Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2003-03-24
2004-04-20
Henle, III, Raymond J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S645000
Reexamination Certificate
active
06723703
ABSTRACT:
BACKGROUND
Cystic fibrosis (CF) is an autosome recessive disease. Affected patients have an average life expectancy of 30 years. This early mortality is primarily related to lung disease, in particular for 95% of patients, death results from progressive respiratory failure associated with impaired mucus clearance and excessive overgrowth of bacteria and fungi in the airways. The lung disease is characterized by 1) abnormal salt and water transport in the airway epithelium, such that too much sodium and too little chloride crosses the epithelial membrane; 2) a defect in glutathione transport out of airway epithelial cells; 3) inspissated secretions and oxidant damage, in part related to salt, water, and glutathione transport abnormalities; 4) impaired ciliary motility associated with thick secretions; 5) chronic colonization with denitrifing organisms such as
Pseudomonas aeruginiosa
and
Aspergillus fumigatus
; and 6) chronic bronchoconstriction associated with recruitment of neutrophils and other inflammatory cels and associated release of bronchoconstricting mediators and, as a result of all of these factors, chronic, progressively worsening, dyspnea.
Cystic fibrosis is caused by mutations in a membrane-associated chloride channel, the cystic fibrosis transmembrane regulatory protein (CFTR). The most common mutation, accounting for 70% of alleles, is a 3 base pair (single amino acid) deletion at the 508 position on the first ATP binding domain, the (&Dgr;F508) mutation. This is referred to as a class II mutation in that intact and potentially functional protein is degraded in the endoplasm reticulum because of a small folding error. It is known that his degradation can be bypassed in vitro by hypothermia and by treatment with compounds,such as glycerol and phenylbutyrate. These treatments result in functional expression of (&Dgr;F508) CFTR on the cell surface. It has recently been proposed that CFTR degradation in the endoplasmic reticulum (ER) is mediated by the ubiquitin-proteasome system. We have preliminary evidence that S-nitrosoglutathione (GSNO) inhibits the ubiquitin proteosome pathway, stabilizing the expression of post-translationally/degradation-regulated proteins such as hypoxy inducible factor 1-&mgr;.
Furthermore, GSNO is of interest in cystic fibrosis for several established reasons. We have shown in 1993, that it is a compound present endogenously in the airways and has activity as a bronchodilator. GSNO is also known to increase ciliary beat frequency, augmenting airway clearance to inhibit amiloride-sensitive sodium transport, augmenting airway lining fluid salt and water retention. It has established antimicrobial properties, inhibiting the replication of viruses, bacteria, and parasites. We have recently discovered that levels of GSNO are low in the bronchoalveolar lavage fluid of patients with mild cystic fibrosis. All of these established functions could have a salutary effect in CF.
Surprisingly, we have discovered that the treatment of cells homozygous to the (&Dgr;F508) mutation with 100 &mgr;M GSNO increases the expression of CFTR and increases the maturation of CFTR (see FIG.
1
). We have also discovered that inhalation of GSNO at concentrations effective to enhance the production of CFTR (a dose of about 0.05 ml/kg of a 10 mM GSNO solution) results in improved oxygenation. Finally we have shown that GSNO is well tolerated in CF and has no adverse systemic affects. Therefore, since replacement of low levels of GSNO is well tolerated, acutely beneficial, and can increase the amount of functional CFTR expressed on the cell surface, its use is proposed to benefit people with the disease.
BRIEF SUMMARY OF INVENTION
The present invention is directed to composition and method for treating CF patients. The method comprises the delivery of S-nitrosoglutathione (GSNO) in concentrations equal to or in excess of 500 nmole/kg (175 mcg/kg), or other nitrosylating agents such as ethyl nitrite, to epithelial surfaces of patients with cystic fibrosis for the purpose of insuring adequate concentrations of S-nitrosylating agent on the epithelial surfaces of CFTR and epithelial function. The compositions of the present invention comprise a nitrosonium donor including, but not limited to GSNO and other S-nitrosothiols (SNOs) in a pharmaceutically acceptable carrier that allows for administration by nebulized or other aerosol treatment to patients with cystic fibrosis.
REFERENCES:
patent: 4900719 (1990-02-01), Means et al.
patent: 5859058 (1999-01-01), Zimmerman et al.
patent: 6314956 (2001-11-01), Stamler et al.
patent: 6331543 (2001-12-01), Garvey et al.
patent: 6359182 (2002-03-01), Stamler et al.
patent: 2001/0012834 (2001-08-01), Stamler
patent: 2002/0002136 (2002-01-01), Hebert
patent: WO 98/52580 (1998-11-01), None
Snyder, A.H., et al, Am J Respir Crit Care Med 165, 1-5, (2002).
Gaston Benjamin
Stamler Jonathan S.
Duke University
Henle, III Raymond J.
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