JP7366408B2 - Preventive and therapeutic agents for lysosomal diseases - Google Patents

Description

The present invention relates to a prophylactic or therapeutic agent for lysosomal diseases. More specifically, the present invention relates to a prophylactic or therapeutic agent for lysosomal diseases containing an HMG-CoA reductase inhibitor.

Lysosomal diseases (hereinafter sometimes abbreviated as "LSD") are caused by genetic defects in acid degrading enzymes in lysosomes or genetic abnormalities that cause lysosomal dysfunction. Due to their deficiency, various substrates and unnecessary substances accumulate in lysosomes, resulting in various problems such as enlargement of the liver and spleen, bone deformities, neurological disorders (convulsions, intellectual disabilities, etc.), eye disorders, kidney disorders, heart failure, etc. It is a disease that exhibits symptoms and is designated as an intractable disease by the Ministry of Health, Labor and Welfare.

Many causes of LSD are genetic defects in acid-degrading enzymes in lysosomes, and they are classified into many diseases depending on the substrates that accumulate and the types of enzymes that are defective (Gaucher disease, Fabry disease, Niemann-Pick disease, GM1). gangliosidosis, mucopolysaccharidosis type I, etc.).

Currently, several enzyme replacement therapies are being used as therapeutic agents for LSD. For example, for Fabry disease, Repregal ^TM (Dainippon Sumitomo Pharma) and Fabrazyme ^TM (JCR Pharma) are on the market, and for Pompe disease, Myozyme ^TM (Sanofi) is on the market and is being administered. However, although these enzyme replacement therapies show certain effects such as improvement of clinical symptoms and prolongation of survival time, they are not effective against 1) central nervous system symptoms or skeletal muscle symptoms, 2) appearance of autoantibodies, and 3) allergic reactions. , 4) There are problems such as autophagy dysfunction. In particular, enzyme replacement therapy using ^MyozymeTM improves life prognosis, but has no effect on skeletal muscle symptoms and does not improve motor function. In addition, central nervous system symptoms do not improve. The cause of this has been reported to be autophagy dysfunction caused by the accumulation of excessive autophagosomes called autophagy buildup (Non-Patent Document 1).

By the way, the induced pluripotent stem cells (hereinafter referred to as "iPS cells") established by Yamanaka et al. (Patent Document 1) can be differentiated into cells of various tissues, so it is difficult to reproduce pathological conditions in vitro. is considered possible. In fact, iPS cells derived from patients with various incurable diseases have been produced using the above method, differentiated into target cells, and screened for therapeutic agents. The present inventors previously expressed exogenous MyoD and Myf5 in pluripotent stem cells cultured under conditions that do not specifically induce skeletal muscle cells, and by regulating the expression period, the skeletal muscle cells were extracted from pluripotent stem cells. We have established a method for efficiently inducing differentiation of muscle cells (Patent Document 2), and have used this method to establish model cells for the disease from iPS cells derived from Pompe disease patients (Non-Patent Document 2).

WO 2008/118820 A2 WO 2013/073246 A1

Fukuda, T. , and H. Sugie. Brain and nerve = Shinkeikenkyu no Shinpo 67.9 (2015): 1091-1098. Yoshida, T. et al. , Sci. Rep. , 7:13473 (2017)

An object of the present invention is to provide a new preventive and/or therapeutic agent for LSD that is more effective and has fewer side effects.

In order to achieve the above object, the present inventors established iPS cells from fibroblasts derived from Pompe disease patients, and used the differentiation induction method developed by the present inventors (Patent Document 2 above) to induce muscle cells. Differentiation was induced into Here, focusing on the fact that autophagosomes were accumulated in the obtained muscle cells, a test compound was brought into contact with the muscle cells, and a compound that reduced the accumulation of autophagosomes was screened. As a result, it was found that an HMG-CoA reductase (hereinafter also referred to as "HMGCR") inhibitor reduces the accumulation of autophagosomes. Furthermore, in experiments using myocytes differentiated from iPS cells derived from patients with distal myopathy with rimmed vacuoles (GNE myopathy), another LSD, we confirmed that HMGCR inhibitors reduced the accumulation of autophagosomes.
Based on these findings, the present inventors concluded that HMGCR inhibitors are effective in preventing and/or treating LSD, and completed the present invention.

That is, the present invention is as follows.
[1] A prophylactic or therapeutic agent for lysosomal diseases containing an HMG-CoA reductase inhibitor.
[2] The agent according to [1], wherein the HMG-CoA reductase inhibitor is lovastatin.
[3] The agent according to [1] or [2], wherein the lysosomal disease is Pompe disease or GNE myopathy.
[4] A method for preventing or treating lysosomal disease in a subject, the method comprising administering to the subject an effective amount of an HMG-CoA reductase inhibitor.
[5] The method according to [4], wherein the HMG-CoA reductase inhibitor is lovastatin.
[6] The method according to [4] or [5], wherein the lysosomal disease is Pompe disease or GNE myopathy.
[7] HMG-CoA reductase inhibitor for use in the prevention or treatment of lysosomal diseases.
[8] The inhibitor according to [7], wherein the HMG-CoA reductase inhibitor is lovastatin.
[9] The agent according to [7] or [8], wherein the lysosomal disease is Pompe disease or GNE myopathy.

According to the present invention, it is possible to improve autophagy dysfunction, which is a pathological condition common to LSD, but which could not be intervened with conventional enzyme replacement therapy, and therefore can be used as an effective new preventive and/or therapeutic means for LSD. Be expected.

FIG. 3 is a diagram showing the results of screening for LSD preventive/therapeutic drugs. The horizontal axis shows the fluorescence intensity, and the vertical axis shows the area of intracellular autophagy vesicles. FIG. 3 shows that lovastatin suppresses the expression of autophagy marker LS3 in Pompe disease-specific muscle cells. FIG. 3 is an electron micrograph showing the therapeutic effect of lovastatin on Pompe disease-specific muscle cells. FIG. 3 is an electron micrograph showing the therapeutic effect of lovastatin on Pompe disease-specific muscle cells. FIG. 3 shows that lovastatin abolishes autophagic vacuoles in GNE myopathy-specific myocytes. FIG. 3 is an electron micrograph showing the therapeutic effect of lovastatin on GNE myopathy-specific muscle cells.

The present invention provides a prophylactic and/or therapeutic agent for lysosomal disease (LSD) containing an HMG-CoA reductase (HMGCR) inhibitor (hereinafter also referred to as "preventive/therapeutic agent of the present invention").

LSD, which is the target of treatment in the present invention, is caused by defects in enzymes related to lysosomes, which cause substances to be degraded to accumulate as waste products, inhibit fusion between lysosomes and autophagosomes, and cause autophagosomes to accumulate and inhibit autophagy. There are no particular restrictions as long as the disease exhibits a dysfunctional pathology, such as Pompe disease, in which glycogen accumulates due to α-glucosidase (GAA) deficiency, and UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. (GNE)-deficient distal myopathy with rimmed vacuoles (GNE myopathy), GM1 gangliosidosis, GM2 gangliosidosis, metachromatic leukodystrophy (MLD), Fabry disease (α-galactosidase A deficiency), Fabry diseases, Gaucher disease (β-glucocerebrosidase deficiency), Niemann-Pick disease (types A, B, C), diseases in which sphingolipids accumulate such as Krabbe disease, mucopolysaccharidosis (types I-VII), Danon's disease, Examples include, but are not limited to, α-mannosidosis, preferably Pompe disease or GNE myopathy.

The HMG-CoA reductase (HMGCR) inhibitor, which is the active ingredient of the prophylactic/therapeutic agent of the present invention, is not particularly limited as long as it is a compound having the activity of inhibiting the enzymatic activity of hydroxymethylglutaryl-CoA reductase, and is derived from microorganisms. natural substances, semi-synthetic substances derived therefrom, and fully synthetic compounds, such as (+)-(1S,3R,7S,8S,8aR)-1,2,3,7,8, 8a-Hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthyl(S)- 2-Methylbutyrate (lovastatin, see JP-A-57-163374 (USP 4231938)), (+)-(1S,3R,7S,8S,8aR)-1,2,3,7,8,8a- hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthyl 2,2-dimethylbuty rate (simvastatin, see JP-A-56-122375 (USP 4444784)), (±)(3R*,5S*,6E)-7-[3-(4-fluorophenyl)-1-(1-methylethyl) )-1H-indol-2-yl]-3,5-dihydroxy-6-heptenoic acid (fluvastatin, see Japanese Patent Application Publication No. 60-500015 (USP 4739073)), (3R,5S)-7-[ 2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-phenylaminocarbonyl-1H-pyrrol-1-yl]-3,5-dihydroxyheptanoic acid (atorvastatin, esp. (See Japanese Patent Publication No. 3-58967 (USP5273995)), (1S,7R,8S,8aR)-8-{2-[(2R,4R)-4-hydroxy-6-oxotetrahydro-2H-pyran-2-yl ] Ethyl}-7-methyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl (2S)-2-methylbutanoate (mevastatin, Journal of Antibiotics (Tokyo) 29 (12) :1346-8 (1976)), (3R,5S,6E)-7-[4-(4-fluorophenyl)-5-(methoxymethyl)-2,6-bis(propan-2-yl)pyridine- 3-yl]-3,5-dihydroxyhept-6-enoic acid (cerivastatin, Br J Pharmacol. 1999 Feb; 126(4):961-968. ), (+)-(3R,5R)-3,5-dihydroxy-7-[(1S,2S,6S,8S,8aR)-6-hydroxy-2-methyl-8-[(S)-2- methylbutyryloxy]-1,2,6,7,8,8a-hexahydro-1-naphthyl]heptanoic acid (pravastatin, see JP-A-57-2240 (USP 4346227)), (+)-(3R, 5S)-7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6(E)- Heptenoic acid (rosuvastatin, see JP-A-5-178841 (USP 5260440)) or (E)-3,5-dihydroxy-7-[4'-(4''-fluorophenyl)-2'-cyclopropylquinoline- 3'-yl]-6-heptenoic acid (pitavastatin, see JP-A-1-279866 (USP 5854259 and USP 5856336)). A preferred HMGCR inhibitor is lovastatin.

The above-mentioned statin compounds include closed lactones thereof or pharmacologically acceptable salts thereof (preferably sodium salts, calcium salts, etc.).

The prophylactic/therapeutic agent of the present invention can be prepared by preparing the active ingredient HMGCR inhibitor alone or by mixing it with a pharmacologically acceptable carrier, excipient, diluent, etc., and preparing a pharmaceutical composition in an appropriate dosage form. It can be administered orally or parenterally.

Compositions for oral administration include solid or liquid dosage forms, in particular tablets (including dragees and film-coated tablets), pills, granules, powders, capsules (including soft capsules), syrups. Examples include formulations, emulsions, suspensions, and the like. On the other hand, as compositions for parenteral administration, for example, injections, suppositories, etc. are used, and injections include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drip injections, etc. Dosage forms may also be included. These formulations contain excipients (e.g. sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, alpha starch, dextrin; cellulose derivatives such as crystalline cellulose; Gum arabic; dextran; organic excipients such as pullulan; and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and magnesium aluminate metasilicate; phosphates such as calcium hydrogen phosphate; carbonic acid carbonates such as calcium; inorganic excipients such as sulfates such as calcium sulfate), lubricants (such as stearic acid, metal salts of stearate such as calcium stearate, magnesium stearate; talc; Colloidal silica; waxes such as beeswax and gay wax; boric acid; adipic acid; sulfates such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; lauryl such as sodium lauryl sulfate and magnesium lauryl sulfate sulfates; silicic acids such as silicic anhydride and silicic acid hydrate; and the above-mentioned starch derivatives), binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the above-mentioned excipients) disintegrants (e.g. cellulose derivatives such as low-substituted hydroxypropylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose, internally cross-linked sodium carboxymethylcellulose; carboxymethyl starch, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone) emulsifiers (e.g. colloidal clays such as bentonite, vegum; metal hydroxides such as magnesium hydroxide, aluminum hydroxide; sodium lauryl sulfate, calcium stearate) anionic surfactants such as; cationic surfactants such as benzalkonium chloride; and nonionic surfactants such as polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid ester. ), stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; Dehydroacetic acid; .

The dosage of the HMGCR inhibitor may vary depending on various conditions such as the patient's symptoms, age, and weight.
The dosage varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 0.1 mg and the upper limit is 1000 mg (preferably 500 mg) per dose, and in the case of parenteral administration, the lower limit is 0.1 mg per dose. 0.01 mg up to 100 mg (preferably 50 mg) can be administered to adults 1 to 6 times per day. The dose may be increased or decreased depending on the symptoms.

The prophylactic/therapeutic agent of the present invention may be used in combination with other drugs, such as drugs conventionally used for the treatment of lysosomal diseases, such as enzyme replacement therapy agents (e.g., α-glucosidase (Pompe disease), α-galactosidase A (Fabry Gaucher's disease (β-glucocerebrosidase), etc.), pharmacological chaperone therapy agents, substrate reduction therapy agents, etc. may be used in combination. The prophylactic/therapeutic agents of the invention and these other agents can be administered simultaneously, sequentially or separately.

EXAMPLES The present invention will be described in more detail with reference to Examples below, but it goes without saying that the present invention is not limited thereto.

Example 1: Pharmacological evaluation using iPS cells established from Pompe disease patients (1) Fibroblasts derived from Pompe disease patients After culturing 4 mm of biopsied skin for 3 weeks, they were cultured as fibroblasts derived from Pompe disease patients. Using.

(2) iPS cell induction Human cDNAs for KLF4, Sox2, Oct3/4 and c-Myc were injected into the fibers using a retrovirus according to the method described in Takahashi K, et al, Cell 131(5), 861, 2007. introduced into blast cells. On the 6th day after the introduction, the fibroblasts were transferred onto SNL feeder cells, and the next day, the medium was replaced with a culture medium for primate ES cells supplemented with 4 ng/ml bFGF (Wako). The medium was replaced every other day, and colonies were picked up 30 days after gene introduction.

(3) Induction of skeletal muscle cell differentiation A tetracycline-responsive MyoD expression vector was introduced into the above Pompe disease patient-derived iPS cells (Tanaka et al. Plos One, 2013), and clones with good muscle differentiation (MyoD-hiPSC) were generated. Selected.
MyoD-hiPSCs were seeded on Matrigel (BD) coated dishes or i-matrix (Nikki) in the absence of feeder cells. Matrigel was diluted 1:50 in primate ES medium. MyoD-hiPSCs were trypsinized and dissociated into single cells. The number of cells per well of a 96-well culture plate ranged from 3.0×10 ³ to 1.0×10 ⁴ . The culture medium was changed to human iPS medium without bFGF and with 10 μM Y-27632 (wako). After 24 hours, it was added to AK02N or AK03 (Ajinomoto) human iPS culture medium containing 1 μg/mL doxycycline (LKT Laboratories). Knockout Serum Replacement (KSR) (Invitrogen), 50 mU/L penicillin/50 μg/L streptomycin (Invitrogen), 1 μg/mL doxycycline (LKT Laboratories) and 100 μM 2-mercaptoethanol (2-ME) (Invitrogen) added Changed to Cell culture was continued until 5 days later to induce differentiation into skeletal muscle cells. All these cultures were performed by incubating at 37° C., 5% CO ₂ and a humidified atmosphere. By this method, MHC-positive cells were obtained, and induction of differentiation into skeletal muscle cells was confirmed.

(4) Screening method and pharmacological evaluation of LSD preventive/therapeutic drugs using autophagy as an indicator. ), for screening, add various compounds at a final concentration of 3 μM; for pharmacological evaluation, add either a final concentration of 10, 3, 1, 0.3, 0.1, 0.03, 0.01, or 0.003 μM. and incubated for 48 hours. Thereafter, the cells were collected and stained using a kit capable of detecting autophagy, the Cyto-ID autophagy detection kit (Enzo Life Science, Inc.). Moreover, the staining method followed the method attached to the kit. The cell-stained plate was measured and analyzed using ArrayScan (Thermo Scientific). Compounds were evaluated using a scatter diagram using the fluorescence value and area of intracellular autophagy as indicators for evaluation (Figure 1). Among them, a group of HMGCoA inhibitors that reduce the autophagy area was one of them, and one of them was lovastatin.

(5) Pharmacological evaluation method of LSD preventive/therapeutic drugs using LC3 as an index Among the statins discovered by HTS screening, lovastatin was evaluated as a representative compound. A base (0.3% dimethylsulfoxide (DMSO)) and lovastatin at final concentrations of 10, 3, 1, and 0.3 μM were added to the diseased iPS cell-derived skeletal muscle cells obtained in (3) above for 48 hours. Incubated. Differentiated cells were fixed with 4% paraformaldehyde (WAKO)/PBS for 10 min at room temperature, washed with PBS, and then incubated with 0.5% Triton X-100 (Sigma-Aldrich) in PBS (Nacalai Tesque). permeabilization was performed at room temperature for 10 minutes. Thereafter, the plate was washed with PBS, blocked using Blocking one (Nacalai Tesque) at 4°C for 30 minutes, and then washed again with PBS. As the primary antibody, rabbit monoclonal antibody (mAb) anti-LC3B (1:200; Cellsignaling) was diluted in the above 10% blocking one solution. Cells were reacted at 4°C for 5 hours and washed with PBS. Next, Alexa fluor488-conjugated anti-rabbit IgG goat antibody (1:500; Invitrogen) as a secondary antibody and Hoechst 33342 for nuclear staining (1:10000; Dojindo) were diluted in the 10% blocking one solution, respectively. The reaction was allowed to proceed at room temperature for 1 hour. After washing with PBS, it was measured and analyzed using ArrayScan (Thermo Scientific). As a result, it was confirmed that LC3, a typical marker protein for autophagy, was expressed more in muscle cells derived from disease than in muscle cells derived from healthy subjects, but it decreased in a concentration-dependent manner in the lovastatin treatment group. (Figure 2).

(6) Pharmacological evaluation of LSD preventive/therapeutic agents using electron microscopy The effects of lovastatin were also evaluated using electron microscopy. A base (0.3% dimethylsulfoxide (DMSO)) and lovastatin at a final concentration of 10 μM were added to the diseased iPS cell-derived skeletal muscle cells obtained in (3) above, and incubated for 48 hours. Thereafter, cells were collected and fixed with 2% paraformaldehyde and 2% glutaraldehyde for 30 minutes. After washing three times with PBS, samples were fixed with 2% osmium in PBS for 1 hour at 4°C. After polymerization at 60° C. for 48 hours, sections were cut out and observed using a transmission electron microscope (JEOL). As a result, in the lovastatin-untreated group, autophagic vacuoles (black arrows in Figure 3) in which many glycogen granules accumulated, which is a pathological condition of Pompe disease, were observed, but in the lovastatin-treated group, autophagic vacuoles disappeared. , an electron microscopic image closer to that of muscle differentiated cells derived from healthy individuals was obtained (Figure 4). From the above, there are many findings regarding the effects on cells due to dysregulation of autophagy function (Galluzzi et al. Nature Reviews Drug Discovery 16:487-511, 2017 and Parenti et al. Annual review of medici ne 66:471-486, 2015 ), it was suggested that lovastatin is useful for the prevention and treatment of lysosomal dysfunction in LSD and the associated excessive accumulation of autophagy.

Example 2: Pharmacological evaluation using iPS cells established from patients with distal myopathy with edging vacuoles (GNE myopathy) (1) Fibroblasts derived from patients with GNE myopathy 4 mm of biopsied skin was cultured for 3 weeks Thereafter, the cells were used as fibroblasts derived from patients with GNE myopathy.

(2) iPS cell induction Human cDNA for OCT3/4, SOX2, KLF4, L-Myc, LIN28 and shRNA-p53 were added to an episomal vector according to the method described in Okita K, et al, Nature Methods, 2011. was used to introduce the fibroblasts into the fibroblasts. On the 6th day after the introduction, the fibroblasts were transferred onto SNL feeder cells, and the next day, the medium was replaced with a culture medium for primate ES cells supplemented with 4 ng/ml bFGF (Wako). The medium was replaced every other day, and colonies were picked up 30 days after gene introduction.

(3) Induction of skeletal muscle cell differentiation A tetracycline-responsive MyoD expression vector was introduced into the above GNE myopathy patient-derived iPS cells (Tanaka et al. Plos One, 2013), and clones with good muscle differentiation (MyoD-hiPSC) were generated. Selected.
MyoD-hiPSCs were seeded on Matrigel (BD) coated dishes or i-matrix (Nikki) in the absence of feeder cells. Matrigel was diluted 1:50 in primate ES medium. MyoD-hiPSCs were trypsinized and dissociated into single cells. The number of cells per well of a 96-well culture plate ranged from 3.0×10 ³ to 1.0×10 ⁴ . The culture medium was changed to human iPS medium without bFGF and with 10 μM Y-27632 (wako). After 24 hours, it was added to AK02N or AK03 (Ajinomoto) human iPS culture medium containing 1 μg/mL doxycycline (LKT Laboratories). After another 24 hours, the culture solution was supplemented with α minimal essential medium (αMEM) (Nacalai Tesque) containing 5% Knockout Serum Replacement (KSR) (Invitrogen), 50 mU/L penicillin/50 μg/L streptomycin (Invitrogen), and 1 μg/mL. Doxycycline (LKT Laboratories) and 100 μM 2-mercaptoethanol (2-ME) (Invitrogen) were added. Cell culture was continued until 5 days later to induce differentiation into skeletal muscle cells. All these cultures were performed by incubating at 37° C., 5% CO ₂ and a humidified atmosphere. By this method, MHC-positive cells were obtained, and induction of differentiation into skeletal muscle cells was confirmed.

(4) Pharmacological evaluation using autophagy as an index Lovastatin was evaluated for GNE myopathy. Lovastatin at a final concentration of 10 μM was added to the muscle-differentiated cells, and after incubation for 48 hours, evaluation was performed using an autophagy detection kit, Cyto-ID autophagy detection kit 2.0 (Enzo Life Science, Inc.). The staining method followed the method attached to the kit. The cell-stained plate was measured and analyzed using ArrayScan (Thermo Scientific). As a result, it was confirmed that autophagy accumulation disappeared in the lovastatin treated group (FIG. 5).

(5) Pharmacological evaluation using an electron microscope The effects of lovastatin were also evaluated using an electron microscope. A base (0.3% dimethylsulfoxide (DMSO)) and lovastatin at a final concentration of 10 μM were added to the diseased iPS cell-derived skeletal muscle cells obtained in (3) above, and incubated for 48 hours. Thereafter, cells were collected and fixed with 2% paraformaldehyde and 2% glutaraldehyde for 30 minutes. After washing three times with PBS, samples were fixed with 2% osmium in PBS for 1 hour at 4°C. After polymerization at 60°C for 48 hours, sections were cut out and observed with a transmission electron microscope (JEOL). As a result, in the lovastatin-untreated group, vesicles in which many aggregates had accumulated (black arrows in the upper panel of FIG. 6) were observed, but in the lovastatin-treated group, the vesicles disappeared (lower panel of FIG. 6).

According to the present invention, it is possible to improve autophagy dysfunction, which is a pathological condition common to LSD, but which could not be intervened with conventional enzyme replacement therapy. It is extremely useful in that it suppresses cell death due to damage/stress and mitochondrial dysfunction, and is expected to improve not only life prognosis but also skeletal muscle symptoms and central nervous system symptoms.

This application is based on Japanese Patent Application No. 2018-019698 filed in Japan on February 6, 2018, and by mentioning it here, the entire contents thereof are included in the present specification.

Claims (1)

A prophylactic or therapeutic agent for Pompe disease or distal myopathy with rimmed vacuoles ( GNE myopathy ) containing lovastatin, simvastatin, or cerivastatin .