JP2003048829A - Prophylactic or therapeutic agent for mitochondrial disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a prophylactic or therapeutic agent having safety and high efficacy by oral administration, against mitochondrial disease, especially chronic progressive external ophthalmoplegia syndrome(CPEO), MERRF(myoclonus epilepsy with ragged-red fiber), MELAS(mitochondrial encephalopathy, lactic acidosis and stroke) and diabetes, cardiomyopathy, Alzheimer's dementia, auditory difficulties, and retinal degenerative disease caused by mitochondrial genetic variation. SOLUTION: This prophylactic or therapeutic agent against mitochondrial diseases and diseases concerned with mitochondrial genetic variation comprises one or more kinds as active ingredients selected from the group consisting of taurine, taurine chloramine, a sulfur-containing amino acid capable of becoming their precursors in vivo and a pharmacologically acceptable salt thereof and a taurine derivative.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to mitochondrial diseases,
Especially chronic progressive external ophthalmoplegia syndrome (CPEO), MER
RF (myoclonus epilepsy with mitochondrial abnormality with red rag fibers), MELAS (mitochondrial myopathy encephalopathy hyperlactic acidemia, stroke-like symptoms), diabetes due to mitochondrial gene mutation, cardiomyopathy, Alzheimer dementia, deafness, retinal degenerative disease Etc. regarding preventive or therapeutic drugs.

[0002]

2. Description of the Related Art Mitochondrial diseases include, specifically, chronic progressive external ophthalmoplegia syndrome (CPEO), MERRF (myoclonus epilepsy with mitochondrial abnormalities with red rag fibers), MELAS (mitochondrial myopathy encephalopathy hyperlactic acidemia, stroke (Ota; Biochemistry 6
7 15 1995, Ota, Yasukawa; Cell Engineering 19 596 2000), which means the entire genetic disease caused by mutation of mitochondrial genes, especially t-RNA (Yasukawa, T.et.al .: J Biol Chem 2
75 4254 2000, FEBS Letters 467 175 2000). Recently, diabetes (van den Ouweland, JM et.al .: Nat Genet 1 368
1992, Kadowaki, T. et.al .: N Engl J Med 330 962 199
4, Hirai, M et.al .: J Clin Endocrinol Metab 83 992
1998) and Alzheimer's dementia (Ito, S. et.al.:Proc N
Atl AcadSci USA 96 2099 1999) has also become known to be involved in mitochondrial gene mutations.

The most important function of mitochondria is
Aerobic and oxidative reaction functions for energy production and apoptosis. In particular, the oxidative metabolism function is different from the apoptotic function, and most of the proteins involved are based on mitochondrial genes, and the effects of mutations appear strongly. Therefore, it is considered that many mitochondrial diseases are due to abnormalities in the internal respiratory and oxidative metabolism of cells for energy production. Generally, there is no fundamental cure for gene diseases except for gene therapy, and it is unavoidable to rely on symptomatic treatment. Mitochondrial disease is no exception to this, and it is the present condition that gene therapy has not been established and remains within the scope of symptomatic therapy. It is no exaggeration to say that there is almost no effective drug therapy, and it is physically It has caused great pain not only economically but also mentally.

[0004]

The object of the present invention is to provide a safe and highly effective mitochondrial orally administered mitochondrial disease, especially chronic progressive external ophthalmoplegia syndrome (CPEO), MERR.
F (myoclonus epilepsy with mitochondrial abnormality with red rag fibers), MELAS (mitochondrial myopathy encephalopathy hyperlactic acidemia, stroke-like symptoms), diabetes due to mitochondrial gene mutation, cardiomyopathy, Alzheimer's dementia, deafness, retinal degenerative disease The purpose is to provide preventive and therapeutic drugs.

[0005]

[Means for Solving the Problems] Mitochondrial disease is a disease caused by an abnormality in cell function caused by mutation of mitochondrial gene, particularly mitochondrial t-RNA gene. Therefore, the present inventor first prepares Hela cells lacking mitochondrial DNA, separately from this, creates enucleated cells from which the mitochondrial gene mutant cells of the patient have been extracted, and then fuses both to produce abnormal mitochondrial only. Others made normal cells (cybrids) and confirmed that the respiratory ability (oxygen consumption) of these cells was impaired. Furthermore, the present inventor, as a result of diligently searching for a substance that improves dysfunction of a mutant mitochondrial gene using this recovery action as an index, surprisingly found that taurine and its related substances have that effect, and completed the present invention. .

That is, the present invention is one or two selected from the group consisting of taurine, taurine chloramine, a stream-containing amino acid which is a precursor of these in vivo, a pharmacologically acceptable salt thereof, and a taurine derivative. It is a prophylactic or therapeutic drug for mitochondrial diseases or diseases involving mitochondrial gene mutations, which comprises one or more species as active ingredients.

In the present invention, mitochondrial diseases are chronic progressive external ophthalmoplegia syndrome (CPEO), MERRF
(Myoclonus epilepsy with mitochondrial abnormality with red rag fibers), MELAS (mitochondrial myopathy encephalopathy hyperlactic acidemia, stroke-like symptom), and diseases associated with mitochondrial gene mutation are diabetes due to mitochondrial gene mutation, mitochondria It means cardiomyopathy due to gene mutation, Alzheimer's dementia due to mitochondrial gene mutation, hearing loss due to mitochondrial gene mutation, and retinal degenerative disease due to mitochondrial gene mutation.

In the present invention, the amino acids which are the precursors of taurine and taurine chloramine in vivo are methionine, S-adenosylmethionine, S-adenosylhomocysteine, homocysteine, cystathionine, cysteine, cystine and cystine. These are disulfoxide, cystamine disulfoxide, cystamine, coenzyme A, cysteamine, citaldimine, thiocysteamine, cysteine sulfinic acid, inorganic sulfate, cysteic acid, and hypotaurine. Taurine chloramine is a chlorine-added product of taurine produced by the reaction of hypochlorous acid generated from hydrogen peroxide by the action of myeloperoxidase in cells such as white blood cells with taurine. When the added chlorine is one, it is called taurine monochloramine, and when it is two, it is called taurine dichloramine, and taurine chloramine in the present case includes both.

The taurine derivative is N-methyltaurine, N, N-dimethyltaurine, N, N, N-trimethyltaurine, guanidinoethanesulfonic acid, guanidinoethanesulfinic acid, N- (2-acetamide) -2.
-Aminoethanesulfonic acid, piperazino-N, N'-bis (2-ethanesulfonic acid), N- [1'-aza-cycloheptane-2'-yl] -2-aminoethanesulfonic acid, N- [1 '-Aza-cyclopentane-2'yl] -2
-Aminoethanesulfonic acid, N- [1'aza-cycloheptane-2'-yl] -3-aminopropanesulfonic acid, N- [1'-aza-cyclopentan-2'-yl]-
3-aminopropanesulfonic acid, 2-aminoethylphosphonic acid, 3-aminopropionic acid, ethanolamine-
O-sulfate, aminomethanesulfonic acid, homotaurine, pyridine-3-sulfonic acid, piperidine-3-sulfonic acid, aniline-2-sulfonic acid, (±) -2-aminocyclohexanesulfonic acid, 2-aminocyclopentanesulfonic acid , Quinoline-8-sulfonic acid, 1,2,
3,4-tetrahydroquinoline-8-sulfonic acid, 3-
Amino-bicyclo [2.2.1] heptane-2-sulfonic acid, 6-aminomethyl-3-methyl-4-1,2,4-benzothiadiazine-, 1-dioxide (TAG), glycine, Retinylidene taurine (TAURET) 3-acetamido-1-propanesulfonic acid Ca salt (ACAMP
ROSATE), 5-taurinomethyluridine, 5-taurinomethyl-2-thiouridine, isethionic acid, cysteine sulfonic acid, litralone, 2-amino-3-hydroxy-1-propanesulfonic acid, N- (2,3-dihydroxy-). n-propyl) taurine, decanoyl sarcosyl taurine, seripin, and GABA are all included.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The active ingredient of the present invention, such as taurine, can be generally taken once or several times a day. The dose varies depending on the symptoms, but is 0.1 g / day to 15 g / day. Taurine, which is the active ingredient of the present invention, may be used as it is or as required, and other known additives such as excipients, disintegrating agents, binders, lubricants, antioxidants, coating agents, coloring agents, and taste masking agents. Granules, powders, powders,
Capsules, tablets, dry syrups, chewable tablets,
It can be an oral preparation such as a candy, a liquid preparation, and a jelly.

Examples of the excipient include mannitol, glucose, sucrose, lactose, cellulose, starch, carboxyvinyl polymer, light anhydrous silicic acid, titanium oxide, magnesium aluminometasilicate, polyethylene glycol, medium chain fatty acid triglyceride and the like. To be Examples of the disintegrator include low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, starch, crystalline cellulose, hydroxypropyl starch, partially pregelatinized starch and the like. As the binder, for example, methyl cellulose, hydroxypropyl cellulose,
Examples thereof include gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, agar and the like. Examples of the lubricant include magnesium stearate, talc, white beeswax, and the like.

Examples of antioxidants include dibutylhydroxytoluene (BHT), propyl gallate, and butylhydroxyanisole (BHA). Examples of the coating agent include hydroxypropyl cellulose, methyl cellulose, polyvinyl acetal diethylaminoacetate and the like. As a colorant,
Examples thereof include tar dyes and titanium oxide. Examples of the flavoring agent include citric acid, adipic acid, ascorbic acid, menthol and the like. Examples of the surfactant include polyoxyethylene hydrogenated castor oil, glyceryl monostearate, sodium lauryl sulfate, macrogols and sucrose fatty acid ester. Examples of the plasticizer include triethyl citrate, triacetin, cetanol and the like.

[0013]

INDUSTRIAL APPLICABILITY According to the present invention, it was found that taurine and the like are effective as prophylactic or therapeutic agents for mitochondrial diseases and diseases involving mitochondrial gene abnormalities.

[0014]

EXAMPLES The present invention will be described in more detail with reference to Examples and Test Examples. Example 1 Prescription example (in one package) Taurine 3000 mg Powdered sugar 600 mg Erogir 36 mg Aspartame 9 mg Low-substituted hydroxypropylcellulose 54 mg A granule having the above-mentioned formulation was produced by a conventional method.

Example 2 Prescription example (1 package) Taurine 3000mg Vitamin E 100mg Powdered sugar 600mg Aspartame 9mg Low-substituted hydroxypropyl cellulose 54mg Magnesium stearate 24 mg Dye Fragrance Granules having the above formulation were produced by a conventional method.

Example 3 Prescription example (1 package) Cysteine 160mg Powdered sugar 600mg Erogir 36 mg Aspartame 9mg Low-substituted hydroxypropyl cellulose 54mg Granules having the above formulation were produced by a conventional method.

Embodiment 4 Prescription example (1 package) Cystine 0.3mg Vitamin E 100mg Powdered sugar 600mg Aspartame 9mg Low-substituted hydroxypropyl cellulose 54mg Magnesium stearate 24 mg Dye Fragrance Granules having the above formulation were produced by a conventional method.

Example 5 Prescription example (1 package) Methionine 200mg Powdered sugar 600mg Erogir 36 mg Aspartame 9mg Low-substituted hydroxypropyl cellulose 54mg Granules having the above formulation were produced by a conventional method.

Test Example [Action of taurine on dysfunctional cells having mitochondrial gene mutation] (Test method) Mitochondrial tRNA ^{Leu (UUR)}
Of 3 types of enucleated cells from fibroblasts of MELAS patients with mitochondrial disease due to point mutations of 3243 or 3271 of the DNA sequence that controls DNA, and MERRF patients with 8344 point mutation of tRNA ^Lys (Represented as MELAS3243, MELAS3271, MERRF8344, respectively) and then He containing no mitochondrial DNA
La cells were fused to prepare three types of cybrid cells each having an abnormality only in mitochondria.

It has already been confirmed that the cybrid cells having a mutation in such a mitochondrial gene have a reduced respiratory ability (oxygen consumption). These cells were cultured for 4 days with 10-50 mM taurine. After culturing, the cells were washed once and suspended in a normal medium containing 10% calf serum. The number of cells was adjusted to 5 × 10 ⁷ cells / ml under a microscope, 2 ml of the cells were taken, and the oxygen consumption rate was measured at 37 ° C. using a Clark-type electrode. As control cells, cybrid cells prepared in the same manner using normal human fibroblasts and HeLa cells were used. The results are shown in Fig. 1.

(Experimental Results and Discussion) Mitochondrial tR
Control cells with no mutation in NA had no effect on their respiratory ability by taurine, while all cells with a tRNA mutation had their respiratory ability enhanced by taurine. Mutations in the mitochondrial tRNA gene have already been detected in MELAS and MER.
Since it has been confirmed that it causes RF and that these mutant cells have reduced respiratory ability compared to normal cells, this test example improves taurine's functional abnormality such as oxygen consumption ability due to mitochondrial gene mutation. It shows that you do.

[0022]

[Brief description of drawings]

FIG. 1 shows the oxygen consumption rate ratio on the vertical axis when the taurine is not added, and the horizontal axis shows the taurine concentration added to the medium. Each graph in the figure shows control cells (□), MELA
S3243 (◇), MELAS3271 (△), MER
The graph shows how the oxygen consumption rate ratio of each cybrids of RF8344 (◯) changes with taurine at various concentrations.

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Claims (4)

[Claims] 1. One or more selected from the group consisting of taurine, taurine chloramine, a stream-containing amino acid which is a precursor of these in vivo, a pharmacologically acceptable salt thereof, and a taurine derivative are effective. A preventive or therapeutic drug for mitochondrial disease, which is a component. 2. The mitochondrial disease is chronic progressive external ophthalmoplegia syndrome (CPEO), MERRF (myoclonic epilepsy with mitochondrial abnormality with red rag fibers)
Or MELAS (mitochondrial myopathy encephalopathy hyperlactic acidemia,
The preventive or therapeutic agent for mitochondrial disease according to claim 1, which is a stroke-like symptom. 3. One or more selected from the group consisting of taurine, taurine chloramine, amino acids containing these as precursors in vivo and pharmacologically acceptable salts thereof, and taurine derivatives are effective. A preventive or therapeutic drug for a disease involving a mitochondrial gene mutation as a component. 4. A disease associated with a mitochondrial gene mutation is diabetes due to a mitochondrial gene mutation, cardiomyopathy due to a mitochondrial gene mutation, Alzheimer's dementia due to a mitochondrial gene mutation, deafness due to a mitochondrial gene mutation, or retinal degenerative disease due to a mitochondrial gene mutation. The preventive or therapeutic drug for a disease associated with the mitochondrial gene mutation according to claim 3.