• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Use of pharmacological chaperones for the treatment of lysosomal storage diseases. The invention relates to the use of galactose analogs of the formula (I) which have the ability to stabilize the structure of the α -GalA enzyme, to treat lysosomal storage diseases and, in a preferred embodiment, to treat the disease of Fabry. The present invention also relates to pharmacological compositions comprising an effective amount of at least one of the galactose analogues described herein for treating depot lysosomal diseases and, in a preferred embodiment, for treating Fabry disease. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2716305A1
    申请号:ES201731396
    申请日:2017-12-11
    公开日:2019-06-11
    发明作者:Saida Ortolano；Pereira Pedro Besada；Moldes Carmen Teran
    申请人:Fund Biomedica Galicia Sur；Universidade de Vigo；
    IPC主号:
    专利说明:

    [0001]
    [0002]
    [0003]
    [0004] SECTOR OF THE TECHNIQUE
    [0005]
    [0006] This invention is part of the pharmaceutical and chemical sector. More specifically, this document refers to the new use of pharmacological chaperones for the treatment of lysosomal storage diseases.
    [0007]
    [0008] BACKGROUND OF THE INVENTION
    [0009]
    [0010] Metabolic diseases known as storage or lysosomal storage diseases are known in the state of the art. The main cause of these diseases, is that an enzyme responsible for metabolizing a particular substrate, has some mutation in the gene that transcribes it, reducing and even nullifying its metabolic activity, causing the accumulation of its substrate.
    [0011]
    [0012] A well-known example of this type of disease is Fabry Disease (EF) which is a hereditary disease linked to the X chromosome and caused by a deficiency of a -galactosidase A (a-GalA), a hydrolytic enzyme expressed in lysosomes and encoded by the GLA gene (position Xq22). This deficit causes a misfolding of the enzyme, causing the accumulation of unmetabolized substrates such as globotriaosylceramide (Gb3) and other structurally related glycosphingolipids, such as globotriaosylphingosine (LysoGb3). Said deposits of non-metabolized substrates in the vascular endothelium and in other cells of different organs cause progressive systemic manifestations, such as renal failure, cardiomyopathy and juvenile stroke, which increase the risk of early mortality. Deposits also affect the quality of life of patients by causing other clinical manifestations such as chronic neuropathic pain, gastrointestinal disorders, to name a few.
    [0013]
    [0014] This disease is considered a rare disease since it has an incidence of approximately 1: 7000 live births, although experts indicate that the number of affected potential is growing, as observed in the data provided by the neonatal screening studies that are being carried out routinely in different countries.
    [0015]
    [0016] The current treatment for PE consists of enzyme replacement therapy (TSE), based on the intravenous administration of recombinant human a-GalA (agalsidase alfa and agalsidase beta). The TSE facilitates the elimination of vascular endothelium deposits and slows the progression of the disease, as well as improving some aspects of patients' quality of life, such as the reduction of pain crises.
    [0017]
    [0018] In this therapeutic field there are patent applications WO9811206A2 and US2004071686 (A1) which describe the treatment of a disease characterized by a-GalA deficiency, and particularly Fabry disease, by the administration of purified human alpha-galactosidase A which is obtained from the use of genetically modified cell lines to overexpress and secrete human recombinant alpha-galactosidase A.
    [0019]
    [0020] However, currently authorized enzymatic substitution treatments have a series of limitations among which are:
    [0021] 1. - Its administration is very uncomfortable for patients since it is intravenous, it must be done every 2 weeks (since the half-life of the drug in the body is low) and lasts 40-60 min.
    [0022] 2. - They do not present a homogeneous distribution in the patient's organism,
    [0023] 3. - They do not cross the blood-brain barrier (BBB), being inactive against the symptoms of the central nervous system.
    [0024] 4 There is a risk of inactivation of the drug due to the response of the adaptive immune system. 5.- These drugs of biological origin also have a high production cost during the process due to the high risk of contamination, which can lead to significant economic losses.
    [0025]
    [0026] There are also other therapeutic alternatives, such as gene therapy, in vivo or ex vivo that are in development. These therapies also combine the use of therapeutic molecules known in the state of the art with the definition of pharmacological chaperones (CFs), of which some of said pharmacological chaperones are already approved by the European Medicines Agency (European Medicines Agency). , EMA).
    [0027] In this therapeutic field, Dr. Fan's research group synthesized the first CF for EF therapy called 1-deoxygalactonojirimycin (DGJ), which is a competitive inhibitor of α-GalA. This iminoazucar is the active compound of deoxygalactonojirimycin hydrochloride (Galafold®, Amicus Therapeutics), a drug that has given good results in phase III clinical trials (NCT01458119; NCT00925301, https://clinicaltrials.gov) and in July 2016 has obtained the approval of the EMA for its commercialization. Said study is related to the EP2143420 B1 patent which describes the method to increase the activity of the A-α-lysosomal (±) in mammalian cells and for the treatment of Fabry disease by administration of DGJ and related compounds, and the application of Patent EP2874648A1 which describes the administration of the pharmacological compositions comprising this drug. It has been shown that DGJ is effective in low concentrations for those mutations responsible for the disease that cause a misfolding of the enzyme a-GalA which in turn prevents its transport from the endoplasmic reticulum, causing the accumulation of the mutated enzyme in said organelle . This accumulation of mutated α-GalA causes its aggregation and subsequent degradation, preventing said enzyme from reaching the lysosomes, which is where it must act. Therefore, the mechanism of action of this drug focuses on binding to the mutated enzyme to prevent its aggregation within the endoplasmic reticulum and subsequent degradation, thus allowing the mutated a-GalA to reach the lysosomes. However, this drug has a great limitation and is not effective for all mutations responsible for Fabry disease, and thus can be confirmed in the list of mutations that can be treated with DGJ published by the European Medicines Agency (tab Product technique for the Galafold EMA (Annex I), Spanish version (WC500208434)). The fact that DGJ is not effective for all the mutations responsible for Fabry disease, makes it necessary to look for other treatments capable of treating the greatest possible number of mutations of the GLA gene responsible for this disease, with special emphasis on those mutations of said gene. responsible for phenotypes of the disease are not available an effective oral treatment.
    [0028]
    [0029] There is, therefore, the need to develop new drugs that allow the treatment of lysosomal depositional diseases caused by the decrease and, in some cases, inactivity of the enzymes involved in metabolizing the substrates present inside the lysosomes, by a incorrect folding of these proteins, where said diseases still do not present an adequate and effective treatment, and even in some cases do not have treatment.
    [0030]
    [0031] In other words, it would be desirable to have effective treatments with a broad spectrum of action, based on increasing the efficacy of the mutated enzyme α-GalA responsible for lysosomal storage diseases.
    [0032]
    [0033] DESCRIPTION OF THE INVENTION
    [0034]
    [0035] The object of the present invention is the use of galactose analogs of the formula (I) which have the ability to stabilize the structure, favoring the correct folding of the enzyme a-galactosidase A (a-GalA). This fact causes that at certain concentrations, as set forth herein, the analogs of the formula (I) stabilize the structure of the enzyme a-galactosidase A, increasing the enzymatic activity of said enzyme.
    [0036]
    [0037] In a first aspect, the present patent application refers to the use of galactose analogs having the following formula:
    [0038]
    [0039]
    [0040]
    [0041]
    [0042] where R1 is selected from the group consisting of an azide (N3), a nitrile (CN), an amino (NH2), a ureido (NHCONH2), an aminomethyl (NHCH3), a methylamino (CH2NH2), a methylureido (CH2NHCONH2) and a halogen. In turn, the halogen can be I, Br, Cl and F.
    [0043]
    [0044] In the context of the present invention, these galactose analogues of the formula (I) are also called pharmacological chaperones since these molecules have a mechanism of action reminiscent of biological chaperones and are designed to stabilize the structure of certain target proteins. In this protection environment, said chaperones bind to the target protein, stabilizing its three-dimensional structure, thus allowing said mutated enzyme to acquire its correct folding and be able to perform its biological function.
    [0045]
    [0046] In the particular case of the present invention, the galactose analogues of the formula (I), which are described herein, are intended to stabilize the agalactosidase A.
    [0047]
    [0048] The pharmacological chaperones described herein have the ability to increase the enzymatic activity of the enzyme α-galactosidase A (α-GalA), wherein said enzyme comprises in turn at least one mutation that affects its folding.
    [0049]
    [0050] In the context of the present invention, the deficit of the α-GalA enzyme can be caused by at least one mutation, among the more than 600 mutations that are known in the GLA gene, and which are responsible for a misfolding of a-GalA. Illustrative examples are the mutations p.R301Q, p.Q279R, p.P205S, p.L131Q to demonstrate the efficacy of the galactose analogs of the formula (I), but in no case as an exclusion to other mutations of the G1_A gene that cause the decrease or inactivity of the enzyme to GalA, due to incorrect folding. In this document, as described below, when administering the galactose analogues of the formula (I) in cell cultures that exhibit any of the mentioned mutations, a significant increase in the activity of the α-GalA enzyme can be observed .
    [0051]
    [0052] Therefore, the galactose analogs described herein have the ability to bind to the mutated a-GalA enzyme, regardless of whether or not the mutation is in the active site, and stabilize its structure, thereby allowing its correct folding.
    [0053]
    [0054] The medical use of the galactose analogues of the formula (I), and in a preferred embodiment, the use of PB48 and PB51 is therefore the object of the invention. These compounds can bind to the active site of a-GalA and stabilize its structure to consequently increase its enzymatic activity.
    [0055]
    [0056] Analogue PB48 has the following formula:
    [0057]
    [0058]
    [0059]
    [0060] Analogue PB51 has the following formula:
    [0061]
    [0062]
    [0063]
    [0064]
    [0065] Said analogues PB48 and PB51 of galactose can bind to the active site of a-GalA by interacting with aspartic acid residues (D170, D231, D92, D93) and glutamic acid (E203).
    [0066]
    [0067] It should be noted that the analogs of the formula (I) which are described in the present invention are generally obtained as a mixture to the equilibrium of the alpha and beta isomers. For this reason, analogous compounds of the galactose of the formula (I), preferably PB48, PB51 or a combination thereof, are capable of treating depositional lysosomal diseases.
    [0068]
    [0069] It is therefore the object of the present invention to use at least one of the galactose analogs described herein to treat lysosomal storage diseases.
    [0070]
    [0071] In a preferred embodiment, the galactose analogues PB48 and / or PB51 are capable of intervening by acting on the folding of a-GalA to treat Fabry disease.
    [0072]
    [0073] In a preferred embodiment, the subject of the present invention is the use of at least one of the galactose analogs described herein for treating Fabry disease.
    [0074]
    [0075] The galactose analogues of formula (I), which are described herein, can be synthesized by following and / or adapting procedures described in the following documents bibliographical:
    [0076] • N. B. Hamadi, M. Msaddek, Synthesis and reactivity of N-sugar-maleimides: an Access to novel highly substituted enantiopure pyrazolines, Tetrahedron: Asymmetry, 2012, 23, 1689-1693.
    [0077] • M. Koketsu, B. Kuberan, R. J. Linhardt, Stereoselective synthesis of the a-glycoside of a KDO "C" -disaccharide, Organic Letters, 2000, 21, 3361-3363.
    [0078] • J. M. Benito, C. Ortiz Mellet, J. M. Garcia Fernandez, Synthesis of 6,7-dideoxy-7-isothiocyanatoheptoses: stable fully unprotected monosaccharide isothiocyanates, Carbohydrate Research, 2000, 323, 218-225.
    [0079] • R. W. Binkley, M. Ambrose, D. G. Hehemann, Synthesis of Deoxyhalogen Sugars. Displacement of the (Trifluoromethanesulfony1) oxy (Triflyl) Group by Halide Ion, Journal of Organic Chemistry, 1980, 45, 4387-4391.
    [0080]
    [0081] In the present document, a series of tests are described by way of illustration in which the enzymatic activity of a-GalA is measured to assess the efficiency of the molecules object of the present invention. Said enzymatic activity of α-GalA has been measured in cell lysates by adapting the fluorometric method described by Chamoles et al (Clin Chim Acta 308, 195 196). In synthesis, the assay was performed in 0.15M phosphate-citrate buffer at pH 4.2, using 4-methylumbelliferyl-aD-galactopyranoside 4mM (4-MU, # 44039, Glycosinth) as a substrate and in the presence of N-acetyl-D-galactosamine 50mM. The specific activity of the enzyme is referred to a standard curve of fluorescence / substrate concentration.
    [0082]
    [0083] Also object of the present invention are pharmacological compositions comprising an effective amount, in particular between 50 mg and 200 mg every two days, and in a preferred embodiment, said amount being between 145 mg and 155 mg every two days, and in an even more preferred embodiment being said amount of 150 mg every other day, of the galactose analogs of the formula (I) described herein.
    [0084]
    [0085] Based on the foregoing, the present invention relates to the above pharmacological compositions for treating deposit lysosomal diseases.
    [0086]
    [0087] In addition, in a preferred embodiment, it is also an object of the present invention the above pharmacological compositions for treating Fabry disease.
    [0088]
    [0089] In the context of the present invention, the effective amount is understood as the quantity minimum necessary to observe a therapeutic effect in patients suffering from a lysosomal deposit disease.
    [0090]
    [0091] In a preferred embodiment of the invention, effective amount is understood as the minimum amount necessary to be able to observe a therapeutic effect in patients suffering from Fabry disease.
    [0092]
    [0093] The galactose analogs of formula (I) described herein have a number of advantages over conventional treatments for lysosomal storage diseases:
    [0094] 1. - Compared to TSE therapies, the galactose analogs described in this document are biodistributed in a homogeneous way since, since they are small molecules, they are able to cross biological membranes, which may include the blood-brain barrier. In contrast, in TSE therapies, what is administered to the patient is recombinant α-GalA. Said recombinant enzyme enters the cells transported by the Mannosium-6-phosphate receptor, so that said recombinant enzyme does not reach the tissues that do not express this receptor.
    [0095] 2. The galactose analogs of formula (I) have the ability to bind with mutated GalA enzymes responsible for Fabry disease that it is not possible to treat with pharmacological chaperones currently in use by expanding the therapeutic spectrum of patients who can opt for oral treatment. As an example of the current treatments, the cells presenting the mutation Q279R or L131Q, to mention a few, show an increase in the activity of the mutated a-GalA, when treated with the galactose analogues of the formula (I) , while said enzymatic activity does not present the same increase or even activity when treated with the pharmacological chaperones that are approved and are currently used in the clinic.
    [0096] 3. - Much lower production cost, since the chemical chaperones are chemical compounds, their production costs and risk of contamination, with their consequent economic losses, are significantly lower than the production costs of substitution treatments enzymatic, whose drugs are biological.
    [0097]
    [0098] BRIEF DESCRIPTION OF THE FIGURES
    [0099]
    [0100] Figures 1.A and 1.B. Assessment of the increases in the enzymatic activity of α-GalA in a human cell line (293T) transfected with plasmids expressing different mutants of α-GalA: p.R301Q, p.Q279R, p.P205S, treated with galactose, PB48 and PB51. In Figure 1.A, the increase in the enzymatic activity of α-GalA is shown for the 3 indicated treatments at a concentration of 5 pM. In the case of figure 1.B, the 3 treatments employed are at a concentration of 10 pM. In both figures, 3 columns are observed for each of the mutations, representing the treatments to which the human cell line (293T) transfected with plasmids expressing different a-GalA mutants has been subjected. The column on the left (closest to the vertical coordinate axis) represents the cell line treated with galactose. The central column represents the cell line treated with PB48. In the right column (the one furthest from the vertical coordinate axis) represents the cell line treated with PB51. The activity increases have been calculated by subtracting for each value the activity value obtained for the untreated transfected with the corresponding plasmid.
    [0101]
    [0102] Figure 2. Assessment of the enzymatic activity of α-GalA in cells extracted from three hemizygous patients with Fabry disease expressing the p.Q279R mutation of α-GalA. Said cells were treated with PB48 at concentrations of 2.5 pM, 5 pM, 7.5 pM and 10 pM and with DGJ at concentrations of 2.5 pM, 5 pM and 10 pM.
    [0103]
    [0104] Figure 3. Assessment of the enzymatic activity of α-GalA in cells extracted from a hemizygous patient expressing the p.Q279R mutation of α-GalA. Said cells were treated with PB51 at concentrations of 2.5 pM, 5 pM, 7.5 pM and 10 pM and with DGJ at concentrations of 2.5 pM, 5 pM and 10 pM.
    [0105]
    [0106] Figure 4. Assessment of the enzymatic activity of α-GalA in a hemizygous patient with the mutation p.Q279R, a patient heterozygous with the mutation p.Q279R and healthy individuals, treated with PB48 at concentrations of 5 pM and 10 pM, PB51 at concentrations of 5 pM and 10 pM, DGJ at concentrations of 5 pM and 10 pM, and galactose at a concentration of 5 pM. For each of the treatments, 3 columns are observed, representing the cell groups that have been subjected to each of the treatments. The column on the left (closest to the vertical coordinate axis) represents the leukocytes extracted from peripheral blood from a hemizygous patient for the mutation Q279R (group of hemizygous cells). The central column represents leukocytes extracted from peripheral blood from a heterozygous patient. In the right column (the one furthest from the vertical coordinate axis) represents leukocytes extracted from peripheral blood from two healthy volunteers, one male and one female (control). In the vertical axis represents the activity of α-GalA, normalized to the untreated control.
    [0107]
    [0108] Figure.5 Assessment of the enzymatic activity of α-GalA with the p.L131Q mutation in cells extracted (from a hemizygous patient and a heterozygous patient) treated with PB48 at concentrations of 2.5 pM, 5 pM, 7.5 pM and 10 pM or with DGJ at concentrations of 2.5 pM, 5 pM and 10 pM. For each of the treatments, 2 columns are observed, representing the cell groups that have been subjected to each of the treatments. The column on the left (closest to the vertical coordinate axis) represents leukocytes extracted from peripheral blood from a hemizygous patient for the L131Q mutation. In the right column (the one furthest from the vertical coordinate axis) represents leukocytes extracted from peripheral blood from a patient heterozygous for the L131Q mutation.
    [0109]
    [0110] EXAMPLES
    [0111]
    [0112] Below we proceed to set forth, by way of example and without limitation, certain results of efficacy assays of the invention where the enzymatic activity of α-GalA was evaluated after treatment with pharmacological chaperones of formula (I) described herein. .
    [0113]
    [0114] Experiment 1:
    [0115] PB48 and PB51 analogues were tested at concentrations of 5 and 10 pM, compared to galactose, in a human cell line (293T) transfected with different plasmids expressing different mutants of a-GalA: p.R301Q, p.Q279R, p.P205S.
    [0116]
    [0117] As can be seen in Figures 1.A and 1.B, PB48 and PB51 produce a positive increase in the enzymatic activity of the different a-GalA mutants, highlighting the increase in activity of said a-GalA enzyme in the cells treated with PB48.
    [0118]
    [0119] Experiment 2:
    [0120] Similar studies were done on leukocytes extracted from peripheral blood from 3 hemizygous patients for the p.Q279R mutation. In this study the activity of a-GalA was evaluated in cells treated with PB48 at concentrations of 2.5 pM, 5 pM, 7.5 pM and 10 pM and with DGJ at concentrations of 2.5 pM, 5 pM and 10 pM. p.m. As can be seen in Figure 2, PB48 significantly increases the activity of a-Gal A at concentrations of 2.5 pM, 5 pM, 7.5 pM and it is more active than DGJ in cells from patients hemizygous for the p.Q297R mutation.
    [0121]
    [0122] On the other hand, the activity of α-GalA in cells from a hemizygous patient with the mutation p.Q279R treated with PB51 at concentrations of 2.5 pM, 5 pM, 7.5 pM and 10 pM and with DGJ at concentrations was also evaluated. of 2.5 pM, 5 pM and 10 pM, see figure 3.
    [0123]
    [0124] As can be seen in Figure 3, PB51 shows an increase in enzyme activity greater than DGJ. The treatment with PB51 at the concentration of 2.5 pM also determines an increase in activity with respect to the untreated cells.
    [0125]
    [0126] Therefore, these results demonstrate that the analogs described herein, and in particular PB48, are a very suitable alternative for patients suffering from Fabry disease, and that they can not be treated with DGJ, since a treatment based on DGJ does not present the necessary increase in the activity of mutated a-GalA to treat the disease, when the mutation of the GLA gene is Q279R.
    [0127]
    [0128] Experiment 3:
    [0129] Studies were carried out on the activity of a-GalA in leukocytes extracted from peripheral blood from a hemizygous patient for the mutation Q279R (group of hemizygous cells), a heterozygous patient and two healthy volunteers (one male and one female, indicated as control). ). In this study the activity of a-GalA was evaluated in cells treated with PB48 at concentrations of 5 pM, and 10 pM, another cell group treated with PB51 at concentrations of 5 pM, and 10 pM and with DGJ at concentrations of 5 pM and 10 pM. In order to compare the results obtained in the treatments with the galactose analogues that are described herein, assessments were made on the activity of a-GalA for the same group of cells, which were treated with galactose at concentrations of 5 pM, and a cell group without treatment.
    [0130]
    [0131] As can be seen in Figure 4, the PB48 causes at the concentration of 5 pM a greater increase in enzymatic activity with respect to the DGJ in the cells of the hemizygous patient and a significant increase in activity with respect to the untreated cells. The a-GalA activity values have been normalized to the untreated control, that is, the enzymatic activity value of α-GalA from the samples that have been subjected to each of the pharmacological treatments (PB48, DGJ or Gal) has been divided by the value of α-GalA activity obtained for the respective untreated control sample (activity value of α-GalA obtained for each patient's cells that have not received treatment).
    [0132]
    [0133] On the other hand, it has been observed that DGJ (5 pM) is more effective than PB48 (5 pM) as a protein stabilizer when tested in leukocytes of the heterozygous LSD21 patient. This leads to the conclusion that DGJ (5pM) can be a more efficient chaperone for the a-Gal A native form (wild type), while the PB48 at the same concentration is more efficient than the DGJ when the form is exclusively present mutated of the enzyme.
    [0134]
    [0135] The data obtained in healthy controls with the same concentration (5 pM) support this conclusion.
    [0136]
    [0137] Experiment 4:
    [0138] The compounds PB48 and DGJ were tested in cells of a hemizygous patient and a patient heterozygous with the p.L131Q mutation of α-GalA and also expressing the allele in a native (wild type) form of the enzyme, which produces the classical phenotype. of Fabry's disease.
    [0139]
    [0140] As seen in Figure 5, the enzymatic activity of α-GalA is significantly higher in cells from the hemizygous patient that have been treated with PB48 at the concentration of 5 pM compared to untreated cells and in cells that have been treated. been treated with DGJ. On the other hand, it can be verified that the enzymatic activity of α-GalA is higher in cells of the heterozygous patient treated with DGJ.
    [0141]
    [0142] Experiment 5:
    [0143] The analogs PB48, PB51 at concentrations of 2.5 pM, 5 pM, 10 pM and 20 pM, compared to DGJ and galactose, were tested in a non-transfected human (293T) cell line.
    权利要求:
    Claims (9)
    [1]
    1.- Use of a galactose analog represented by the following formula:

    [2]
    2.- Galactose analog represented by the following formula:

    [3]
    3. The galactose analogue according to claim 2, for use in the treatment of lysosomal storage diseases.
    [4]
    4 - Galactose analogue according to claim 2, wherein the enzyme is α-galactosidase A for the treatment of Fabry disease.
    [5]
    5. Galactose analog according to any one of claims 3 to 4, wherein R1 is select from the group consisting of N3 and CN.
    [6]
    6. Pharmacological composition comprising at least one galactose analog represented by the following formula:

    [7]
    7. Pharmacological composition according to claim 6, for the treatment of lysosomal storage diseases.
    [8]
    8. - Pharmacological composition according to claim 7, wherein the enzyme is agalactosidase A for the treatment of Fabry disease.
    [9]
    9. - Pharmacological composition according to any one of claims 7 or 8, wherein R1 is selected from the group consisting of N3 and CN.
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    同族专利:
    公开号 | 公开日
    WO2019115854A1|2019-06-20|
    ES2716305B2|2019-11-27|
    US20210179575A1|2021-06-17|
    EP3725310A1|2020-10-21|
    US11192874B2|2021-12-07|
    引用文献:
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    EP1538202B1|1996-09-13|2014-01-22|Shire Human Genetic Therapies, Inc.|Production of human alpha-galactosidase A|
    US6274597B1|1998-06-01|2001-08-14|Mount Sinai School Of Medicine Of New York University|Method of enhancing lysosomal α-Galactosidase A|
    CA2917995C|2012-07-17|2021-01-26|Amicus Therapeutics, Inc.|Alpha-galactosidase a and 1-deoxygalactonojirimycin co-formulation|
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    优先权:
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    ES201731396A|ES2716305B2|2017-12-11|2017-12-11|USE OF PHARMACOLOGICAL CHAPERONS FOR THE TREATMENT OF LISOSOMAL DEPOSIT DISEASES|ES201731396A| ES2716305B2|2017-12-11|2017-12-11|USE OF PHARMACOLOGICAL CHAPERONS FOR THE TREATMENT OF LISOSOMAL DEPOSIT DISEASES|
    US16/771,512| US11192874B2|2017-12-11|2018-12-10|Use of pharmacological chaperones for the treatment of lysosomal storage diseases|
    EP18852733.7A| EP3725310A1|2017-12-11|2018-12-10|Use of pharmacological chaperones for the treatment of lysosomal storage diseases|
    PCT/ES2018/070794| WO2019115854A1|2017-12-11|2018-12-10|Use of pharmacological chaperones for the treatment of lysosomal storage diseases|
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