Light inhibitors for asthma, lung and airway inflammation, respiratory, interstitial, pulmonary and fibrotic disease treatment

This application claims priority to application Ser. No. 60/973,383, filed Sep. 18, 2007, which application is incorporated by reference herein in its entirety.

The invention was supported in part by National Institute of Health RO1 Grant AI070535. The government may have certain rights in the invention.

Allergic asthma afflicts 10 million people in the US and is responsible for approximately five thousand deaths annually. The prevalence of asthma has significantly increased over the past few decades along with other allergic diseases, which are characterized by helper T cell 2 (Th2) responses. Current therapy primarily includes corticosteroids, bronchodilators, and leukotriene antagonists. A subset of those with more severe disease have a progressive decline in lung function attributed to airway remodeling which includes bronchial epithelial mucus metaplasia, airway smooth muscle hypertrophy/hyperplasia, subepithelial fibrosis, and increased angiogenesis. Current asthma treatment has little impact, if any, on airway remodeling.

Inflammatory cells including T cells, eosinophils, macrophages, and mast cells, as well as structural cells including epithelial, smooth muscle, and fibroblasts have roles in the establishment and maintenance of remodeling. Growth factors and cytokines that regulate remodeling include TGF-, VEGF, IL-5, IL-9, IL-13, and eotaxin. An understanding of novel mechanisms may lead to much needed therapies that target airway remodeling and Th2 driven lung inflammation.

LIGHT (TNFSF14, p30 polypeptide) is a protein expressed on activated CD4/CD8 T cells, dendritic cells (DCs), monocytes, and natural killer cells (NK). The binding of LIGHT to herpes virus entry mediator (HVEM), which is expressed on resting T cells, DCs, and monocytes, or the lymphotoxin beta receptor (LTβR), which is expressed on DCs and stromal cells, promotes T cell activation, proliferation, and cytokine production. Studies have determined that LIGHT deficient animals have no significant abnormalities in the development of lymphoid organs and lymphocytes.

The invention is based at least in part on the finding that LIGHT (P30 polypeptide), a TNF superfamily protein expressed on activated T cells, and other immune cells such as dendritic cells, controls the development of airway remodeling and TH2 driven lung responses. Inhibiting or blocking LIGHT from interacting with its receptors, HVEM or LTβR, can be used as an anti-inflammatory, for example, to inhibit or suppress asthmatic inflammation, as well as treat airway remodeling, among other inflammatory conditions, diseases and disorders. In addition, inhibiting or blocking LIGHT from interacting with its receptors, HVEM or LTβR, is applicable towards a wide range of chronic and acute fibroproliferative diseases of the lung and airways, including pulmonary fibrosis and COPD (chronic obstructive pulmonary disease), and other tissue and organ systems.

In accordance with the invention, there are provided, methods of reducing or inhibiting lung or airway inflammation (chronic or acute). In one embodiment, a method includes contacting or administering a sufficient amount of an inhibitor of LIGHT (p30 polypeptide) to a subject in need thereof to reduce or inhibit lung or airway inflammation in the subject.

In accordance with the invention, there are also provided, methods of treating asthma. In one embodiment, a method includes contacting or administering a sufficient amount of an inhibitor of LIGHT (p30 polypeptide) to a subject in need thereof to treat asthma.

In accordance with the invention, there are further provided, methods for treating a respiratory, interstitial, pulmonary disease or disorder, and fibrotic diseases and disorders (chronic or acute). In one embodiment, a method includes contacting or administering a sufficient amount of an inhibitor of LIGHT (p30 polypeptide) to a subject to treat the respiratory, interstitial, or pulmonary disease or disorder, or the fibrotic disease or disorder.

LIGHT inhibitors include, for example, molecules that bind to LIGHT and inhibit LIGHT binding or interaction with HVEM. LIGHT inhibitors also include molecules that bind to LIGHT and inhibit LIGHT binding or interaction with LTβR. LIGHT inhibitors further include molecules that bind to HVEM and inhibit LIGHT binding or interaction with HVEM. LIGHT inhibitors additionally include molecules that bind to LTβR and inhibit LIGHT binding or interaction with LTβR. LIGHT inhibitors moreover include prodrugs of the foregoing.

Invention methods include contact or administration, in vitro, ex vivo or in vivo (e.g., to a subject in need of treatment). In various embodiments, lung or airway inflammation, asthma, or a symptom caused by or associated with respiratory, interstitial, or pulmonary disease or disorder, or the fibrotic disease or disorder is reduced, decreased, inhibited, delayed, halted, or prevented in the subject, locally, or regionally in an area (region), tissue or organ of the subject. In particular aspects, a symptom is reduced, decreased, inhibited, delayed, halted, or prevented in a respiratory, interstitial or pulmonary tissue or organ. In another aspect, a method reduces, decreases, inhibits, delays, halts, or prevents inflammation or constriction of lung, airways or respiratory mucosum. In yet another embodiment, contacting or administration in vivo is in a subject that has previously experienced an asthmatic episode or airway- or broncho-constriction or is in need of airway- or broncho-dilation.

In accordance with the invention, there are also provided, methods of inhibiting, reducing or decreasing progression, severity, frequency, duration or probability of one or more symptoms caused by or associated with lung or airway inflammation or asthma. In one embodiment, a method includes administering to a subject an amount of a LIGHT inhibitor sufficient to inhibit, reduce or decrease progression, severity, frequency, duration or probability of a symptom associated with lung or airway inflammation or asthma. In various aspects, asthma is caused by an allergen or by exercise.

Symptoms include, for example, lung, airway or respiratory mucosum inflammation or tissue damage or remodeling, shortness of breath (dyspnea), rapid breathing (tachypnea), wheezing, stridor, coughing, decreased or reduced lung capacity, chest-tightness, chest pain, prolonged expiration, increased heart rate (tachycardia), runny nose, airway-constriction, decreased lung capacity, or an acute asthmatic episode, or infiltration of a lung or pulmonary or lymphatic tissue (draining lymph nodes), lymph nodes or airway with immune cells, such as leukocytes and eosinophils, hyperplasia of mucus secreting epithelium, inflammatory lesion of lung, goblet cell hyperplasia, or increased Th2 cytokine production (e.g., an interleukin such as IL-4, IL-5, IL-9, IL-13, IL-16, IL-17 or IL-25).

Respiratory diseases can affect the upper or lower respiratory tract. Non-limiting examples include asthma, allergic asthma, bronchiolitis and pleuritis. Additional non-limiting examples include allergic disorders, such as Extrinsic bronchial asthma; Allergic rhinitis; Onchocercal dermatitis; Atopic dermatitis, Drug reactions; Nodules, eosinophilia, rheumatism, dermatitis, and swelling (NERDS); Eosophageal and gastrointestinal allergies. Further non-limiting examples include Airway Obstruction, Apnea, Asbestosis, Atelectasis, Berylliosis, Bronchiectasis, Bronchiolitis, Bronchiolitis Obliterans, Organizing Pneumonia, Bronchitis, Bronchopulmonary Dysplasia, Common Cold, Cough, Empyema, Pleural Empyema, Pleural Epiglottitis, Hemoptysis, Hypertension, Kartagener Syndrome, Meconium Aspiration, Pleural Effusion, Pleurisy, Pneumonia, Pneumothorax, Respiratory Distress Syndrome, Respiratory Hypersensitivity, Respiratory Tract Infections, Rhinoscleroma, Scimitar Syndrome, Severe Acute Respiratory Syndrome, Silicosis, Tracheal Stenosis and Whooping Cough. Still further non-limiting examples of respiratory diseases include influenza.

In another embodiment, a method includes administering an amount sufficient to inhibit, reduce or decrease progression, severity, frequency, probability, duration or prevent one or more adverse physiological or psychological symptoms caused by or associated with a chronic or acute condition, disorder or disease caused by or associated with undesirable or abnormal lung or airway inflammation, asthma, or a respiratory, interstitial, or pulmonary disease or disorder. In particular aspects, a condition, disorder or disease is allergic asthma, an acute asthmatic episode, airway constriction, or lung or airway inflammation, or a respiratory, interstitial, or pulmonary disease or disorder.