs of Cftr mice. FIG. 5: M. ab CFU in the Cftr+ / +and Cftr^ mouse lung. FIGS. 6-7: qRT-PCR of pl6INK4aand p21CIP1in mouse F4 / 80 lung macrophages isolated from Cftr^ (FIG. 6) and Cftr+ / +(FIG. 7) mice. For qRT- PCR in (FIG. 6) and (FIG. 7), the results were normalized to Gapdh. pl6INK4aand p21CIF>1expression levels were expressed as fold changes relative to the untreated group. All data are presented as the mean ± SD (n = 4 / group). ND, not detected, n.s., not statistically significant. ***P < 0.001 by two-way (A) or one-way (B and C) ANOVA, followed by Tukey's post-hoc test.DETAILED DESCRIPTION

[0011] Before explaining at least one embodiment of the inventive concept(s) in detail by way of exemplary language and results, it is to be understood that the inventive concept(s) is not limited in its application to the details of construction and the arrangement of the components set forth in the following description. The inventive concept(s) is capable of other embodiments or of being practiced or carried out in various ways. As such, the language used herein is intended to be given the broadest possible scope and meaning; and the embodiments are meant to be exemplary - not exhaustive. Also, it is to be understood that the phraseology and terminology employed herein is for the purpose of description and should not be regarded as limiting.

[0012] Unless otherwise defined herein, scientific and technical terms used in connection with the presently disclosed inventive concept(s) shall have the meanings that are commonly understood by those of ordinary skill in the art. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular. The foregoing techniques and procedures 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. The nomenclatures utilized in connection with, and the laboratory procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Standard techniques are used for chemical syntheses and chemical analyses.

[0013] All patents, published patent applications, and non-patent publications mentioned in the specification are indicative of the level of skill of those skilled in the art to which this presently disclosed inventive concept(s) pertains. All patents, published patent applications, and nonpatent publications referenced in any portion of this application are herein expresslyincorporated by reference in their entirety to the same extent as if each individual patent or publication was specifically and individually indicated to be incorporated by reference.

[0014] All of the compositions and / or methods disclosed herein can be made and executed without undue experimentation in light of the present disclosure. While the compositions and methods of the inventive concept(s) have been described in terms of particular embodiments, it will be apparent to those of skill in the art that variations may be applied to the compositions and / or methods and in the steps or in the sequence of steps of the methods described herein without departing from the concept, spirit, and scope of the inventive concept(s). All such similar substitutions and modifications apparent to those skilled in the art are deemed to be within the spirit, scope, and concept of the inventive concept(s) as defined by the appended claims.

[0015] As utilized in accordance with the present disclosure, the following terms, unless otherwise indicated, shall be understood to have the following meanings:

[0016] The use of the term "a" or "an" when used in conjunction with the term "comprising" in the claims and / or the specification may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one." As such, the terms "a," "an," and "the" include plural referents unless the context clearly indicates otherwise. Thus, for example, reference to "a compound" may refer to one or more compounds, two or more compounds, three or more compounds, four or more compounds, or greater numbers of compounds. The term "plurality" refers to "two or more."

[0017] The use of the term "at least one" will be understood to include one as well as any quantity more than one, including but not limited to, 2, 3, 4, 5, 10, 15, 20, 30, 40, 50, 100, etc. The term "at least one" may extend up to 100 or 1000 or more, depending on the term to which it is attached; in addition, the quantities of 100 / 1000 are not to be considered limiting, as higher limits may also produce satisfactory results. In addition, the use of the term "at least one of X, Y, and Z" will be understood to include X alone, Y alone, and Z alone, as well as any combination of X, Y, and Z. The use of ordinal number terminology (i.e., "first," "second," "third," "fourth," etc.) is solely for the purpose of differentiating between two or more items and is not meant to imply any sequence or order or importance to one item over another or any order of addition, for example.

[0018] The use of the term "or" in the claims is used to mean an inclusive "and / or" unless explicitly indicated to refer to alternatives only or unless the alternatives are mutually exclusive. For example, a condition "A or B" is satisfied by any of the following: A is true (or present) and Bis false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).

[0019] As used herein, any reference to "one embodiment," "an embodiment," "some embodiments," "one example," "for exam pie," or "an example" means that a particular element, feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment. The appearance of the phrase "in some embodiments" or "one example" in various places in the specification is not necessarily all referring to the same embodiment, for example. Further, all references to one or more embodiments or examples are to be construed as non-limiting to the claims.

[0020] Throughout this application, the term "about" is used to indicate that a value includes the inherent variation of errorfor a composition / apparatus / device, the method being employed to determine the value, or the variation that exists among the study subjects. For example, but not by way of limitation, when the term "about" is utilized, the designated value may vary by plus or minus twenty percent, or fifteen percent, or twelve percent, or eleven percent, or ten percent, or nine percent, or eight percent, or seven percent, or six percent, or five percent, or four percent, or three percent, or two percent, or one percent from the specified value, as such variations are appropriate to perform the disclosed methods and as understood by persons having ordinary skill in the art.

[0021] As used in this specification and claim(s), the words "comprising" (and any form of comprising, such as "comprise" and "comprises"), "having" (and any form of having, such as "have" and "has"), "including" (and any form of including, such as "includes" and "include"), or "containing" (and any form of containing, such as "contains" and "contain") are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0022] The term "or combinations thereof" as used herein refers to all permutations and combinations of the listed items preceding the term. For example, "A, B, C, or combinations thereof" is intended to include at least one of: A, B, C, AB, AC, BC, or ABC, and if order is important in a particular context, also BA, CA, CB, CBA, BCA, ACB, BAC, or CAB. Continuing with this example, expressly included are combinations that contain repeats of one or more item or term, such as BB, AAA, AAB, BBC, AAABCCCC, CBBAAA, CABABB, and so forth. The skilled artisan will understand that typically there is no limit on the number of items or terms in any combination, unless otherwise apparent from the context.

[0023] As used herein, the term "substantially" means that the subsequently described event or circumstance completely occurs or that the subsequently described event orcircumstance occurs to a great extent or degree. For example, when associated with a particular event or circumstance, the term "substantially" means that the subsequently described event or circumstance occurs at least 80% of the time, or at least 85% of the time, or at least 90% of the time, or at least 95% of the time. For example, the term "substantially adjacent" may mean that two items are 100% adjacent to one another, or that the two items are within close proximity to one another but not 100% adjacent to one another, or that a portion of one of the two items is not 100% adjacent to the other item but is within close proximity to the other item.

[0024] As used herein, the phrases "associated with" and "coupled to" include both direct association / binding of two moietiesto one another as well as indirect association / binding of two moieties to one another. Non-limiting examples of associations / couplings include covalent binding of one moiety to another moiety either by a direct bond or through a spacer group, non- covalent binding of one moiety to another moiety either directly or by means of specific binding pair members bound to the moieties, incorporation of one moiety into another moiety such as by dissolving one moiety in another moiety or by synthesis, and coating one moiety on another moiety, for example.

[0025] The terms "peptide" and "polypeptide" as used herein will be understood to refer to a polymer of amino acids. The polymer may include d-, I-, or artificial variants of amino acids. In addition, the terms "peptide" and "polypeptide" will be understood to include peptides, proteins, and glycoproteins.

[0026] The term "pharmaceutically acceptable" refers to compounds and compositions which are suitable for administration to humans and / or animals without undue adverse side effects, such as (but not limited to) toxicity, irritation, and / or allergic response, commensurate with a reasonable benefit / risk ratio.

[0027] The phrase "pharmaceutically-acceptable carrier" as used herein means a pharmaceutically-acceptable material, composition, excipient, or vehicle, such as a liquid or solid filler, diluent, excipient, or solvent encapsulating material, involved in carrying or transporting the subject compound from one organ, or portion of the body, to another organ, or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. The term "pharmaceutically- acceptable carrier" refers to any carrier, vehicle, excipient, and / or diluent known in the art or otherwise contemplated herein that may improve solubility, deliverability, dispersion, stability, and / or conformational integrity of the compositions disclosed herein. For example (but not by way of limitation), a physiological compatible carrier (e.g., saline) that is compatible withmaintaining the structure / activity of the active ingredient(s) when administered, and compatible with the desired mode of administration, may be utilized as the pharmaceutically acceptable carrier in accordance with the present disclosure. In addition, the active ingredient(s) may be mixed with carriers / excipients which are pharmaceutically acceptable and compatible with the active ingredient(s). Suitable carriers / excipients include, for example but not by way of limitation, water, saline, dextrose, glycerol, ethanol, and the like, or any combination thereof.

[0028] The term "patient" or "subject" as used herein includes human and veterinary subjects. "Mammal" for purposes of treatment refers to any animal classified as a mammal, including (but not limited to) humans, domestic and farm animals, nonhuman primates, and any other animal that has mammary tissue.

[0029] The term "treatment" refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treatment include, but are not limited to, individuals already having a particular condition / disease / infection as well as individuals who are at risk of acquiring a particular condition / disease / infection (e.g., those needing prophylactic / preventative measures). The term "treating" refers to administering an agent to a subject / patient for therapeutic and / or prophylactic / preventative purposes.

[0030] A "therapeutic composition" or "pharmaceutical composition" refers to an agent that may be administered in vivo to bring about a therapeutic and / or prophylactic / preventative effect.

[0031] Administering a therapeutically effective amount or prophylactically effective amount is intended to provide a therapeutic benefit in the treatment, prevention, and / or management of a disease, condition, and / or infection. The specific amount that is therapeutically effective can be readily determined by the ordinary medical practitioner, and can vary depending on factors known in the art, such as (but not limited to) the type of condition / disease / infection, the patient's history and age, the stage of the condition / disease / infection, and the co-administration of other agents.

[0032] The term "effective amount" refers to an amount of a biologically active molecule or sufficient to exhibit a detectable therapeutic effect without undue adverse side effects (such as (but not limited to) toxicity, irritation, and allergic response) commensurate with a reasonable benefit / risk ratio when used in the manner of the inventive concept(s). The therapeutic effect may include, for example but not by way of limitation, preventing, inhibiting, or reducing the occurrence of infection by or growth of microbes and / or opportunistic infections. The effective amount for a subject will depend upon the type of subject, the subject's size and health, thenature and severity of the condition / disease / infection to be treated, the method of administration, the duration of treatment, the nature of concurrent therapy (if any), the specific formulations employed, and the like. Thus, it is not possible to specify an exact effective amount in advance. However, the effective amount for a given situation can be determined by one of ordinary skill in the art using routine experimentation based on the information provided herein.

[0033] As used herein, the term "concurrent therapy" is used interchangeably with the terms "combination therapy" and "adjunct therapy," and will be understood to mean that the patient in need of treatment is treated or given another drug for the disease / infection in conjunction with the compositions of the present disclosure. This concurrent therapy can be sequential therapy, where the patient is treated first with one composition and then the other composition, or the two compositions are given simultaneously.

[0034] The terms "administration" and "administering," as used herein, will be understood to include all routes of administration known in the art, including but not limited to, oral, topical, transdermal, parenteral, subcutaneous, intranasal, intratracheal, intrabronchial, mucosal, intramuscular, intraperitoneal, intravitreal, and intravenous routes, and including both local and systemic applications. In addition, the compositions of the present disclosure (and / or the methods of administration of same) may be designed to provide delayed, controlled, or sustained release using formulation techniques which are well known in the art.

[0035] Turning now to the inventive concepts, certain non-limiting embodiments of the present disclosure are directed to compositions, systems, kits, and methods of treating infections. In particular, the present disclosure is related to compositions, systems, and kits comprising one or more senolytic agents, as well as methods for treating lung infections in patients utilizing the compositions, systems, or kits comprising one or more senolytic agents.

[0036] Certain non-limiting embodiments of the present disclosure are directed to methods of treating at least one infection in a patient in need thereof (such as, but not limited to, a cystic fibrosis patient), wherein the method comprises administering to the cystic fibrosis patient at least one senolytic agent.

[0037] Certain non-limiting embodiments of the present disclosure are also directed to pharmaceutical compositions for use in any of the methods disclosed or otherwise contemplated herein, wherein the pharmaceutical compositions comprise at least one senolytic agent. In certain particular (but non-limiting) embodiments, the pharmaceutical compositions further include at least one pharmaceutically acceptable carrier.

[0038] Certain non-limiting embodiments of the present disclosure are also directed to kits that comprise at least one of any of the pharmaceutical compositions disclosed or otherwise contemplated herein. In certain particular (but non-limiting) embodiments, each of the pharmaceutical compositions comprises at least one senolytic agent. In certain particular (but non-limiting) embodiments, each of the pharmaceutical compositions comprises two or more senolytic agents. Alternatively, in certain particular (but non-limiting) embodiments, the kits may comprise two or more pharmaceutical compositions, wherein each pharmaceutical composition contains one or more senolytic agents, and wherein the two pharmaceutical compositions may each contain at least one senolytic agent that is not present in the other pharmaceutical composition.

[0039] In certain particular (but non-limiting) embodiments, the pharmaceutical compositions, kits, and methods utilize at least two senolytic agents. The combination of two or more senolytic agents may provide a synergistic effect overthe individual senolytic agents alone.

[0040] Cystic fibrosis (CF) is a genetic disorder caused by the mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Microbial lung infections are currently a main cause of mortality and morbidity in CF patients. The present disclosure found that Non- tuberculous Mycobacteria (NTM), a group of bacterial pathogens identified in cystic fibrosis patients, induced cellular senescence in cystic fibrosis mouse model, and that elimination of senescent cells using senolytics increased mycobacterial killing in cystic fibrosis mice. Therefore, the present disclosure utilizes drugs targeting senescent cells to treat cystic fibrosis patients with lung infections.

[0041] Senolytic agents are a class of drugs that selectively clear senescent cells (Kirkland et al. (2020) Journal of Internal Medicine, 288:518-536). Any senolytic agents (or combinations of senolytic agents) known in the art or otherwise contemplated herein may be utilized in accordance with the present disclosure. Certain senolytic agents are well-known in the art and are commercially available. Non-limiting examples of senolytic agents that may be utilized in accordance with the present disclosure include Dasatinib, Quercetin, Fisetin, Luteolin, Curcumin, Curcumin Analog EF24, Navitoclax (ABT263), A1331852, A155463, Geldanamycin, Tanespimycin, Alvespimycin, Piperlongumine, FOXO-4 related peptide, Nutlin3a, Ouabain, Proscil laridin A, Digoxin, and the like, as well as any combination thereof.

[0042] In certain particular (but non-limiting) embodiments, the at least one senolytic agent is a peptide or other small molecule. The term "small molecule" as used herein refers to natural or artificial chemical compounds with well-defined structures that bind to specific biologicalmacromolecules and act as an effector, altering the activity or function of the target to which they bind. Small molecules typically have a molecular weight generally in a range of from about 1 Da to about 1.5 kDa, and their small size allows the molecules to diffuse across cell membranes and reach intracellular sites of action, if necessary. Small molecules are typically smaller than nucleic acids, proteins, enzymes, antibodies, polysaccharides, biologies, and other bio- therapeutic modalities, which are generally more than 1.5 kDa in size.

[0043] When the senolytic agent(s) utilized in accordance with the present disclosure are peptides or small molecules, the peptide(s) / small molecule(s) may be encapsulated in a delivery vehicle. Non-limiting examples of delivery vehicles that may be utilized in accordance with the present disclosure include a liposome, a lipoplex, a microvesicle, an exosome, a lipidoid nanoparticle, a polymeric nanoparticle, an inorganic nanoparticle, and a stable nucleic acid particle (SNALP), and the like, as well as variations, derivatives, and combinations thereof.

[0044] Any pharmaceutically-acceptable carriers known in the art or otherwise contemplated herein may be utilized in accordance with the present disclosure. Non-limiting examples include a pharmaceutically acceptable solvent, suspending agent, or vehicle that aid in delivery of the compositions of the present disclosure to the human or animal. The carrier may be liquid or solid and is selected with the planned manner of administration in mind. Examples of pharmaceutically acceptable carriers that may be utilized in accordance with the present disclosure include, but are not limited to, PEG, liposomes, ethanol, DMSO, aqueous buffers, oils, DPPC, lipids, other biologically-active molecules, vaccine-adjuvants, and combinations thereof. In addition, in certain particular (but non-limiting) examples, pharmaceutically-acceptable carriers can also contain a physiologically acceptable compound that acts to stabilize the compound and / or increase or decrease the absorption or clearance rates of the pharmaceutical compositions. Physiologically acceptable compounds can include (for example, but not by way of limitation) carbohydrates, such as glucose, sucrose, or dextrans; antioxidants, such as ascorbic acid or glutathione; chelating agents; low molecular weight proteins; detergents; liposomal carriers; and / or excipients or other stabilizers and / or buffers. Other physiologically acceptable compounds include (for example, but not by way of limitation) wetting agents, emulsifying agents, dispersing agents, and / or preservatives.

[0045] The senolytic agent-containing compositions utilized in accordance with the present disclosure may be provided in any form and any formulation that allows the compositions to function in accordance with the present disclosure. For example (but not by way of limitation), the compositions may be in solid form (such as, but not limited to, tablets, powders, and drypowder inhalers), liquid form (such as, but not limited to, emulsions, microemulsions, solutions, suspensions, syrups, and elixirs), or provided as gels, sprays, mists, or aerosols.

[0046] The methods may be utilized to treat non-tuberculosis Mycobacterial infections in any patients, but are particularly useful for treating patients suffering from various lung disorders and diseases, such as (but not limited to), cystic fibrosis, bronchiectasis, or chronic obstructive pulmonary disease (COPD). In a particular (but non-limiting) embodiment, the patient has cystic fibrosis.

[0047] The methods may be utilized to treat any Mycobacterial strains that cause nontuberculosis infections in any of the patients described herein. Non-limiting examples thereof include the Mycobacterium avium complex, the Mycobacterium abscessus complex, as well as the individual species of M. avium, M. intracellulare, M. abscessus (M. ab), M. massiliense, M. bolletii, and the like, as well as any combinations thereof.

[0048] The methods of the present disclosure may optionally include one or more therapeutic steps that are performed substantially simultaneously or wholly or partially sequentially with the administration of the senolytic agent(s). For example, but not by way of limitation, the method may further comprise administering at least one antibiotic to the subject. Non-limiting examples of antibiotics that may be utilized in accordance with the present disclosure include clarithromycin, clofazimine, amikacin, rifampicin, and the like, as well as any combinations thereof.

[0049] In the methods of the present disclosure, the compositions may be administered in therapeutically effective amounts. An effective amount is a dosage of the composition sufficient to provide a therapeutically or medically desirable result or effect in the subject to which the composition is administered. The effective amount will vary with the particular condition being treated, the age and physical condition of the subject being treated, the severity of the condition, the duration of the treatment, the nature of the concurrent or combination therapy (if any), the specific route of administration, and like factors within the knowledge and expertise of the health practitioner. For example, in connection with methods directed towards treating subjects having a condition characterized by pulmonary fibrosis, an effective amount would be an amount sufficient to mitigate, reduce, modulate, inhibit, or otherwise effectively treat the condition in the subject.

[0050] Generally, a therapeutically effective amount will vary with the subject's age, condition, and sex, as well as the nature and extent of the disease in the subject, all of which can be determined by one of ordinary skill in the art. The dosage may be adjusted by the individualphysician or veterinarian, particularly in the event of any complications. Non-limiting examples of therapeutically effective amounts that may be utilized in accordance with the present disclosure include about 0.01 pg / kg (weight of the at least one agent / body weight of patient), about 0.05 pg / kg, about 0.1 pg / kg, about 0.5 pg / kg, about 1 pg / kg, about 5 pg / kg, about 10 pg / kg, about 50 pg / kg, about 100 pg / kg, about 200 pg / kg, about 300 pg / kg, about 400 pg / kg, about 500 pg / kg, about 600 pg / kg, about 700 pg / kg, about 800 pg / kg, about 900 pg / kg, about 1 mg / kg, about 2 mg / kg, about 3 mg / kg, about 4 mg / kg, about 5 mg / kg, about 6 mg / kg, about 7 mg / kg, about 8 mg / kg, about 9 mg / kg, about 10 mg / kg, about 11 mg / kg, about 12 mg / kg, about13 mg / kg, about 14 mg / kg, about 15 mg / kg, about 16 mg / kg, about 17 mg / kg, about 18 mg / kg, about 19 mg / kg, about 20 mg / kg, about 21 mg / kg, about 22 mg / kg, about 23 mg / kg, about 24 mg / kg, about 25 mg / kg, about 26 mg / kg, about 27 mg / kg, about 28 mg / kg, about 29 mg / kg, about 30 mg / kg, about 31 mg / kg, about 32 mg / kg, about 33 mg / kg, about 34 mg / kg, about 35 mg / kg, about 36 mg / kg, about 37 mg / kg, about 38 mg / kg, about 39 mg / kg, about 40 mg / kg, about 41 mg / kg, about 42 mg / kg, about 43 mg / kg, about 44 mg / kg, about 45 mg / kg, about 46 mg / kg, about 47 mg / kg, about 48 mg / kg, about 49 mg / kg, about 50 mg / kg, about 51 mg / kg, about 52 mg / kg, about 53 mg / kg, about 54 mg / kg, about 55 mg / kg, about 56 mg / kg, about 57 mg / kg, about 58 mg / kg, about 59 mg / kg, about 60 mg / kg, about 61 mg / kg, about 62 mg / kg, about 63 mg / kg, about 64 mg / kg, about 65 mg / kg, about 66 mg / kg, about 67 mg / kg, about 68 mg / kg, about 69 mg / kg, about 70 mg / kg, about 71 mg / kg, about 72 mg / kg, about 73 mg / kg, about 74 mg / kg, about 75 mg / kg, about 76 mg / kg, about 77 mg / kg, about 78 mg / kg, about 79 mg / kg, about 80 mg / kg, about 81 mg / kg, about 82 mg / kg, about 83 mg / kg, about 84 mg / kg, about 85 mg / kg, about 86 mg / kg, about 87 mg / kg, about 88 mg / kg, about 89 mg / kg, about 90 mg / kg, about 91 mg / kg, about 92 mg / kg, about 93 mg / kg, about 94 mg / kg, about 95 mg / kg, about 96 mg / kg, about 97 mg / kg, about 98 mg / kg, about 99 mg / kg, about 100 mg / kg, about 110 mg / kg, about 120 mg / kg, about 130 mg / kg, about 140 mg / kg, about 150 mg / kg, about 160 mg / kg, about 170 mg / kg, about 180 mg / kg, about 190 mg / kg, about 200 mg / kg, about 225 mg / kg, about 250 mg / kg, about 275 mg / kg, about 300 mg / kg, about 325 mg / kg, about 350 mg / kg, about 375 mg / kg, about 400 mg / kg, about 425 mg / kg, about 450 mg / kg, about 475 mg / kg, about 500 mg / kg, about 525 mg / kg, about 550 mg / kg, about 575 mg / kg, about 600 mg / kg, about 625 mg / kg, about 650 mg / kg, about 675 mg / kg, about 700 mg / kg, about 725 mg / kg, about 750 mg / kg, about 775 mg / kg, about 800 mg / kg, about 825 mg / kg, about 850 mg / kg, about 875 mg / kg, about 900 mg / kg, about 925 mg / kg, about 950 mg / kg, about 975 mg / kg, about 1000 mg / kg, about 1100 mg / kg, about 1200 mg / kg, about 1300 mg / kg, about 1400mg / kg, about 1500 mg / kg, about 1600 mg / kg, about 1700 mg / kg, about 1800 mg / kg, about 1900 mg / kg, about 2000 mg / kg, and the like, as well as a range formed from two of any of the above values.

[0051] Non-limiting examples of ranges of therapeutically effective amounts that may be utilized in accordance with the present disclosure include a range from about 0.1 pg / kg to about 2000 mg / kg, or a range of from about 1 pg / kg to about 1000 mg / kg, or a range of from about 0.1 mg / kg to about 500 mg / kg, or a range of from about 0.5 mg / kg to about 100 mg / kg, or a range of from about 5 mg / kg to about 500 mg / kg, or a range of from about 100 mg / kg to about 500 mg / kg, or a range of from about 1 mg / kg to about 20 mg / kg, or a range of from about 5 mg / kg to about 50 mg / kg, or a range of from about 5 mg / kg to about 10 mg / kg, or a range of from about 0.01 mg / kg to about 5 mg / kg, or a range of from about 25 mg / kg to about 50 mg / kg, or a range of from about 0.1 mg / kg to about 1 mg / kg, or a range of from about 0.25 mg / kg to about 5 mg / kg, or a range of from about 10 mg / kg to about 200 mg / kg, or a range of from about 0.5 mg / kg to about 20 mg / kg, or a range of from about 10 mg / kg to about 60 mg / kg, and the like. The therapeutically effective amount may be delivered in one or more dose administrations. For example (but not by way of limitation, the therapeutically effective amount may be delivered in one or more dose administrations daily, for one or more days. If desired, the effective daily dose of the active compound may be administered as two, three, four, five, six, or more subdoses, for example, administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. In some non-limiting embodiments, the agents / compositions are administered for more than 7 days, more than 10 days, more than 14 days, or more than 20 days. In still other non-limiting embodiments, the agent(s) / composition is administered over a period of weeks or months. In still other embodiments, the agent(s) / composition is delivered on alternate days. For example, the agent / composition may be delivered every two days, or every three days, or every four days, or every five days, or every six days, or every week, or every month, or similar.

[0052] The compositions of the present disclosure may be administered alone or in combination with one or more additional therapies and may be administered by a variety of administration routes. The particular mode selected will depend, of course, upon the agent(s) selected, the condition being treated, the severity of the condition, whether the treatment is therapeutic or prophylactic, and the dosage required for efficacy. The methods of the present disclosure, generally speaking, may be practiced using any mode of administration that is medically acceptable, meaning any mode that produces effective levels of the active compoundswithout causing clinically unacceptable adverse effects. Non-limiting examples of administration routes that may be utilized in accordance with the present disclosure include oral, topical, transdermal, parenteral, subcutaneous, intranasal, intratracheal, intrabronchial, mucosal, intramuscular, intraperitoneal, intravitreal, and / or intravenous routes, and the like.

[0053] For example (but not by way of limitation), the composition can be administered to the pulmonary tract by any methods known in the art or otherwise contemplated herein. For example, but not by way of limitation, commercially available devices are known for many different methods and mechanisms of delivering various liquid or aerosolized pharmaceutical formulations to pulmonary tissue, including (but not limited to), intranasal instillation devices, intratracheal instillation devices, intratracheal injection devices, dry powder inhalers (DPIs), pressurized metered dose inhalers (pMDIs), nebulizers (such as, but not limited to, pneumatic (jet) nebulizers and electromechanical nebulizers), electrohydrodynamic aerosol devices, insufflators, respirators, and the like. These devices can include a single dose or multiple doses of the compositions of the present disclosure.

[0054] In addition, the formulations of the compositions of the present disclosure may include one or more additional components / elements that aid in the administration of the compositions, as based upon the delivery device. For example (but not by way of limitation), pMDIs, DPIs, and nebulizers typically employ one or more propellants to propel the liquid or cloud of dry powder formulation out of the device, to form an aerosol, and / or to atomize the liquid formulation. Any suitable propellants / pressurized gas supplies may be utilized. The propellant may take a variety of forms. For example, the propellant may be a compressed gas or a liquefied gas. Aerosol formulations for use in the subject method typically include (for example, but not by way of limitation) propellants, surfactants, and / or co-solvents. Suitable liquid compositions comprise the active ingredient in an aqueous, pharmaceutically acceptable inhalant solvent such as (but not limited to) isotonic saline or bacteriostatic water. Suitable liquid formulations for nasal sprays or nasal drops typically include (for example, but not by way of limitation) aqueous or oily solutions of the active ingredient.

[0055] When the compositions are formulated for being inhaled, the inhaled formulation may be designed for application to the upper (such as, but not limited to, the nasal cavity, pharynx, and larynx) and / or lower respiratory tract (such as, but not limited to, the trachea, bronchi, and lungs). Different devices and excipients can be used depending on whether the application is to the upper and / or lower respiratory tract and can be determined by those skilled in the art.EXAMPLES

[0056] Examples are provided hereinbelow. However, the present disclosure is to be understood to not be limited in its application to the specific experimentation, results, and laboratory procedures disclosed herein after. Rather, the Examples are simply provided as one of various embodiments and are meant to be exemplary, not exhaustive.

[0057] Example 1: Elimination of Senescent Cells Increased M. ab Killing in Cystic Fibrosis Mice

[0058] M. ab lung infection induces senescence-like macrophages in mice.

[0059] It has been reported that mouse and human tissues carry multiple subtypes of macrophages. Macrophages are mainly classified into two main populations based on macrophage polarization: Ml and M2 macrophages (Ginhoux et al., 2016; Gordon and Pluddemann, 2017; Mehta et al., 2021; Orecchioni et al., 2019). Additionally, there are three well-known subtypes of M2 macrophages: M2a, M2b, and M2c (Roszer, 2015; Zigmond et al., 2014). M. abscessus (M. ab) can survive and replicate within alveolar macrophages (AMs) in mice and human CF patients. To better understand the role of AMs in the pathology of CF during NTM lung infection, F4 / 80 AMs were isolated using anti-F4 / 80 MicroBeads (Miltenyi Biotech, Gaithersburg, MD; it 130-110-443) from bronchoalveolar lavage fluid of mice that were intratracheally infected with M. ab for 10 days. The heterogeneity of isolated AMs was determined by a single cell RNA sequencing technique (scRNA-seq) using 10X Genomics Chromium technology in combination with an Illumina next-generation sequencing (NGS) system (Illumina, Inc., San Diego, CA). As seen in FIG. 1, six clusters of F4 / 80 AMs were identified in M. ab- infected C / tr / _mice. The relative expression of macrophage marker genes in the clusters was further analyzed. Similar to previous studies, Ml and M2 (M2a and M2c) macrophages were detected. These populations were not observed in uninfected cystic fibrosis mice (Data not shown). Surprisingly, the scRNA-seq analysis indicates that two clusters of M2 AMs (Cluster 0 and 1) express very high levels of cellular senescence markers pl6INK4a, p21CIP1, p53, and Glbl compared to the other clusters (FIG. 2). Further, AMs were isolated from naive Cftr+ / +and C / frzmice (8-10 week-old females) as described previously (Cheng et al., 2020) and were then infected with M. ab ex vivo. As seen in FIG. 3, the quantitative RT-PCR (qRT-PCR) showed that M. ab infection significantly induced the expression of cellular senescence markers pl6INK4aand p21CIF>1in Cftr^ AMs but had no oronly limited effect on the expression of these two genes in Cftr+ / +AMs. These results further showed that M. ab infection increased the activity of SA-(3-galactosidase,another marker for cellular senescence (Wiley a nd Campisi, 2021) in Cftr'7AMs ex vivo compared to Cftr+7+AMs or uninfected Cftr7' AMs (FIG. 4). Therefore, these data indicate that M. ab infection induces senescence-like AMs in Cftr7mice.

[0060] The senolytics Dasatinib and Quercetin (D+Q) rescue M. ab killing in the lung of Cftr mice. In this Example, the effect of D+Q on M. ab killing in Cftr7' mice (gut-corrected, Stock No:002364, The Jackson Laboratory, Bar Harbor, ME) was evaluated. Cftr+ / +and Cftr7' mice were randomly divided into 4 groups: (i) Initial, (ii) Untreated, (iii) Vehicle, and (iv) D+Q. All mice were infected intratracheally with M. ab clinical isolate #1 (lxlO7CFU / mouse) as performed previously (Cheng et al., 2020). Ten days post-infection, mice in Groups (iii)-(iv) received three doses of treatment at Days 11, 14, and 15 post M. ab infection, while mice in Group (iii) were left untreated. One week after the treatment, all mice were sacrificed, and tissue samples were harvested for further analysis. Group (i) was sacrificed as an M. ab load control when the treatment started at day 10 post infection. The resultant data indicate that D+Q treatment (5 mg / kg Dasatinib and 50mg / kg Quercetin) significantly decreased M. ab survival in the lungs of Cftr7' mice when compared to the untreated group or the group treated with vehicle (FIG. 5). However, D+Q had no effect on M. ab survival in the lungs of Cftr+7+mice (FIG. 5). The qRT-PCR results further indicate that the M. ab-induced expression of pl6INK4aand p21CIP1was diminished in F4 / 80 lung macrophages that were isolated from Cftr7' mice receiving D+Q treatment when compared to the vehicle or untreated group (FIG. 6). Interestingly, M. ab-induced expression was detected of pl6INK4abut not p21CIP1in F4 / 80 lung macrophages that were isolated from M. ab- infected WT mice (FIG. 7). However, D+Q treatment had no effect on M. ab-induced pl6INK4ain F4 / 80 lung macrophages in Cftr+7+mice. Taken together, these results indicate that senolytics control M. ab infection in vivo in Cftr7' mice, demonstrating an application of senescent celltargetingagents in CF patients with NTM infections.

[0061] While the information contained herein is provided for the purpose of description, the present disclosure is not limited to such exemplary information contained therein. The inventive concept(s) is capable of other embodiments or of being practiced or carried out in various ways.NON-LIMITING ILLUSTRATIVE EMBODIMENTS

[0062] Illustrative embodiment 1. A method of treating at least one infection in a cystic fibrosis patient, the method comprising administering to the cystic fibrosis patient at least one senolytic agent.

[0063] Illustrative embodiment 2. The method of Illustrative embodiment 1, wherein the at least one senolytic agent is selected from the group consisting of Dasatinib, Quercetin, Fisetin, Luteolin, Curcumin, Curcumin Analog EF24, Navitoclax (ABT263), A1331852, A155463, Geldanamycin, Tanespimycin, Alvespimycin, Piperlongumine, FOXO-4 related peptide, Nutlin3a, Ouabain, Proscilla ridin A, Digoxin, and any combination thereof.

[0064] Illustrative embodiment 3. The method of Illustrative embodiment 1 or 2, wherein the at least one senolytic agent comprises Dasatinib.

[0065] Illustrative embodiment 4. The method of any of Illustrative embodiments 1-3, wherein the at least one senolytic agent comprises Quercetin.

[0066] Illustrative embodiment 5. The method of any of Illustrative embodiments 1-4, wherein the at least one senolytic agent comprises Dasatinib and Quercetin.

[0067] Illustrative embodiment 6. The method of any of Illustrative embodiments 1-5, wherein the infection is a lung infection.

[0068] Illustrative embodiment 7. The method of any of Illustrative embodiments 1-6, wherein the infection in the cystic fibrosis patient includes non-tuberculosis mycobacteria (NTM).

[0069] Illustrative embodiment 8. The method of Illustrative embodiment 7, wherein the NTM is selected from M. avium, M. intracellulare, M. abscessus (M. ab), M. massiliense, M. bolletii, and combinations thereof.

[0070] Illustrative embodiment 9. The method of Illustrative embodiment 8, wherein the NTM comprises a Mycobacterium avium complex (MAC) or Mycobacterium abscessus complex (MABSC).

[0071] Illustrative embodiment 10. The method of Illustrative embodiment 8 or 9, wherein the NTM comprises M. abscessus (M. ab).

[0072] Illustrative embodiment 11. The method of Illustrative embodiment 10, wherein the at least one senolytic agent inhibits M. ab-induced expression of at least one cellular senescence marker.

[0073] Illustrative embodiment 12. The method of Illustrative embodiment 11, wherein the at least one cellular senescence marker is selected from the group consisting of pl6INK4a, p21CIF>1, p53, Glbl, and combinations thereof.

[0074] Illustrative embodiment 13. The method of Illustrative embodiment 11 or 12, wherein the at least one cellular senescence marker comprises pl6INK4a.

[0075] Illustrative embodiment 14. The method of any of Illustrative embodiments 11-13,wherein the at least one cellular senescence marker comprises p21CIP1.

[0076] Illustrative embodiment 15. The method of any of Illustrative embodiments 11-14, wherein the at least one cellular senescence marker comprises pl6INK4aand p21CIP1.

[0077] Illustrative embodiment 15A. The method of any of Illustrative embodiments 1-15, wherein the at least one senolytic agent is administered to the cystic fibrosis patient in at least one dose in a range of from about 0.01 mg / kg to about 500 mg / kg.

[0078] Illustrative embodiment 15B. The method of any of Illustrative embodiments 1-15, wherein the at least one senolytic agent is administered to the cystic fibrosis patient in at least one dose in a range of from about 0.5 mg / kg to about 100 mg / kg.

[0079] Illustrative embodiment 15C. The method of any of Illustrative embodiments 1-15, wherein the at least one senolytic agent is administered to the cystic fibrosis patient in at least one dose in a range of from about 0.01 mg / kg to about 5 mg / kg.

[0080] Illustrative embodiment 15D. The method of any of Illustrative embodiments 1-15, wherein the at least one senolytic agent is administered to the cystic fibrosis patient in at least one dose in a range of from about 0.5 mg / kg to about 20 mg / kg.

[0081] Illustrative embodiment 15E. The method of any of Illustrative embodiments 1-15, wherein the at least one senolytic agent is administered to the cystic fibrosis patient in at least one dose in a range of from about 5 mg / kg to about 50 mg / kg.

[0082] Illustrative embodiment 15F. The method of any of Illustrative embodiments 1-15, wherein the at least one senolytic agent is administered to the cystic fibrosis patient in at least one dose in a range of from about 10 mg / kg to about 200 mg / kg.

[0083] Illustrative embodiment 16. A pharmaceutical composition for use in the method of any of Illustrative embodiments 1-15F, wherein the pharmaceutical composition comprises at least one senolytic agent.

[0084] Illustrative embodiment 17. The pharmaceutical composition of Illustrative embodiment 16, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

[0085] Illustrative embodiment 18. The pharmaceutical composition of Illustrative embodiment 16 or 17, wherein the at least one senolytic agent is selected from the group consisting of Dasatinib, Quercetin, Fisetin, Luteolin, Curcumin, Curcumin Analog EF24, Navitoclax (ABT263), A1331852, A155463, Geldanamycin, Tanespimycin, Alvespimycin, Piperlongumine, FOXO-4 related peptide, Nutlin3a, Ouabain, Proscil la ridin A, Digoxin, and any combination thereof.

[0086] Illustrative embodiment 19. The pharmaceutical composition of any of Illustrative embodiments 16-18, wherein the at least one senolytic agent comprises Dasatinib.

[0087] Illustrative embodiment 20. The pharmaceutical composition of any of Illustrative embodiments 16-19, wherein the at least one senolytic agent comprises Quercetin.

[0088] Illustrative embodiment 21. The pharmaceutical composition of any of Illustrative embodiments 16-20, wherein the at least one senolytic agent comprises Dasatinib and Quercetin.

[0089] Illustrative embodiment 22. A kit, comprising at least one pharmaceutical composition of any one of Illustrative embodiments 16-21.

[0090] Illustrative embodiment 23. A kit comprising at least a first composition comprising at least a first senolytic agent; and at least a second composition comprising at least a second senolytic agent.

[0091] Illustrative embodiment 24. The kit of Illustrative embodiment 23, wherein the first and second senolytic agents are different.

[0092] Illustrative embodiment 25. The kit of Illustrative embodiment 23 or 24, for use in the method of any of Illustrative embodiment 1-15F.

[0093] Illustrative embodiment 26. The kit of any of Illustrative embodiments 23-25, wherein each of the first and second senolytic agents is independently selected from the group consisting of Dasatinib, Quercetin, Fisetin, Luteolin, Curcumin, Curcumin Analog EF24, Navitoclax (ABT263), A1331852, A155463, Geldanamycin, Tanespimycin, Alvespimycin, Piperlongumine, FOXO-4 related peptide, Nutlin3a, Ouabain, Proscil la ridin A, Digoxin, and any combination thereof.

[0094] Illustrative embodiment 27. A kit comprising: at least a first composition comprising Dasatinib; and at least a second composition comprising Quercetin.

[0095] Illustrative embodiment 28. The kit of Illustrative embodiment 27, further comprising at least one pharmaceutically acceptable carrier in which the Dasatinib and Quercetin can be combined.

[0096] Illustrative embodiment 29. The kit of Illustrative embodiment 27 or 28, for use in the method of any of Illustrative embodiment 1-15F.

[0097] Illustrative embodiment 30. The kit of any of Illustrative embodiments 23-29, wherein the first and second compositions are pharmaceutical compositions that each further comprises at least one pharmaceutically acceptable carrier.

[0098] Illustrative embodiment 31. A system, comprising at least a first composition comprising at least a first senolytic agent; and at least a second composition comprising at leasta second senolytic agent.

[0099] Illustrative embodiment 32. The system of Illustrative embodiment 31, for use in the method of any of Illustrative embodiment 1-15F.

[0100] Illustrative embodiment 33. The system of Illustrative embodiment 31 or 32, wherein the first and second senolytic agents are different.

[0101] Illustrative embodiment 34. The system of any of Illustrative embodiments 31-33, wherein each of the first and second senolytic agents is independently selected from the group consisting of Dasatinib, Quercetin, Fisetin, Luteolin, Curcumin, Curcumin Analog EF24, Navitoclax (ABT263), A1331852, A155463, Geldanamycin, Tanespimycin, Alvespimycin, Piperlongumine, FOXO-4 related peptide, Nutlin3a, Ouabain, Proscillaridin A, Digoxin, and any combination thereof.

[0102] Illustrative embodiment 35. A system comprising: at least a first composition comprising Dasatinib; and at least a second composition comprising Quercetin.

[0103] Illustrative embodiment 36. The system of Illustrative embodiment 35, further comprising at least one pharmaceutically acceptable carrier in which the Dasatinib and Quercetin can be combined.

[0104] Illustrative embodiment 37. The system of Illustrative embodiment 35 or 36, for use in the method of any of Illustrative embodiment 1-15F.

[0105] Thus, in accordance with the present disclosure, there have been provided compositions, kits, and systems, as well as methods of producing and using same, which fully satisfy the objectives and advantages set forth herein. Although the present disclosure has been described in conjunction with the specific drawings, experimentation, results, and language set forth hereinabove, it is evident that many alternatives, modifications, and variations will be apparent to those skilled in the art. Accordingly, it is intended to embrace all such alternatives, modifications, and variations that fall within the spirit and broad scope of the present disclosure.REFERENCESThe following references, to the extent that they provide exemplary procedural or other details supplementary to those set forth herein, are specifically incorporated herein by reference. However, the following is not intended to be an Information Disclosure Statement; rather, an Information Disclosure Statement in accordance with the provisions of 37 CFR § 1.97 will be submitted separately.1. Veit G, et al. Molecular Biology of the Cell. 2016;27(3):424-33.2. Shteinberg M, et al. The Lancet. 2021;397(10290):2195-211.3. Filkins LM, and O'Toole GA. PLoS Pathogens. 2015;ll(12):el005258.4. Floto RA, and Haworth CS. Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society. 2015;14(l):l-2.5. Park IK, and Olivier KN. Seminars in respiratory and critical care medicine. 2015;36(2) :217- 24.6. Martiniano SL, et al. Thoracic Surgery Clinics. 2019;29(l):95-108.7. Esther CR, et al. Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society. 2010;9(2):117-23.8. Skolnik K, et al. Current Treatment Options in Infectious Diseases. 2016;8(4):259-74.9. Qvist T, et al. Journal of Cystic Fibrosis: Official Journal of the European Cystic Fibrosis Society. 2015;14(l):46-52.10. Bruscia EM, et al. American Journal of Respiratory Cell and Molecular Biology. 2009;40(3):295-304.11. Hartl D, et al. The Journal of Allergy and Clinical Immunology. 2006;117(l):204-ll.12. Tiringer K, et al. American Journal of Respiratory and Critical Care Medicine.2013;187(6):621-9.13. Hector A, et al. American Journal of Respiratory and Critical Care Medicine.2015;191(8):914-23.14. Tan H-L, et al. American Journal of Respiratory and Critical Care Medicine.2011;184(2):252-8.15. Cheng Y, et al. PLOS Pathogens. 2020;16(5):el008569.16. Hayes D, et al. JCI insight. 2022;7(12):el57865.17. Becker KL, et al. The European Respiratory Journal. 2016;47(3):990-3.CLAIMS

Claims

1. A method of treating at least one infection in a cystic fibrosis patient, the method comprising the step of: administering to the cystic fibrosis patient at least one senolytic agent.

2. The method of claim 1, wherein the at least one senolytic agent is selected from the group consisting of Dasatinib, Quercetin, Fisetin, Luteolin, Curcumin, Curcumin Analog EF24, Navitoclax (ABT263), A1331852, A155463, Geldanamycin, Tanespimycin, Alvespimycin, Piperlongumine, FOXO-4 related peptide, Nutlin3a, Ouabain, Proscil la ridin A, Digoxin, and any combination thereof.

3. The method of claim 1, wherein the at least one senolytic agent comprises Dasatinib.

4. The method of claim 1, wherein the at least one senolytic agent comprises Quercetin.

5. The method of claim 1, wherein the at least one senolytic agent comprises Dasatinib andQuercetin.

6. The method of claim 1, wherein the infection is a lung infection.

7. The method of claim 1, wherein the infection in the cystic fibrosis patient includes nontuberculosis mycobacteria (NTM).

8. The method of claim 7, wherein the NTM is selected from M.avium, M.intracellulare, M. abscessus (M. ab), M. massiliense, M. bolletii, and combinations thereof.

9. The method of claim 8, wherein the NTM comprises a Mycobacterium avium complex (MAC) or Mycobacterium abscessus complex (MABSC).

10. The method of claim 8, wherein the NTM comprises M. abscessus (M. ab).

11. A pharmaceutical composition for use in the method of any of claims 1-10, wherein the pharmaceutical composition comprises at least one senolytic agent.

12. The pharmaceutical composition of claim 11, wherein the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.

13. The pharmaceutical composition of claim 11, wherein the at least one senolytic agent is selected from the group consisting of Dasatinib, Quercetin, Fisetin, Luteolin, Curcumin, Curcumin Analog EF24, Navitoclax (ABT263), A1331852, A155463, Geldanamycin, Tanespimycin, Alvespimycin, Piperlongumine, FOXO-4 related peptide, Nutlin3a, Ouabain, Proscil laridin A, Digoxin, and any combination thereof.

14. The pharmaceutical composition of claim 11, wherein the at least one senolytic agent comprises Dasatinib.

15. The pharmaceutical composition of claim 11, wherein the at least one senolytic agent comprises Quercetin.

16. The pharmaceutical composition of claim 11, wherein the at least one senolytic agent comprises Dasatinib and Quercetin.

17. A kit, comprising at least one pharmaceutical composition of any one of claims 11-16.

18. A kit for use in the method of any one of claims 1-10, wherein the kit comprises: at least a first composition comprising Dasatinib; and at least a second composition comprising Quercetin.

19. The kit of claim 18, further comprising at least one pharmaceutically acceptable carrier in which the Dasatinib and Quercetin can be combined.

20. The kit of claim 18, wherein the first and second compositions are pharmaceutical compositions that each further comprises at least one pharmaceutically acceptable carrier.

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