Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Sulfur – selenium or tellurium compound
Reexamination Certificate
1999-01-22
2002-03-12
Geist, Gary (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Sulfur, selenium or tellurium compound
C514S740000
Reexamination Certificate
active
06355690
ABSTRACT:
TECHNICAL FIELD
This invention is related to a remedy for a CAG repeat expansion disease.
BACKGROUND ART
Expansion of CAG trinucleotide repeats coding for polyglutamine stretches has been identified as a common pathogenic mutation for eight neurodegenerative diseases including spinal and bulbar muscular atrophy (SBMA)
1
, Huntington disease (HD)
2
, spinocerebellar ataxia type1 (SCA1)
3
, dentatorubral-pallidoluysian atrophy (DRPLA)
4,5
, Machado-Joseph disease (MJD)
6
, SCA2
7-9
, SCA6
10
and SCA7
11
, and the number of diseases caused by the same mechanism is expected to increase further. There are many common features shared among these diseases; 1. The central nervous system is commonly affected with distinct distributions of neuronal loss, which are unique to each disorder. 2. Considerable heterogeneities of the clinical presentations even within the same pedigree, which are a function of the size of expanded CAG repeats. 3. Genetic anticipation i.e. accelerated age at onset in successive generations, which is also a result of intergenerational increase in the size of expanded CAG repeats.
There are no common homologous domains shared among the gene products except for the polyglutamine stretches
1-14
, and the gene products of the mutant genes have been shown to be expressed at levels comparable to those of wild-type genes
15-18
. These observations raise the possibility that the polyglutamine stretch itself exerts a “gain of toxic function”. In accordance with this, transgenic mice harboring a full-length SCA1 cDNA containing an expanded CAG repeat under control of the L7 promoter have been shown to exhibit cerebellar ataxia and degeneration of Purkinje cells in the cerebellum
19
. More interestingly, transgenic mice carrying mostly the expanded CAG repeat of the MJD1 gene
20
or exon 1 of huntingtin gene containing the expanded CAG repeat have also been demonstrated to exhibit neurological phenotypes and neurodegeneration. Very recently it has been demonstrated that mice transgenic for exon 1 of the HD gene carrying expanded CAG repeats develop neuronal intranuclear inclusions
22
. The toxicity of a peptide containing mostly the expanded polyglutamine stretch of MJD1 protein has also been demonstrated in a transient expression system using COS cells
20
. Thus, evidence which indicates that expanded polyglutamine stretches have toxic functions is accumulating.
Various hypotheses have been proposed to explain the mechanisms of the toxicity of expanded polyglutamine stretches. Perutz and the colleague proposed that polyglutamine stretches may function as polar zippers by joining complementary proteins through hydrogen bondings, and that extensions of the polyglutamine stretches may result in strong joining and aggregation of the affected proteins
23,24
. Another intriguing hypothesis has recently been proposed by Kahlem et al.
25
. They proposed that proteins with expanded polyglutamine stretches may serve as better substrates for transglutaminase than wild-type proteins, and that expanded polyglutamine stretches preferentially become cross-linked with polypeptides containing lysyl groups to form covalently bonded aggregates. However, the following questions has not elucidated yet. 1. Do the full-length or truncated proteins with expanded polyglutamine stretches form aggregates and exhibit cytotoxicity? and 2. Are transglutaminases involved in the formation of aggregates or in cytotoxicity? Moreover, there is no information on means for alleviate the cytotoxicity of the mutant proteins. Therefore, there has been no remedy for CAG repeat expansion diseases.
SUMMARY OF THE INVENTION
The object of this invention is to elucidate the molecular mechanism of “gain of toxic function” caused by polyglutamine stretch at CAG repeat expansion diseases and thus to provide the therapeutic remedy for CAG repeat expansion diseases. That is, a CAG repeat exists on a protein coding region and encodes polyglutamine stretches. Increase in the size of CAG repeat causes longer polyglutamine stretch, and as the result, it comes to exhibit cytotoxicity. Elucidation of the mechanism to cause cytotoxicity and establishment of the means to moderate cytotoxicity enable to develop a remedy for CAG repeat expansion disease. The object of this invention is to develop the therapeutic measures for CAG repeat expansion diseases through such kind of approach.
To address these questions, the inventors established an expression system of full-length and truncated cDNAs for dentatorubral-pallidoluysian atrophy (DRPLA) and found that truncated DRPLA proteins containing the expanded polyglutamine stretch, but not the full-length protein, form peri- and intra-nuclear aggregates consisting of filaments and induce concomitant apoptosis. Moreover, formation of the aggregates was found at cerebellar dentate nucleus of all DRPLA patients examined. That is, the relationship between truncated DRPLA protein and DRPLA was found.
The effect of various transglutaminase inhibitors was examined to elucidate the involvement of transglutaminase on the aggregation formation and apoptotic cell death. As the result, some transglutaminase inhibitors were found to inhibit the aggregate formation and apoptotic cell death. Then involvement of transglutaminase on DRPLA was confirmed.
The series of results revealed that transglutaminase inhibitors are available as a remedy for CAG repeat expansion diseases including DRPLA. In short, this invention relates to the use of transglutaminase inhibitors for treating CAG repeat expansion diseases. In preferred embodiments,
(1) A remedy for a CAG repeat expansion disease containing a transglutaminase inhibitor as its active ingredient.
(2) The remedy as described in (1), wherein the transglutaminase inhibitor is selected from a group consisting of cyctamine and monodansyl cadaverine.
(3) The remedy as described in (1) wherein the CAG repeat expansion disease is selected from a group consisting of: spinal and bulbar muscular atrophy, Huntington disease, spinocerebellar ataxia type1, dentatorubral-pallidoluysian atrophy, Machado-Joseph disease, spinocerebellar ataxia 2, spinocerebellar ataxia 6 and spinocerebellar ataxia 7.
(4) The remedy as described in (2) wherein the CAG repeat expansion disease is selected from a group consisting of: spinal and bulbar muscular atrophy, Huntington disease, spinocerebellar ataxia type1, dentatorubral-pallidoluysian atrophy, Machado-Joseph disease, spinocerebellar ataxia 2, spinocerebellar ataxia 6 and spinocerebellar ataxia 7.
(5) A pharmaceutical composition for treating a CAG repeat expansion disease: comprising
a transglutaminase inhibitor as its active ingredient, and a pharmaceutically accepted ingredients for formulation.
(6) The pharmaceutical composition as described in (5), wherein the transglutaminase inhibitor is selected from a group consisting of cyctamine and monodansyl cadaverine.
(7) The pharmaceutical composition as described in (5) wherein the CAG repeat expansion disease is selected from a group consisting of: spinal and bulbar muscular atrophy, Huntington disease, spinocerebellar ataxia type1, dentatorubralpallidoluysian atrophy, Machado-Joseph disease, spinocerebellar ataxia 2, spinocerebellar ataxia 6 and spinocerebellar ataxia 7.
(8) The use of a transglutaminase inhibitor for manufacturing a pharmaceutical composition for treating a CAG repeat expansion disease.
(9) The use as described in (8) wherein the transglutarninase inhibitor is selected from a group consisting of cystamine and monodansyl cadaverine.
This invention relates to a remedy for CAG repeat expansion diseases wherein the effective ingredients are transglutaminase inhibitors. The therapeutic target of this invention includes spinal and bulbar muscular atrophy, Huntington disease, spinocerebellar ataxia type1, dentatorubral-pallidoluysian atrophy, Machado-Joseph disease, SCA2, SCA6 and SCA7.
There is no limitation for the effective ingredients of this invention such as cystamin or MDC, so far as they have inhibitory effect on transglutaminase activity. The rem
Burns Doane , Swecker, Mathis LLP
Geist Gary
Maier Leigh C.
Niigata University
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