WO2017127810A1 - Methods for repairing lung tissue - Google Patents

Abstract

Disclosed are methods for treating chronic obstructive pulmonary disease (COPD), and more particularly emphysema. The present disclosure relates to methods for repairing lung tissue damage caused by COPD by administering AMD3100.

Description

METHODS FOR REPAIRING LUNG TISSUE

STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0001] This invention was made with government support under HL105772 awarded by the National Institutes of Health. The government has certain rights in the invention.

CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application Serial No. 62/286,041 filed on January 22, 2016, which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE DISCLOSURE

[0003] The present disclosure relates generally to treating chronic obstructive pulmonary disease (COPD), and in particular, emphysema, in subjects in need thereof. More particularly, the present disclosure relates to repairing lung tissue damage caused by emphysema. In one aspect, the emphysema is a result of cigarette smoking.

[0004] Chronic obstructive pulmonary disease (COPD) is a generic term that covers several chronic inflammatory lung diseases (e.g., emphysema and chronic bronchitis) that cause obstructed airflow from the lungs. Cigarette smoking is the leading cause of COPD.

[0005] Emphysema and chronic bronchitis can be difficult to tell apart, but each presents problems with breathing and other lung symptoms. The difference between emphysema and chronic bronchitis lies in how each disease affects the lungs. Emphysema involves the gradual destruction of the air sacs in the lungs (alveoli), hindering breathing. Alveoli are responsible for providing oxygen to the bloodstream. Over time, emphysema weakens the alveoli and destroys the elasticity of pulmonary airways. As a result, emphysema sufferers experience shortness of breath and a constant struggle to breathe.

[0006] Chronic bronchitis is the opposite of emphysema. This condition causes a person's lungs to become very inflamed. Bronchitis commonly affects the windpipe and passageways of the lungs and is the result of severe irritation or infection. It can be a brief illness, or ongoing (chronic). The body's natural reaction to chronic bronchitis is to clear the air passages, resulting in severe coughing. [0007] Mistakenly, many believe that asthma is a type of COPD. Although COPD and asthma are both respiratory diseases characterized by underlying inflammation, the nature of the inflammation is quite different in each case. In COPD, inflammation is characterized by inflammatory cells such as neutrophils, CD8+ T-lymphocytes and macrophages and the disease is associated with airflow limitation that is not fully reversible. In asthma, however, airflow limitation is often fully reversible, either spontaneously or with treatment and has a different profile of inflammatory cells, namely eosinophils and CD4+ T-lymphocytes. Additionally, in COPD, both the airways and lung parenchyma are affected by the disease and airflow limitation is progressive. However, in asthma only the airways are affected. Asthma is usually present from childhood, whereas COPD is predominantly diagnosed in patients greater than 40 years old.

[0008] Most current treatments for COPD, and particularly, emphysema and chronic bronchitis, include oxygen support, medications and the use of steroids to lessen the severity of symptoms; however, there is currently no cure for these diseases. Accordingly, it would be advantageous to develop treatments for COPD, and in particular, emphysema and chronic bronchitis, that not only reduce the symptoms, but also reduce and even reverse the tissue damage caused by COPD.

SUMMARY OF THE DISCLOSURE

[0009] In one aspect, the present disclosure is directed to a method for treating COPD in a subject in need thereof. The method comprises administering a compound capable of inhibiting the binding of cytokine stromal cell-derived factor (SDF-1) to C-X-C chemokine receptor type 4 (CXCR-4) to the subject. In one particular embodiment, the compound is 1,1'- [ 1 ,4-Phenylenebis(methylene) ]bis- 1 ,4 ,8 , 11 -tetraazacyclotetradecane octahydrochloride.

[0010] In another aspect, the present disclosure is directed to a method for repairing lung tissue in a subject in need thereof. The method comprises chronically administering a compound capable of inhibiting the binding of cytokine stromal cell-derived factor (SDF-1) to C-X-C chemokine receptor type 4 (CXCR-4) to the subject. In one particular embodiment, the compound is 1,1 '- [1 ,4-Phenylenebis(methylene)]bis- 1 ,4,8 , 11 -tetraazacyclotetradecane octahydrochloride.

[0011] In yet another aspect, the present disclosure is directed to a method for treating myelosuppression in a subject in need thereof. The method comprises chronically administering a compound capable of inhibiting the binding of cytokine stromal cell-derived factor (SDF-1) to C-X-C chemokine receptor type 4 (CXCR-4) to the subject. In one particular embodiment, the compound is l,l'-[l,4-Phenylenebis(methylene)]bis-l,4,8,l l- tetraazacyclotetradecane octahydrochloride.

DESCRIPTION OF THE DRAWINGS

[0012] The disclosure will be better understood, and features, aspects and advantages other than those set forth above will become apparent when consideration is given to the following detailed description thereof. Such detailed description makes reference to the following drawings, wherein:

[0013] FIG. 1 depicts SDF-1 levels as analyzed in the Example.

[0014] FIG. 2 depicts lung volumes as analyzed in the Example.

[0015] FIG. 3 depicts airspace enlargement, measured by mean linear intercept, as analyzed in the Example.

[0016] FIG. 4 depicts progenitor cells as analyzed after six months in the Example.

[0017] FIG. 5 depicts progenitor cells as analyzed after one week in the Example.

DETAILED DESCRIPTION

[0018] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the disclosure belongs. Although any methods and materials similar to or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods and materials are described below.

[0019] In accordance with the present disclosure, methods for treating COPD, and in particular emphysema, are disclosed. In particular, methods for repairing lung tissue damaged by COPD in a subject in need thereof are disclosed. Also disclosed are methods for treating myelosuppression in a subject in need thereof.

[0020] Target organ injury is thought to be "sensed" by bone marrow progenitor cells (BMPCs) that actively participate in the repair through direct migration to the site of injury. The mechanisms of crosstalk between the injured lung and the bone marrow remain unclear. A major player in recruiting bone marrow-derived circulating cells to injured organs is the cytokine stromal cell-derived factor (SDF)-1. Interactions with its receptor, C-X-C chemokine receptor type 4 (CXCR-4; also known as fusin or CD184 (cluster of differentiation 184)), on bone marrow cells guides their homing to respective organs. In turn, SDF-1-CXCR4 interactions within the bone marrow retain progenitor cells, decreasing their release in the circulation.

[0021 ] 1 , 1 '- [ 1 ,4-Phenylenebis(methylene) ]bis- 1 ,4 ,8 , 11 -tetraazacyclotetradecane octahydrochloride, also known as AMD3100 or Plerixafor, is a highly specific chemokine receptor CXCR4 antagonist. AMD3100 has been used in a study to determine the blockade of CXCR4 in oral squamous cell carcinoma and inhibition of lymph node metastases. Further, it has been used for mobilization of hematopoietic stem cells into the peripheral blood following bone marrow transplantation by inhibiting the SDF-1 receptor (CXCR4).

[0022] Cigarette smoking (CS) is the main risk factor for chronic obstructive pulmonary disease (COPD), and particularly, emphysema. It has now been found that CS has a direct suppressive effect on bone marrow progenitor cell number and proliferation, which may decrease their ability to repair the lung. Based on the foregoing, it was believed that mobilization of bone marrow progenitor cells following lung injury would be sufficient to enhance lung repair and improve outcomes during cigarette smoke exposure.

[0023] Accordingly, the present disclosure is generally directed to administering to a subject in need thereof, a compound capable of inhibiting the binding of cytokine stromal cell- derived factor (SDF-1) to C-X-C chemokine receptor type 4 (CXCR-4), and in particular, to administering AMD3100. It should be understood by one skilled in the art that, while described herein with respect to AMD3100, any compound capable of inhibiting the binding of cytokine stromal cell-derived factor (SDF-1) to C-X-C chemokine receptor type 4 (CXCR-4) may be used in the methods of the present disclosure. As used herein, the methods are directed to be used with a subject in need thereof. More particularly, the methods of the present disclosure are to be used with a subset of subjects who are suspected of having and/or have COPD, and in particular, emphysema caused by cigarette smoking, and/or are suffering from myelosuppression. Subjects may be susceptible to or at elevated risk for COPD (e.g., emphysema) and/or myelosuppression due to family history, age, environment, and/or lifestyle (e.g., cigarette smoking). Based on the foregoing, because some of the method embodiments of the present disclosure are directed to specific subsets or subclasses of identified subjects (that is, the subset or subclass of subjects "in need" of assistance in addressing one or more specific conditions noted herein), not all subjects will fall within the subset or subclass of subjects as described herein for COPD.

[0024] In another aspect of the present disclosure, pharmaceutically acceptable compositions are provided, wherein these compositions comprise AMD3100 as described herein, and optionally comprise a pharmaceutically acceptable carrier, adjuvant or vehicle, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired.

[0025] The pharmaceutically acceptable compositions of this disclosure can be administered to humans and other animals orally, parenterally, intravenously, subcutaneously, intracisternally, intraperitoneally, buccally, as an oral or nasal spray, or the like, depending on the severity of the disorder being treated. Another suitable delivery to subjects is airway delivery of AMD3100. Suitable airway delivery methods include inhalation as aerosols, nebulized liquids and dry-powder formulations. Other suitable methods of administration include, for example, by intratracheal inhalation and insufflation.

[0026] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to AMD3100, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyl glycol, 1,3-butyl glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethyl glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0027] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0028] The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions, which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0029] In order to prolong the effect of AMD3100 of the present disclosure, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of AMD3100 then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of parenterally administered AMD3100 is accomplished by dissolving or suspending AMD3100 in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of AMD3100 in biodegradable polymers such as polylactide- polyglycolide. Depending upon the ratio of AMD3100 to polymer and the nature of the particular polymer employed, the rate of AMD3100 release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping AMD3100 in liposomes or microemulsions that are compatible with body tissues.

[0030] Suitable concentrations of AMD3100 administered include from about 1.0 mg/kg to about 160 mg/kg per day, including about 2.0 mg/kg to about 75 mg/kg. A particularly suitable concentration of AMD3100 includes about 5 mg/kg per day.

[0031] Further, in some particular aspects of the present disclosure, AMD3100 is chronically administered to the subject. As used herein, "chronically administered", "chronically administering" or "chronic administration" refer to administering AMD3100 more than one time (i.e., multiple dosages over a time period) to a subject in need thereof. In one particular embodiment, AMD3100 is administered continuously over a time period. In another particular embodiment, AMD3100 is administered repeatedly, but intermittently, over a time period. For example, in some suitable embodiments, AMD3100 can be administered to the subject daily for at least 3 days, or at least 5 days, or at least 7 days or more. In other embodiments, AMD3100 can be administered periodically for a period of at least 1 week, at least 12 weeks, at least 24 weeks or more.

[0032] It will be understood that the total daily/weekly usage of AMD3100 and compositions of the present disclosure (also referred to herein as "effective amount") will be decided by the attending physician within the scope of sound medical judgment. More particularly, as used herein, the phrase "effective amount" of AMD3100 and/or compositions used in the methods of the present disclosure refers to a sufficient amount of AMD3100 to treat COPD and/or repair lung tissue damage caused by COPD as defined herein, at a reasonable benefit/risk ratio applicable to any medical treatment. It can be understood, however, that the total usage of AMD3100 and pharmaceutically acceptable compositions including AMD3100 for use in the methods of the present disclosure can be decided by the attending physician within the scope of sound medical judgment. The specific effective dose level for any particular subject can depend upon a variety of factors including the severity of lung tissue damage being treated; the specific pharmaceutically acceptable composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of AMD3100 from the subject; the duration of the treatment; drugs used in combination or coincidental with AMD3100; and like factors well-known in the medical arts. For example, it is well within the skill of the art to start doses of AMD3100 at levels lower than required to achieve the desired effect and to gradually increase the dosage until the desired effect is achieved.

[0033] In one aspect, the present disclosure is directed to a method for treating COPD in a subject in need thereof. The method comprises chronically administering 1,1 '-[1,4- Phenylenebis(methylene)]bis-l,4,8,ll-tetraazacyclotetradecane octahydrochloride to the subject. In one particular aspect, the subject in need thereof is or was a cigarette smoker and is suffering (i.e., diagnosed as having emphysema) or at risk of suffering from emphysema.

[0034] In another aspect, the present disclosure is directed to a method for repairing lung tissue in a subject in need thereof. The method comprises chronically administering 1,1'- [l,4-Phenylenebis(methylene)]bis-l,4,8,ll-tetraazacyclotetradecane octahydrochloride to a subject in need thereof. In one particular aspect, the subject in need thereof is or was a cigarette smoker and has lung damage caused by COPD. [0035] In yet another aspect, the present disclosure is directed to a method for treating myelosuppression. The method comprises chronically administering 1,1 '-[1,4- Phenylenebis(methylene)]bis-l,4,8,ll-tetraazacyclotetradecane octahydrochloride to a subject in need thereof. Myelosuppression is the decrease in production of cells responsible for providing immunity (leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting (thrombocytes).

[0036] The disclosure will be more fully understood upon consideration of the following non-limiting Example.

EXAMPLE

Materials and Methods

[0037] C57BL/6 mice were exposed to cigarette smoke (CS) for six months with or without subcutaneous injection of AMD3100. Particularly, AMD3100 was administered subcutaneously 5 mg/kg daily for 5 days during weeks 1, 12, and 24. Mice were harvested after 24 weeks of CS exposure, when lung function, lung morphometry, SDF-1 levels in bronchial alveolar lavage fluid (BALF), as well as bone marrow progenitor cells, were measured.

[0038] Mice exposed to CS for 24 weeks had an 85% decrease in SDF-1 levels in the BALF compared to age-matched mice exposed to ambient air (P<0.05; FIG. 1). As expected, chronic CS exposure led to a significant decrease in the number of bone marrow progenitor cell colony forming units (CFU) and emphysema-like morpho-functional manifestations in the lung. Treatment of CS exposed mice with AMD3100 significantly ameliorated CS-induced increases in lung volumes (16% improvement; p <0.05; FIG. 2), static lung compliance (15% improvement; p<0.05), and airspace enlargement, measured by mean linear intercept (p <0.05; FIG. 3). Unexpectedly, compared to untreated mice, AMD3100 treatment significantly increased, by 2.5-fold, the number of progenitor cells (CFU) in the bone marrow, despite ongoing CS exposure (p<0.05; FIG. 4). Even after only one week, AMD3100 showed shielding from cigarette smoke-induced myelosuppression (p<0.05; FIG. 5).

[0039] These results suggest that despite inducing lung injury, chronic CS exposure inhibits SDF-1 secretion in lung cells, which may impair the homing of circulating bone marrow- derived progenitor cells to the injured lung. Treatment with a bone marrow cells mobilizing agent (i.e., AMD3100) improved both lung and bone marrow outcomes following chronic CS exposure in mice, suggesting drugs such as AMD3100 may enhance repair of CS-induced emphysema and myelosuppression.

Claims

What is claimed is:

1. A method for treating chronic obstructive pulmonary disease (COPD) in a subject in need thereof, the method comprising administering a compound capable of inhibiting the binding of cytokine stromal cell-derived factor (SDF-1) to C-X-C chemokine receptor type 4 (CXCR-4) to the subject.

2. The method of claim 1 wherein l,l'-[l,4-Phenylenebis(methylene)]bis-l,4,8,l l- tetraazacyclotetradecane octahydrochloride is chronically administered to the subject.

3. The method of claim 2 wherein the subject is administered 1,1 '-[1,4- Phenylenebis(methylene)]bis-l,4,8,ll-tetraazacyclotetradecane octahydrochloride in an amount of about 5 mg/kg per day.

4. The method of claim 1 wherein the subject is administered the compound daily for a period of at least 3 weeks.

5. The method of claim 1 wherein the subject is administered the compound daily for a period of at least 12 weeks.

6. The method of claim 1 wherein the subject is administered the compound daily for a period of at least 24 weeks.

7. The method of claim 1 wherein the subject suffers from emphysema.

8. The method of claim 1 wherein the subject is a cigarette smoker.

9. A method for repairing lung tissue in a subject in need thereof, the method comprising chronically administering a compound capable of inhibiting the binding of cytokine stromal cell-derived factor (SDF-1) to C-X-C chemokine receptor type 4 (CXCR-4) to the subject..

10. The method of claim 9 wherein l,l'-[l,4-Phenylenebis(methylene)]bis-l,4,8,l l- tetraazacyclotetradecane octahydrochloride is chronically administered to the subject.

11. The method of claim 10 wherein the subject is administered 1,1 '-[1 ,4- Phenylenebis(methylene)]bis-l,4,8,ll-tetraazacyclotetradecane octahydrochloride in an amount of about 5 mg/kg per day.

12. The method of claim 9 wherein the subject is administered the compound daily for a period of at least 3 weeks.

13. The method of claim 9 wherein the subject is administered the compound daily for a period of at least 12 weeks.

14. The method of claim 9 wherein the subject is administered the compound daily for a period of at least 24 weeks.

15. The method of claim 9 wherein the subject suffers from emphysema.

16. The method of claim 9 wherein the subject is a cigarette smoker

17. A method for treating myelosuppression in a subject in need thereof, the method comprising chronically administering a compound capable of inhibiting the binding of cytokine stromal cell-derived factor (SDF-1) to C-X-C chemokine receptor type 4 (CXCR-4) to the subject..

18. The method of claim 17 wherein l,l'-[l,4-Phenylenebis(methylene)]bis-l,4,8,ll- tetraazacyclotetradecane octahydrochloride is chronically administered to the subject.

19. The method of claim 18 wherein the subject is administered 1,1 '-[1 ,4- Phenylenebis(methylene)]bis-l,4,8,ll-tetraazacyclotetradecane octahydrochloride in an amount of about 5 mg/kg per day.

20. The method of claim 17 wherein the subject is a cigarette smoker.