Treatment of emphysema using RARy selective retinoid agonists

Details Treatment of emphysema using RARy selective retinoid agonists Treatment of emphysema using RARy selective retinoid agonists

2000-10-18

2001-10-09

Henley, III, Raymond (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S458000, C514S538000, C514S563000, C514S569000

Reexamination Certificate

active

06300350

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to methods of treating emphysema to regenerate functional alveoli using retinoic acid receptor agonists, in particular a retinoic acid receptor agonist that is RAR&ggr; selective.
2. Background Information
A. Emphysema
Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality, ranking third and fourth as the leading cause of death in the European Union and North America respectively. COPD is characterized by reduced maximum expiratory flow that does not change over several months and persists for 2 or more consecutive years. Patients with the most severe form of COPD generally present with a significant degree of emphysema.
Emphysema is defined anatomically by permanent airspace enlargement distal to the terminal bronchioles, and it is characterized by gradual loss of lung recoil, alveolar destruction, decreased alveolar surface area and gas exchange, leading to a reduced FEV
1
(American Thoracic Society: Am. J. Resp. and Critical Care 152: S77-S124, 1995). Impaired gas exchange and reduction in expiratory flow are characteristic physiological abnormalities from which emphysema patients suffer. The main symptom of severely affected emphysema patients is shortness of breath during minimal physical activity.
Although other potential environmental toxins may contribute, the most common cause of emphysema is cigarette smoking. These injurious agents activate destructive processes in the lung, including release of active proteases and free radical oxidants in excess of protective mechanisms. The uncontrolled release of active proteases creates an imbalance in protease/anti-protease levels in the lungs that leads to elastin matrix destruction, elastic recoil loss, tissue damage, and continuous lung function decline. The rate of this damage may be slowed by removing the injurious agents (for example, by quitting smoking); however, the damaged alveolar structures are not repaired and lung function is not regained.
B. Lung Development and Alveolar Septation
All-trans retinoic acid (ATRA) is a multifunctional modulator of cellular behavior, having the potential to alter both extracellular matrix metabolism and normal epithelial differentiation. In the lungs, ATRA has been shown to modulate various aspects of lung differentiation by interacting with specific retinoic acid receptors (RAR) that are selectively expressed temporally and spatially. Coordinated activation of RAR&bgr; and RAR&ggr; has been associated with lung branching, alveolization/septation and gene activation of tropoelastin in neonatal rats.
During alveolar septation, retinonic acid storage granules (retinyl-esters) increase in the fibroblastic mesenchyme surrounding alveolar walls (Liu et al; Am. J. Physiol. 265: L430-L437, 1993; McGowan et al Am. J. Physiol. 269: L463-L472, 1995), and RAR&ggr; expression in the lung peaks (Ong, D. E. and Chytil, F., Proc. Natl. Acad. of Sciences 73: 3976-3978, 1976; Grummer, M. A., Thet, L. and Zachman, R. D., Pediatr. Pulm. 17: 234-238, 1994). Depletion of these retinyl-ester stores parallels the deposition of new elastin matrix and sepation. In support of this concept, Massaro and Massaro (Massaro, D. and Massaro, G., Am. J. Physiol. 270, L305-L310, 1996) demonstrated that postnatal administration of retinoic acid increases the number of alveoli in rats. Treatment of newborn rat pups with dexamethasone inhibits the process of septation in the lungs. This effect can be overcome by supplemental treatment with retinoic acid. Furthermore, the capacity of dexamethasone to prevent the expression of CRBP and RAR&bgr; mRNA and subsequent alveolar septation in developing rat lung was abrogated by ATRA.
C. Retinoid Agonists in the Treatment of Emphysema.
Recent studies demonstrated that ATRA can induce formation of new alveoli and return elastic recoil to near normal in animal models of emphysema (Massaro, D. and Massaro, G., Nature Med. 3: 675-677, 1997; “Strategies to Augment Alveolization,” National Heart, Lung, and Blood Institute, RFA: HL-98-011, 1998.). However the mechanism by which this occurs remains unclear.
D. Retinoids
Retinoids are a class of compounds structurally related to vitamin A, comprising natural and synthetic compounds. Several series of retinoids have been found clinically useful in the treatment of dermatological and oncological diseases. All-trans retinoic acid (ATRA) and its other naturally occurring retinoid analogs (9-cis retinioc acid, all-trans 3-4 didehydro retinioc acid, 4-oxo retinoic acid and retinol) are pleiotrophic regulatory compounds that modulate the structure and function of a wide variety of inflammatory, immune and structural cells. They are important regulators of epithelial cell proliferation, differentiation and morphogenesis in lung. Retinoids exert their biological effects through a series of nuclear receptors that are ligand inducible transcription factors belonging to the steroid/thyroid receptor superfamily.
The retinoid receptors are classified into two families, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs), each consisting of three distinct subtypes (&agr;, &bgr;, and &ggr;). Each subtype of the RAR gene family encodes a variable number of isoforms arising from differential splicing of two primary RNA transcripts. ATRA is the physiological hormone for the retinoic acid receptors and binds with approximately equal affinity to all the three RAR subtypes. ATRA does not bind to the RXR receptors; instead, for these receptors, 9-cis retinoic acid is the natural ligand.
In many non-pulmonary tissues, retinoids have anti-inflammatory effects, alter the progression of epithelial cell differentiation, and inhibit stromal cell matrix production. These properties have led to the development of topical retinoid therapeutics for dermatological disorders such as psoriasis, acne, and hypertrophic cutaneous scars. Other applications include the control of acute promyelocytic leukemia, adeno- and squamous cell carcinoma, and hepatic fibrosis. However, therapeutic use of retinoids outside of cancer is limited due to the relative toxicities observed with the naturally occurring retinoids, ATRA and 9-cis RA. These natural ligands are non-selective and, therefore, have pleiotrophic effects throughout the body, which are often toxic. Recently various retinoids have been described that interact selectively or specifically with the RAR or RXR receptors or with specific subtypes (&agr;, &bgr;, &ggr;) within a class. Using these novel retinoids, the transrepression of AP-1 and transactivation activities of retinoids have been separated. (Li, J. J. et al, Cancer Research, 56: 483-489 (1996); Fanjul, A. et al., Nature, 372: 107-111 (1994); Schule R. et al., PNAS, 88: 6092-6096 (1991); Nagpal et al., Journal of Biological Chemistry 270: 923-927 (1995)). In addition, the receptor selective compounds have shown reduced general toxicity in vitro and in vivo. (Chandraratna, R., J. Am. Acad. Dermatology, 39: S149-S152, 1998; Look, J. et al., Am. J. Physiol. 269: E91-E98, 1995).
SUMMARY OF THE INVENTION
In one aspect, this invention provides methods of treating emphysema and associated pulmonary diseases by treatment of a mammal with an RAR&ggr; selective agonist. For this treatment systemic administration is a preferred mode of delivery. Use of retiniods that are at least RAR&ggr; selective and RAR&agr; sparing will promote repair without inducing adverse effects on levels of plasma triglycerides.
In another aspect, this invention provides methods of stimulating tropo-elastin gene expression in a human lung fibroblast by contacting the cell with an RAR&ggr; selective agonist.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
As used herein, the term (C
x
-C
y
) alkyl means a linear or branched fully-saturated hydrocarbon radical having from x to y carbon atoms; a (C
x
-C
y
) fluoroalkyl is an alkyl radical, as defined above, in which one or more hydrogen atoms attached to the carbon backbone have been substituted with one or more fluorine at

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