Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-04-30
2001-01-23
Davis, Zinna Northington (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S195000
Reexamination Certificate
active
06177447
ABSTRACT:
FIELD OF THE INVENTION
This invention is in the fields of therapy and pharmaceutical compositions for the treatment of various diseases, in particular diseases characterized by elevated plasma chitotriosidase levels, such as Gaucher disease.
BACKGROUND OF THE INVENTION
CERAMIDE, A SECOND MESSENGER
In recent years the importance of ceramide as second messenger in signal transduction has been recognized. It has become clear that the signalling induced by a number of cytokines is mediated by changes in the intracellular concentration of this lipid [1,2]. For example, crucial for the transduction of the signal exerted by TNF-&agr; (tumor necrosis factor alpha) upon binding to its receptor are local changes in ceramide concentration in specific regions, or invaginations, of the plasma membrane. Upon binding of the cytokine to its receptor, a sphingomyelinase catalyzes the conversion of sphingomyelin into phosphorylcholine and ceramide. The ceramide that is generated in this manner propagates the signal by activating specific protein kinases and phosphatases, resulting in a cellular response.
FIG. 1
gives an overview of the signalling mechanism of TNF-&agr; and other cytokines such as interferon gamma and interleukin 6.
There is now convincing experimental evidence for the role of ceramide in signalling. It has been shown that the effects of TNF-&agr; can be experimentally mimicked by administration of a permeable ceramide with truncated fatty acyl moiety or, alternatively, by the generation of ceramide at the cell surface by the treatment of cells with a bacterial sphingomyelinase (see e.g. ref. 2).
The above described signal transduction process is most likely a highly local event, occurring near the cytokine receptor. The concentration of ceramide in the plasma membrane is believed to be very low under normal conditions. However, considerable amounts of ceramide are present in the plasma membrane as a building block in sphingomyelin. The hydrolysis of sphingomyelin would allow a considerable local change in ceramide concentration and subsequent signal propagation.
Via action of a specific transferase, ceramide can be reconverted to sphingomyelin by transfer of the phosphorylcholine moiety from phosphatidylcholine (PC), resulting in the concomitant formation of diacylglycerol. The total pathway, resulting in the netto hydrolysis of phosphatidylcholine to phosphorylcholine and diacylglycerol, is named the sphingomyelin cycle [2].
CERAMIDE AND SPHINGOLIPID METABOLISM
Obviously, not all fluctuations in intracellular ceramide concentrations are affecting signal transduction. Ceramide is extensively metabolized in cells. The lipid is synthesized at the membrane of the endoplasmic reticulum from acylCoA and sphingosine. It may be converted at the level of the Golgi apparatus into sphingomyelin, glucosylceramide and related complex gangliosides, or galactosylceramide and related globosides and sulfatides. Sphingomnyelin and glycosphingolipids are also catabolized into ceramide and other components in the lysosomal compartment of cells. The intralysosomally formed ceramide may be locally hydrolyzed into sphingosine and fatty acid by the action of the lysosomal ceramidase or it may be exported to the cytosol and re-used for synthesis of sphingolipids. A schematic overview of the ceramide metabolism is presented in FIG.
2
.
SPHINGOLIPIDOSES: GAUCHER DISEASE
In man a number of inherited disorders in lysosomal sphingolipid catabolism occur, the so called sphingolipidoses (see Table 1). For example, an inherited deficiency of the lysosomal sphingomyelinase underlies Niemann-Pick disease, and defective activity of the lysosomal ceramidase causes Farber disease. The most frequently encountered sphingolipidosis is Gaucher disease [3]. The metabolic basis of this disorder is a deficiency of the lysosomal beta-glucosidase, glucocerebrosidase (E.C.3.2.1.45). This enzyme catalyzes the hydrolysis of glucosylceramide (glucocerebroside) to glucose and ceramide. In patients with Gaucher disease glucosylceramide accumulates in tubular aggregates, in particular in lysosomes of macrophages. The lipid-laden macrophages have a typical morphology and are usually referred to as ‘Gaucher cells’. In the course of clinical manifestation of Gaucher disease the abnormal macrophages may accumulate in large quantities in various body locations, such as the bone marrow compartment, spleen, liver, kidney, and lungs. The most pronounced clinical symptoms associated with Gaucher disease are progressive splenomegaly, hepatomegaly, and skeletal deterioration. Most Gaucher disease patients do not develop neurological complications. The common non-neuronopathic form of the disease is called Type 1 Gaucher disease. In very severe cases of Gaucher disease characteristic neurological abnormalities may also occur, resulting in lethal complications at infantile (Type 2) or juvenile (Type 3) age [3].
GAUCHER CELLS
The glucosylceramide-laden Gaucher cells are believed to play a crucial role in the pathophysiology. Their massive presence in various body locations is thought to lead to local pathology.
Gaucher cells should not be viewed as inert containers of glycosphingolipid. The storage cells are viable and actually, being activated macrophages, secrete large amounts of specific proteins such as hydrolases and cytokines. These factors in turn act as pathogenetic agents that cause local tissue damage and turnover. Moreover, Gaucher-cell derived factors such as cytokines promote the recruitment of additional activated macrophages (see
FIG. 3
for a schematic overview).
Recently a sensitive marker for Gaucher cells has been discovered by us [4]. Using the technique of in situ hybridization we observed that Gaucher cells synthesize large quantities of the secretory enzyme chitotriosidase, the human analogue of chitinases present in various species. This explains the dramatic elevation in plasma chitotriosidase levels in clinically affected Gaucher patients. On the average chitotriosidase levels are about 1000 fold higher in plasma of these patients as compared to corresponding normal subjects. In presymptomatic or asymptomatic individuals with an inherited glucocerebrosidase deficiency plasma chitotriosidase levels are (almost) within the normal range (see Table 2). Interestingly, elevated levels of plasma chitotriosidase have also been noted for patients with other sphingolipidoses, in particular Niemann-Pick disease [5].
It has been observed that in cultured macrophages, derived from peripheral blood monocytes, the concentration of glucosylceramide gradually increases. The increase in glycolipid is more pronounced when cells are grown in the presence of conduritol B-epoxide, a potent irreversible inhibitor of glucocerebrosidase. After approximately 7 days of culture the macrophages start to produce chitotriosidase mRNA and secrete the enzyme [4,6]. The expression of the chitotriosidase gene subsequently dramatically increases: after about three weeks chitotriosidase constitutes almost 1% of the total synthesized protein, as revealed by the incorporation of radioactively labeled methionine [7]. The continuous presence in the culture medium of glucosylceramide, or of conduritol B-epoxide (an irreversible inhibitor of lysosomal glucocerebrosidase), promotes chitotriosidase expression.
THERAPEUTIC INTERVENTION FOR GAUCHER DISEASE
The sparse and anecdotal information on the natural history of Gaucher disease indicates that although clinical symptoms develop progressively, the disease manifestation is usually not a gradual proces. In the case of most patients abnormalities develop rapidly at a particular age in a specific tissue, may subsequently stabilize for considerable time, to become next rapidly progressive again. In other words, disease progression has a local and chaotic feature. Most likely, Gaucher cells play a critical role in these local pathogenetic processes. The presence of the activated storage cells will locally induce tissue damage and tu
Aerts Johannes Maria F. G.
Koomen Gerrit-Jan
Overkleeft Herman Steven
Pandit Upendra Kumar
Vianello Paola
Cooper & Dunham LLP
Davis Zinna Northington
Universiteit Van Amsterdam
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