Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-01-22
2003-12-02
Barts, Samuel (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S299000, C514S042000, C514S673000, C546S183000
Reexamination Certificate
active
06656912
ABSTRACT:
TECHNICAL FIELD
The invention relates to treatment of &agr;1-antitrypsin (&agr;1-AT) deficiency in individuals containing a mutant form of &agr;1-AT exhibiting symptoms of, or at-risk for, liver damage and/or emphysema. In particular, the invention concerns the use of inhibitors of glucosidase and in some instances, of mannosidase in ameliorating these conditions.
BACKGROUND ART
The enzyme &agr;1-antitrypsin (&agr;1-AT) is important in maintaining the condition of lung tissue by virtue of its ability to inhibit neutrophil elastase. If this elastase inhibitor is lacking in the lungs, lung diseases such as emphysema can develop. A substantial number of individuals are deficient in this important enzyme by virtue of the presence of a mutant form of the glycoprotein, designated &agr;1-ATZ, differing from the wild type by a single amino acid substitution. Although &agr;1-ATZ this retains approximately 80% of the functional activity of the wild type in inhibiting neutrophil elastase, because it is misfolded and polymerized in the endoplasmic reticulum (ER) of liver cells rather than excreted into the extracellular fluid, it exerts a hepatotoxic effect, especially in infants and children, and is not available in the lungs to carry out its function. There are, however, known pathways for degradation of the mutant &agr;1-ATZ in the ER—one involving the sequence of stable binding to calnexin, conjugation of ubiquitin to the cytoplasmic tail of the complexed calnexin and degradation of the resulting complex by the proteasome (Qu, D., et al.,
J. Biol. Chem.
(1996) 271:22791-22795). There is also a ubiquitin-independent proteasomal mechanism (Teckman, J. H., et al.,
Biochem J.
(1986) 236:853-860).
It is apparent that individuals having the genotype which results in the production of the mutant &agr;1-ATZ would benefit if the secretion of this mutant form of &agr;1-AT could be enhanced, since this mutant form does retain the desired neutrophil elastase inhibition activity. Such individuals would also benefit by any protocol which would result in the enhanced degradation of this mutant form in the ER, thus ameliorating the hepatotoxicity of the misfolded polymer. It has been shown that glucosidase and mannosidase inhibitors inhibit secretion of wild type &agr;1-AT (Gross, V., et al,
Biochem. J.
(1986) 236:853-860). It has also been shown that a different mutant &agr;1-AT which is retained and degraded in the ER, &agr;1-AT
HONG KONG
, is affected by such inhibitors in that ER degradation is accelerated by glucosidase inhibitors and delayed by mannosidase inhibitors (Liu, Y., et al.,
J. Biol. Chem.
(1997) 272:7946-7951; Liu, Y., et al.,
J. Biol. Chem.
(1999) 274:5861-5867).
In general, it is understood that addition and trimming of oligosaccharide side chains are significant factors in the secretion, degradation, and transport of secretory, membrane and lyosomal glycoproteins. It is also known that transport of secretory and membrane glycoproteins from the ER to their appropriate destination depends on the interaction of the innermost glucose residue of oligosaccharide side chains with the ER molecular chaperones calnexin and calreticulin so that trimming of the oligosaccharide coupled to the asparagine residue in the peptide backbone by, for example, glucosidases I and II influence the proper folding and translocation of glycosylated proteins.
Experimental work related to the present invention has been described by applicants in Marcus, N.Y., and Perlmutter, D. H.,
Gastroenterology
(2000) 118:1160 (meeting abstract entitled “Glucosidase and Mannosidase Inhibitors Mediate Increased Secretion of A1 Antitrypsin Z”; Burrows, J. A. J., et al.,
Proc. Natl. Acad. Sci
(
USA
) (2000) 97:1796-1801 (article entitled “Chemical Chaperones Mediate Increased Secretion of Mutant alpha 1-Antitrypsin (alpha 1-AT) Z: A Potential Pharmacological Strategy for Prevention of Liver Injury and Emphysema in alpha 1-AT deficiency”); Marcus, N.Y., et al.,
J. Biol. Chem.
(2000) 275:1987-1992 (article entitled “Glucosidase and Mannosidase Inhibitors Mediate Increased Secretion of Mutant alpha 1-Antitrypsin Z”); and Teckman, J. H., et al.,
Am. J. Physiol
-
Gastro and Liver Physiol.
(2000) 278:G39-G48 (article entitled “Role of Ubiquitin in Proteosome al Degradation of Mutant alpha 1-Antitrypsin Z in the Endoplasmic Reticulum”). The contents of these publications are incorporated herein by reference.
DISCLOSURE OF THE INVENTION
It has now been found that inhibitors of glucosidase enhance the secretion of the mutant &agr;1-ATZ glycoprotein without impairing its degradation in the ER. Inhibitors of mannosidase I also enhance secretion of mutant &agr;1-ATZ, but delay its degradation in the ER. Compounds which are imino sugars or reduced forms thereof, such as derivatized deoxynojirimycin, are also useful in the methods of the invention.
Thus, in one aspect, the invention is directed to treat conditions associated with &agr;1-antitrypsin deficiency caused by the presence of mutant &agr;1-ATZ glycoprotein which method comprises administering to a subject in need of such treatment an effective amount of an inhibitor of glucosidase so as to enhance the secretion of the mutant &agr;1-ATZ. In another aspect, the invention relates to methods to treat hepatotoxic conditions caused by the presence of mutant &agr;1-ATZ in the endoplasmic reticulum which method comprises administering an effective amount of a glucosidase inhibitor to a subject in need of such treatment. In still another aspect, the invention is directed to ameliorating emphysema in individuals wherein the emphysema is caused by an &agr;1-AT deficiency due to the presence of the mutant &agr;1-ATZ which method comprises administering to individuals in need of such treatment an effective amount of a glucosidase inhibitor or a mannosidase I inhibitor.
Also useful in the various methods of the invention set forth above are imino sugars and their reduced forms. Imino sugars include analogs of hexoses or pentoses wherein the 5 or 4 position contains amino as opposed to hydroxy.
In other aspects, the invention relates to pharmaceutical compositions containing the aforementioned inhibitors and compounds.
Modes of Carrying Out the Invention
Clinical studies have shown that only partial correction is needed for prevention of both liver and lung injury in patients having &agr;1-antitrypsin deficiency. See Wu, Y., et al.,
Proc. Natl. Acad. Sci.
(
PNAS
)
U.S.A.
(1994) 91:9014-9018; Campbell, E. J., et al.,
J. Clin. Invest.
(1999)104:337-344). Thus, the ability of glucosidase inhibitors and mannosidase I inhibitors to enhance the secretion of &agr;1-ATZ, which retains significant portion of the activity of the wild type &agr;1-AT, make such compounds effective medications for treating the clinical symptoms associated with deficiency caused by the presence of &agr;1-ATZ. Secretion can also be enhanced by 4-phenylbutyric acid (PBA).
Suitable subjects are those individuals whose genetic composition results in the production of the mutant form of &agr;1-antitrypsin, &agr;1-ATZ. These individuals can be determined by known methods, such as genetic typing and immunological tests. If subjects present with symptoms such as emphysema or liver malfunction, determination of whether or not the individual produces &agr;1-ATZ is straightforward, routine, and readily performed. For use of the method of the invention in preventing the onset of such conditions, a suitable screening program would be desirable.
As used herein, “treat” or “treatment” includes ameliorating the effects of a condition already present as well as preventing the onset of symptomologies. Thus, “treatment” includes both therapeutic and prophylactic protocols.
The active ingredients in the compositions used in the methods of the invention are preferably glucosidase inhibitors, since these inhibitors both enhance the secretion of &agr;1-ATZ and enhance its degradation in the ER. Such inhibitors include castanospermine (CST), which is a polyhydroxy alkaloid isolated from plant sources known to inhibit enzyma
Marcus Nancy
Perlmutter David H.
Barts Samuel
Henry Michael C.
Morrison & Foerster / LLP
Washington University in St. Louis
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