Application of vitamin B12

Abstract

The invention relates to the technical field of vitamin B12, and discloses application of vitamin B12, which comprises application of vitamin B12 in preparation of a medicine for treating glycogen accumulation disease. The vitamin B12 disclosed by the invention can be applied to preparation of the medicine for treating the glycogen accumulation disease and can be used for treating the glycogen accumulation disease.

Description

Technical Field

[0001] This invention relates to the field of vitamin B12 technology, and more particularly to the uses of vitamin B12. Background Technology

[0002] Glucose metabolism provides a large amount of ATP for cellular life activities through coupled glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation. Excess glucose in the body is mainly stored as glycogen in the liver and muscles, with a small amount stored in brain tissue. Glucose and glycogen are interconverted through glycogenogenesis and glycogenolysis, respectively, thus playing a role in stabilizing blood sugar and meeting normal cellular energy needs. Disorders of glucose metabolism are associated with a variety of human diseases, including cardiovascular disease, diabetes, and glycogen storage diseases.

[0003] Glycogen storage diseases (GSDs) are a group of metabolic disorders caused by single-gene defects, resulting from biochemical deficiencies in different metabolic steps of glycogen production, glycogenolysis, or glycolysis. They can occur at a wide age, from newborns to adults. Affected organs include the liver, muscles, kidneys, and nervous system. Typical symptoms include hypoglycemia, exercise intolerance, growth retardation, confusion, and hepatomegaly. Based on the different genes affected and their expression in different tissues, at least 15 types of GSDs (some of which contain multiple subtypes) have been identified clinically, as well as several atypical GSDs (such as Fanconi–Bickel syndrome, PGK deficiency, and Lafora disease). Currently, there is no effective treatment for any type of GSD. Clinical care primarily involves dietary management for patients with GSDs. In liver-related glycogen storage diseases, metabolic imbalances are generally prevented by providing adequate nutrition (such as managing the frequency, amount, and type of food). In some types of glycogen storage diseases, corn starch and high-protein diets can be used to provide energy. While dietary management can alleviate glycogen storage disease symptoms to some extent, the strict requirements on food frequency and type severely impact patients' quality of life. Furthermore, enzyme replacement therapy (ERT) has been used for type II glycogen storage disease. Some patients with severe glycogen storage disease may require liver transplantation or other organ transplantation. However, enzyme replacement therapy or organ transplantation imposes a significant financial burden on patients. Summary of the Invention

[0004] To address the aforementioned technical problems, this invention provides the use of vitamin B12, which can be applied in the preparation of drugs for treating glycogen storage disease, and can treat glycogen storage disease.

[0005] The present invention provides the use of vitamin B12, the use of which includes using vitamin B12 in the preparation of medicaments for treating glycogen storage diseases.

[0006] Furthermore, the vitamin B12 may be replaced by a vitamin B12 derivative, a vitamin B12 precursor, a vitamin B12-rich probiotic, or a pharmaceutically acceptable salt of vitamin B12.

[0007] Furthermore, the daily dosage of the vitamin B12 is 2 × 10⁻⁶ in molar amounts. -3 nmol-0.2nmol.

[0008] Furthermore, the daily dosage of the vitamin B12 is 2 × 10⁻⁶ in molar amounts. -2 nmol-0.1nmol.

[0009] The present invention also provides the use of vitamin B12 and N-acetylcysteine ​​in the preparation of medicaments for treating glycogen storage diseases.

[0010] Furthermore, the vitamin B12 may be replaced by a vitamin B12 derivative, a vitamin B12 precursor, a vitamin B12-rich probiotic, or a pharmaceutically acceptable salt of vitamin B12.

[0011] Furthermore, the daily dosage of the vitamin B12 is 0.2 × 10⁻⁶ in molar amounts. -3 The daily dose of N-acetylcysteine ​​at 0.01 nmol is 2 × 10⁻⁶. -3 mmol-0.01mmol.

[0012] Furthermore, the daily dosage of the vitamin B12 is 2 × 10⁻⁶ in molar amounts. -3 The daily dose of N-acetylcysteine ​​is 0.01 mmol.

[0013] The present invention also provides a medicament for treating glycogen storage disease, the medicament being made of vitamin B12 and N-acetylcysteine.

[0014] Furthermore, the drug dosage form is an injection, tablet, capsule, dispersant, rapidly disintegrating formulation, effervescent tablet, ointment, gel, or transdermal sustained-release formulation.

[0015] Furthermore, the vitamin B12 may be replaced by a vitamin B12 derivative, a precursor that can generate vitamin B12, a vitamin B12-rich probiotic, or a pharmaceutically acceptable salt of vitamin B12.

[0016] Furthermore, the glycogen storage diseases include GSD type 0 glycogen storage disease, GSD type 1 glycogen storage disease, GSD type 2 glycogen storage disease, GSD type 3 glycogen storage disease, GSD type 4 glycogen storage disease, GSD type 5 glycogen storage disease, GSD type 6 glycogen storage disease, GSD type 7 glycogen storage disease, GSD type 9 glycogen storage disease, GSD type 10 glycogen storage disease, GSD type 11 glycogen storage disease, GSD type 12 glycogen storage disease, GSD type 13 glycogen storage disease, GSD type 14 glycogen storage disease, GSD type 15 glycogen storage disease, GSD type 16 glycogen storage disease, GSD type 15 glycogen storage disease, Fanconi-Bicker syndrome, PGK deficiency, and Lafra disease.

[0017] The embodiments of the present invention have the following technical effects: 1. In the present invention, when vitamin B12 is used in a drug for treating glycogen storage disease, it can effectively treat glycogen storage disease; based on this, when vitamin B12 and N-acetylcysteine ​​are used in a drug for treating glycogen storage disease, the synergistic effect of N-acetylcysteine ​​can not only reduce the dosage of vitamin B12, but also further treat glycogen storage disease by restoring mitochondrial ATP synthesis levels and reducing mitochondrial stress. Attached Figure Description

[0018] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0019] Figure 1 This invention provides the results of feeding different bacteria on glycogen storage disease; wherein Figure 1 The horizontal axis 'a' represents the standard bacteria OP50 E. coli, vitamin B12-rich bacteria K-12, and vitamin B12-rich bacteria HT115 fed to *C. elegans*. The blue bars (WT) represent wild-type *C. elegans* fed with different bacteria, and the red bars (GSD IX) represent *C. elegans* fed with different bacteria in a glycogen storage disease model. Figure 1In the middle, the horizontal axis WT represents wild-type *C. elegans* fed with the standard bacterium OP50 E. coli (OP50); GSD IX represents *C. elegans* in a glycogen storage disease model fed with the standard bacterium OP50 E. coli; GSD IX+VB6 represents *C. elegans* in a glycogen storage disease model fed with both the standard bacterium OP50 E. coli and vitamin B6; and GSD IX+VB12 represents *C. elegans* in a glycogen storage disease model fed with both the standard bacterium OP50 E. coli and vitamin B12. Figure 1 In the diagram, the horizontal axis N2 represents the feeding of wild-type *C. elegans*, GSD Ⅲ represents the feeding of *C. elegans* in a glycogen storage disease model involving glycogenolysis, GSD VII represents the feeding of *C. elegans* in a glycogen storage disease model involving glycolysis, GSD 0 represents the feeding of *C. elegans* in a glycogen storage disease model involving glycogen synthesis, blue columns (OP50) represent the feeding of standard bacteria OP50 *E. coli*, and green columns (OP50+VB12) represent the feeding of standard bacteria OP50 *E. coli* and vitamin B12. Figure 1 In the diagram, the horizontal axis of 'd' represents the following: OP50 indicates feeding with the standard bacterium OP50 E. coli; OP50+10nM indicates feeding with the standard bacterium OP50 E. coli and 10nM of vitamin B12; OP50+50nM indicates feeding with the standard bacterium OP50 E. coli and 50nM of vitamin B12; OP50+100nM indicates feeding with the standard bacterium OP50 E. coli and 100nM of vitamin B12; OP50+500nM indicates feeding with the standard bacterium OP50 E. coli and 500nM of vitamin B12; OP50+1000nM indicates feeding with the standard bacterium OP50 E. coli and 1000nM of vitamin B12; blue columns (WT) indicate feeding with wild-type Caenorhabditis elegans; and red columns (GSD IX) indicate feeding with Caenorhabditis elegans from a glycogen storage disease model.

[0020] Figure 2 It is the effect of vitamin B12 on the degradation of propionic acid; Figure 2In the diagram, the horizontal axis WT represents wild-type *C. elegans*, GSD IX represents *C. elegans* pcca-1 in a glycogen storage disease model; GSD IX represents *C. elegans* mce-1 in a glycogen storage disease model with the pcca-1 gene knocked out of the propionate degradation pathway; GSD IX represents *C. elegans* metr-1 in a glycogen storage disease model with the mce-1 gene knocked out of the propionate degradation pathway; GSD IX represents *C. elegans* metr-1 in a glycogen storage disease model with the metr-1 gene knocked out of the methionine cycling pathway; blue columns (OP50) represent the standard bacteria OP50 *E. coli* fed to the animal; and green columns (OP50+VB12) represent the standard bacteria OP50 *E. coli* fed to the animal and vitamin B12. Figure 2 In the diagram, the horizontal axis WT represents wild-type *C. elegans*, GSD IX represents *C. elegans* fed with a glycogen storage disease model, metr-1; GSD IX represents *C. elegans* fed with a glycogen storage disease model whose metr-1 gene has been knocked out; acdh-1; metr-1; GSD IX represents *C. elegans* fed with a glycogen storage disease model whose acdh-1 and metr-1 genes have been knocked out; blue columns (OP50) represent the standard bacteria OP50 *E. coli* fed, and red columns (OP50+VB12) represent the standard bacteria OP50 *E. coli* fed, along with vitamin B12.

[0021] Figure 3 It refers to the effect of vitamin B12 on mitochondria; Figure 3 In the middle, the horizontal axis WT represents wild-type Caenorhabditis elegans, GSD IX represents Caenorhabditis elegans in the glycogen storage disease model, and GSD IX+VB12 represents Caenorhabditis elegans in the glycogen storage disease model fed with vitamin B12. Figure 3 The effect of vitamin B12 on mitochondrial stress was investigated. In b1, the fluorescence intensity of the fluorescent protein phsp-6::gfp in wild-type *C. elegans* fed with the standard bacterium OP50 E. coli corresponds to the x-axis WT on OP50 in b4. In b2, the fluorescence intensity of the fluorescent protein phsp-6::gfp in *C. elegans* in a glycogen storage disease model fed with the standard bacterium OP50 E. coli corresponds to the x-axis GSD IX on OP50 in b4. In b3, the fluorescence intensity of the fluorescent protein phsp-6::gfp in *C. elegans* in a glycogen storage disease model fed with both the standard bacterium OP50 E. coli and vitamin B12 corresponds to the x-axis GSD IX on OP50+VB12 in b4. Figure 3In the middle, the horizontal axis WT represents wild-type Caenorhabditis elegans, GSD IX represents Caenorhabditis elegans in a glycogen storage disease model, GSDIX+50 mM NAC represents Caenorhabditis elegans in a glycogen storage disease model fed with 50 mM N-acetylcysteine, and GSD IX+50 mM NAC+10 nM VB12 represents Caenorhabditis elegans in a glycogen storage disease model fed with 50 mM N-acetylcysteine ​​and vitamin B12. Figure 3 In the diagram, the horizontal axis WT represents wild-type *C. elegans*, GSD IX represents *C. elegans* in a glycogen storage disease model, GSD IX+50 mM NAC represents *C. elegans* in a glycogen storage disease model fed with 50 mM N-acetylcysteine, and GSD IX+50 mM NAC+10 nM VB12 represents *C. elegans* in a glycogen storage disease model fed with 50 mM N-acetylcysteine ​​and 10 nM vitamin B12. Detailed Implementation

[0022] To make the objectives, technical solutions, and advantages of this invention clearer, the technical solutions of this invention will be clearly and completely described below. Obviously, the described embodiments are only a part of the embodiments of this invention, and not all of them. Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this invention.

[0023] In a first aspect, some embodiments of the present invention provide the use of vitamin B12, including its use in the preparation of medicaments for treating glycogen storage diseases.

[0024] In some embodiments, the vitamin B12 is replaced by a vitamin B12 derivative, a vitamin B12-producing precursor, a vitamin B12-rich probiotic, or a pharmaceutically acceptable salt of vitamin B12.

[0025] In some embodiments, the daily dosage of vitamin B12 is 2 × 10⁻⁶. -3 nmol-0.2nmol.

[0026] In some embodiments, the daily dosage of vitamin B12 is 2 × 10⁻⁶. -2 nmol-0.1nmol.

[0027] Secondly, some embodiments of the present invention also provide the use of vitamin B12 and N-acetylcysteine ​​in the preparation of medicaments for treating glycogen storage diseases.

[0028] In some embodiments, the vitamin B12 is replaced by a vitamin B12 derivative, a vitamin B12-producing precursor, a vitamin B12-rich probiotic, or a pharmaceutically acceptable salt of vitamin B12.

[0029] In some embodiments, the daily dosage of vitamin B12 is 0.2 × 10⁻⁶. -3 The daily dose of N-acetylcysteine ​​at 0.01 nmol is 2 × 10⁻⁶. -3 nmol-0.01nmol.

[0030] In some embodiments, the daily dosage of vitamin B12 is 2 × 10⁻⁶. -3 The daily dose of N-acetylcysteine ​​is 0.01 mmol.

[0031] Thirdly, some embodiments of the present invention also provide a medicament for treating glycogen storage disease, said medicament being made of vitamin B12 and N-acetylcysteine.

[0032] In some embodiments, the drug dosage form is an injection, tablet, capsule, dispersant, rapidly disintegrating formulation, effervescent tablet, ointment, gel, or transdermal sustained-release formulation.

[0033] In some embodiments, the vitamin B12 is replaced by a vitamin B12 derivative, a vitamin B12-producing precursor, a vitamin B12-rich probiotic, or a pharmaceutically acceptable salt of vitamin B12.

[0034] In some embodiments, the glycogen storage diseases include GSD type 0 glycogen storage disease, GSD type 1 glycogen storage disease, GSD type 2 glycogen storage disease, GSD type 3 glycogen storage disease, GSD type 4 glycogen storage disease, GSD type 5 glycogen storage disease, GSD type 6 glycogen storage disease, GSD type 7 glycogen storage disease, GSD type IX glycogen storage disease, GSD type X glycogen storage disease, GSD type XI glycogen storage disease, GSD type XII glycogen storage disease, GSD type XIII glycogen storage disease, GSD type XIV glycogen storage disease, GSD type XV glycogen storage disease, Fanconi-Bicker syndrome, PGK deficiency, and Lafra disease.

[0035] Results and Analysis: Table 1. Glycogen metabolism-related genes and corresponding types of glycogen storage disease (GSD)

[0036] In this invention, Caenorhabditis elegans was used for experiments and verification. The biochemical processes related to glycogen metabolism and the metabolic enzymes involved are highly conserved in humans and Caenorhabditis elegans (as shown in Table 1).

[0037] Glycogen metabolism includes glycogen synthesis, glycogenolysis, and glycolysis. Therefore, we selected four nematode models representing metabolic mutations related to glycogen synthesis (GSD 0), glycogenolysis (GSD III and GSD IX), and glycolysis (GSD VII) to investigate and identify the therapeutic effect of vitamin B12 on glycogen storage diseases. Figure 1 As shown in (a), feeding wild-type (WT) *C. elegans* with the standard bacterium OP50 E. coli (which does not contain vitamin B12) produced approximately 200 offspring. Feeding *C. elegans* from the glycogen storage disease model GSD IX with the standard bacterium OP50 E. coli resulted in embryonic development termination and no offspring were produced. Feeding wild-type (WT) *C. elegans* and *C. elegans* from the glycogen storage disease model GSD IX with the standard bacterium K-12 or HT115 (which contains vitamin B12) resulted in normal embryonic development and more than 200 offspring.

[0038] Based on this, vitamin B6 was further used as a negative control group, such as Figure 1 As shown in (b), wild-type *C. elegans* was fed with the standard bacterium OP50E. coli as the control group (WT). Wild-type (WT) *C. elegans* and *C. elegans* from the glycogen storage disease model GSD IX were fed with either the standard bacterium OP50E. coli or vitamin B6, or the standard bacterium OP50E. coli or vitamin B12. The results showed that *C. elegans* embryos in the glycogen storage disease model GSD IX, fed with OP50E. coli alone or with vitamin B6, still exhibited abnormal embryonic development and failed to produce offspring. However, when fed with vitamin B12, the embryos of *C. elegans* in the glycogen storage disease model GSD IX developed normally and produced more than 250 offspring. This further validated the role of vitamin B12 in the treatment of glycogen storage disease.

[0039] To further verify whether vitamin B12 has an inhibitory effect on other types of glycogen storage disease, the glycogen metabolism process was divided into three stages, and glycogen storage disease models of *C. elegans* were established for glycogen synthesis (GSD 0), glycogenolysis (GSD III), and glycolysis (GSD VII), respectively. Then, the standard bacterium OP50 *E. coli*, alone or co-administered with vitamin B12, was used to feed the patients to represent the glycogen storage disease models of glycogen synthesis (GSD 0), glycogenolysis (GSD III), and glycolysis (GSD VII). The results are as follows: Figure 1 (c) shows that vitamin B12 supplementation significantly inhibited the relevant phenotypes in all three glycogen storage disease models, suggesting that vitamin B12 could be a potential treatment for all types of glycogen storage disease.

[0040] Furthermore, the effective vitamin concentration range for inhibiting glycogen storage disease was explored, such as... Figure 1 As shown in (d), during the study, all patients were fed the same volume (200 μL) of vitamin B12 at different concentrations. The results showed that 10 nM vitamin B12 partially inhibited the relevant phenotype, while 500 nM maximally inhibited it, and 1000 nM vitamin B12 did not further enhance the inhibitory effect. Further preferred formulations included a vitamin B12 concentration of 10 nM–1000 nM and a daily dosage of 2 × 10⁻⁶ molar amounts of vitamin B12. - 3 nmol-0.2 nmol. Further preferred, the concentration of vitamin B12 is 100 nM-500 nM, and the daily dosage of vitamin B12 is 2 × 10⁻⁶ molars. -2 nmol-0.1nmol.

[0041] Genetic pathway studies have revealed that vitamin B12 inhibits the glycogen storage disease-related phenotype through the propionate pathway, rather than the methionine cycle pathway. Figure 2 As shown. In Figure 2 In (a), after knocking out the propionate degradation pathway gene (pcca-1 or mce-1), feeding the glycogen storage disease model GSD IX Caenorhabditis elegans with standard bacteria OP50 E. coli and vitamin B12 resulted in abnormal embryo development and fewer offspring. However, knocking out only the methionine cycle pathway gene (metr-1) suppressed the glycogen storage disease GSD IX phenotype even without vitamin B12 supplementation. Further analysis showed that the suppression of glycogen storage disease was achieved by upregulating the related propionate degradation pathway (acdh-1). Therefore, vitamin B12 inhibits glycogen storage disease by regulating the propionate degradation pathway.

[0042] Glucose is the primary source of energy for cellular production, and in the human body, it is mainly stored in cells as glycogen. The process of glycogen degradation into glucose, and the production of ATP from glucose, is partly completed within the mitochondria. When mitochondria are damaged, leading to functional defects, their ability to synthesize ATP is inhibited. This not only results in lower ATP levels but also increases mitochondrial stress (Phsp-6::gfp), thus affecting glucose metabolism.

[0043] exist Figure 3 In (a), feeding *C. elegans* of the glycogen storage disease model GSD IX with the standard bacterium OP50 *E. coli* resulted in impaired mitochondrial function and reduced ATP synthesis. Feeding *C. elegans* of the glycogen storage disease model GSD IX with the standard bacterium OP50 *E. coli* and vitamin B12 resulted in increased ATP levels in the *C. elegans* of the GSD IX model. Figure 3 (b) It was found that feeding *C. elegans*, a glycogen storage disease model of GSD IX, with the standard bacterium OP50 E. coli increased mitochondrial stress, while feeding *C. elegans* with both the standard bacterium OP50 E. coli and vitamin B12 decreased mitochondrial stress. The study found that propionyl-CoA accumulation inhibits the tricarboxylic acid cycle in mitochondria, leading to impaired mitochondrial function. Propionate generates propionyl-CoA, which in turn generates succinyl-CoA via the vitamin B12-related pathway. Therefore, vitamin B12 promotes the degradation of propionate and propionyl-CoA, thereby reducing the damage of propionyl-CoA to the tricarboxylic acid cycle and mitochondrial function.

[0044] exist Figure 3 In (c), during the study, the subjects were fed 200 μL of 10 nM vitamin B12 and 200 μL of 50 mM N-acetylcysteine. The results showed that when *C. elegans*, a glycogen storage disease model of GSD IX, was co-fed with the standard bacterium OP50 *E. coli* and N-acetylcysteine, the embryos developed normally, producing approximately 100 offspring. This indicates that N-acetylcysteine ​​can protect mitochondria, thereby reducing propionyl-CoA damage to mitochondria and thus partially inhibiting glycogen storage disease. Furthermore, when 50 mM N-acetylcysteine ​​and 10 nM vitamin B12 were used together, glycogen storage disease was completely inhibited, significantly reducing the amount of vitamin B12 required. Figure 3As shown in (d), the combined action of 50 mM N-acetylcysteine ​​and 10 nM vitamin B12 can reduce mitochondrial stress. Therefore, the combined action of vitamin B12 and N-acetylcysteine ​​can inhibit all forms of glycogen storage disease while protecting mitochondria. Thus, further optimization is achieved with 50 mM N-acetylcysteine ​​and 10 nM vitamin B12, with a daily dose of vitamin B12 of 2 × 10⁻⁶ molar amounts. -3 The daily dose of N-acetylcysteine ​​is 0.01 mmol.

[0045] It should be noted that the terminology used in this invention is for describing specific embodiments only and is not intended to limit the scope of this application. As shown in this specification, unless the context clearly indicates otherwise, words such as "a," "an," "an," and / or "the" do not specifically refer to the singular and may include the plural. The terms "comprising," "including," or any other variations thereof are intended to cover a non-exclusive inclusion, such that a process, method, or apparatus that comprises a list of elements includes not only those elements but also other elements not expressly listed, or elements inherent to such a process, method, or apparatus. Without further limitations, an element defined by the phrase "comprising one..." does not exclude the presence of other identical elements in the process, method, or apparatus that includes said element.

[0046] It should also be noted that the terms "center," "upper," "lower," "left," "right," "vertical," "horizontal," "inner," and "outer," etc., indicate the orientation or positional relationship based on the orientation or positional relationship shown in the accompanying drawings, and are only for the convenience of describing the present invention and simplifying the description, and do not indicate or imply that the device or element referred to must have a specific orientation, or be constructed and operated in a specific orientation, and therefore should not be construed as a limitation of the present invention. Unless otherwise expressly specified and limited, the terms "installed," "connected," "linked," etc., should be interpreted broadly. For example, they can refer to a fixed connection, a detachable connection, or an integral connection; they can refer to a mechanical connection or an electrical connection; they can refer to a direct connection or an indirect connection through an intermediate medium; they can refer to the internal communication of two components. For those skilled in the art, the specific meaning of the above terms in the present invention can be understood according to the specific circumstances.

[0047] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the technical solutions of the embodiments of the present invention.

Claims

1. Uses of Vitamin B12, characterized in that, The uses include the use of vitamin B12 in the preparation of medicines for treating glycogen storage diseases.

2. The use according to claim 1, characterized in that, The vitamin B12 is replaced by vitamin B12 derivatives, precursors that can generate vitamin B12, vitamin B12-rich probiotics, or pharmaceutically acceptable salts of vitamin B12.

3. The use according to claim 1, characterized in that, The daily dosage of the vitamin B12 is 2 × 10⁻⁶. -3 nmol-0.2nmol.

4. The use of vitamin B12 and N-acetylcysteine ​​in the preparation of drugs for treating glycogen storage diseases.

5. The application according to claim 4, characterized in that, The vitamin B12 is replaced by vitamin B12 derivatives, precursors that can generate vitamin B12, vitamin B12-rich probiotics, or pharmaceutically acceptable salts of vitamin B12.

6. The application according to claim 4, characterized in that, The daily dosage of vitamin B12 is 0.2 × 10⁻⁶ in molar amount. -3 The daily dose of N-acetylcysteine ​​at 0.01 nmol is 2 × 10⁻⁶. -3 mmol-0.01mmol.

7. A drug for treating glycogen storage disease, characterized in that, The drug includes vitamin B12 and N-acetylcysteine.

8. The medicament according to claim 7, characterized in that, The dosage form of the drug is injection, tablet, capsule, dispersant, rapidly disintegrating formulation, effervescent tablet, ointment, gel, or transdermal sustained-release formulation.

9. The drug according to claim 7, characterized in that, The vitamin B12 is replaced by vitamin B12 derivatives, precursors that can generate vitamin B12, vitamin B12-rich probiotics, or pharmaceutically acceptable salts of vitamin B12.

10. The medicament according to claim 7, characterized in that, The glycogen storage diseases mentioned include GSD type 0 glycogen storage disease, GSD type 1 glycogen storage disease, GSD type 2 glycogen storage disease, GSD type 3 glycogen storage disease, GSD type 4 glycogen storage disease, GSD type 5 glycogen storage disease, GSD type 6 glycogen storage disease, GSD type 7 glycogen storage disease, GSD type 9 glycogen storage disease, GSD type 10 glycogen storage disease, GSD type 11 glycogen storage disease, GSD type 12 glycogen storage disease, GSD type 13 glycogen storage disease, GSD type 14 glycogen storage disease, GSD type 15 glycogen storage disease, Fanconi-Bicker syndrome, PGK deficiency, and Lafra disease.

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