Application of GCH1 inhibitor in preparation of medicine for preventing and treating hearing impairment

Abstract

The invention relates to an application of a GCH1 inhibitor in preparation of a medicine for preventing and / or treating hearing impairment.

Description

Use of GCH1 inhibitors in the preparation of drugs for preventing and treating hearing loss Technical Field

[0001] The present invention belongs to the field of biomedicine, and more specifically, the present invention relates to the use of a GCH1 inhibitor in preparing a medicament for preventing and / or treating hearing loss. Background Art

[0002] Approximately 270 million people worldwide are affected by hearing loss. Hearing loss is primarily caused by genetic and environmental factors, and progresses with aging. Environmental factors contributing to hearing loss primarily include ototoxic drugs, noise trauma, and bacterial infections. Hearing loss caused by genetic factors is primarily categorized as syndromic (20%-30%) and non-syndromic (70%-80%). According to statistics, hereditary hearing loss accounts for 68% of cases in newborns and 55% of cases in children under four years old. Autosomal recessive, dominant, and X-linked inheritance account for 77%, 22%, and 1% of hereditary hearing loss, respectively. Most hereditary hearing loss is sensorineural, typically due to abnormalities of the inner ear or auditory nerve. Approximately 50% of prelingual hearing loss is caused by genetic mutations, but mutations in some deafness-related genes (such as GJB3, KCNQ4, and COCH) can also lead to postlingual hearing loss. Although over 50 genes have been identified as deafness genes in the past few decades, a significant number remain undiscovered. Serpinb6 (serine protease inhibitor) is the first protease inhibitor reported to be associated with hearing loss. It is also known as DFNB91 based on the nomenclature of deafness genes. It was discovered in a Turkish family with consanguineous marriage.

[0003] Currently, treatments for hearing loss primarily rely on device-assisted hearing aids, lacking effective drug intervention strategies. Existing device-assisted treatments primarily rely on hearing aids and cochlear implants, but these methods suffer from the following drawbacks: First, the effectiveness of assistive devices for hereditary hearing loss is limited; second, current hearing aid production falls far short of meeting the global demand for hearing-impaired individuals. In developing countries, fewer than 2.5 out of every 100 hearing-impaired individuals wear hearing aids, and some patients are reluctant to undergo invasive surgical treatments.

[0004] Therefore, there is an urgent need in the art for a different method and drug for preventing and / or treating hearing loss, which does not require the use of expensive auxiliary devices such as hearing aids and cochlear implants, and has a therapeutic effect on both hereditary and acquired hearing loss.

[0005] Summary of the Invention

[0006] As mentioned above, existing treatments for hearing loss primarily rely on medical assistance. However, assistive devices such as hearing aids and cochlear implants are expensive, have low production volumes, and are limited in their effectiveness in treating hereditary hearing loss, thus failing to meet the needs of the majority of hearing-impaired individuals. Therefore, there is an urgent need for alternative methods and medications for treating hearing loss that would effectively treat hereditary or acquired hearing loss without the need for medical assistance.

[0007] Therefore, in a first aspect, the present invention provides the use of a GCH1 (GTP-dependent cyclohydrolase 1) inhibitor in the preparation of a medicament for preventing and / or treating hearing loss.

[0008] In some embodiments, the GCH1 inhibitor is capable of inhibiting the expression, activity and / or function of GCH1.

[0009] In some embodiments, the GCH1 inhibitor inhibits GCH1 activity and / or function by engaging the endogenous feedback inhibition mechanism of GCH1.

[0010] In some embodiments, the GCH1 inhibitor is selected from a nucleic acid molecule, a protein molecule, or a chemical compound.

[0011] In some embodiments, the nucleic acid molecule is selected from a substance for knocking out or knocking down the expression of the GCH1 gene. In some embodiments, the nucleic acid molecule is selected from a short hairpin RNA (shRNA), a small interfering RNA (siRNA) and / or an antisense oligonucleotide (ASO).

[0012] In some embodiments, the GCH1 inhibitor is DAHP (2,4-diamino-6-hydroxypyrimidine).

[0013] In some embodiments, the hearing loss is hereditary hearing loss or acquired hearing loss. In a specific embodiment, the acquired hearing loss is drug-induced hearing loss.

[0014] In some embodiments, the hearing loss is hearing loss associated with abnormal expression of Serpinb6.

[0015] In some embodiments, the medicament is an injectable formulation.

[0016] In a second aspect, the present invention provides a pharmaceutical composition for preventing and / or treating hearing loss, wherein the pharmaceutical composition comprises the GCH1 inhibitor or a pharmaceutically acceptable salt, ester, isomer, prodrug, polymorph or solvate thereof for the use described in the first aspect of the present invention, and a pharmaceutically acceptable carrier.

[0017] In a third aspect, the present invention provides a method for preventing and / or treating hearing loss, the method comprising inhibiting the expression, activity and / or function of GCH1 in a subject. In some embodiments, the method comprises administering a GCH1 inhibitor to the subject.

[0018] In some embodiments, the GCH1 inhibitor is selected from a nucleic acid molecule, a protein molecule or a compound. In some embodiments, the nucleic acid molecule is selected from a short hairpin RNA (shRNA), a small interfering RNA (siRNA) and / or an antisense oligonucleotide (ASO).

[0019] In some embodiments, the compound is DAHP.

[0020] In some embodiments, the hearing loss is hereditary hearing loss or acquired hearing loss. In a specific embodiment, the acquired hearing loss is drug-induced hearing loss.

[0021] In some embodiments, the hearing loss is hearing loss associated with abnormal expression of Serpinb6.

[0022] The beneficial effects of the present invention are: providing the use of a GCH1 inhibitor in the preparation of a medicament for preventing and / or treating hearing loss, thereby providing a method for preventing and / or treating hearing loss using a GCH1 inhibitor, reducing treatment costs without the need for auxiliary equipment, and achieving effective treatment of hereditary or acquired hearing loss. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other implementation plans can be obtained based on these drawings without paying any creative work.

[0024] FIG1 is a photograph showing the expression of the Serpinb6 gene in hair cells (HC), supporting cells (SC), and cornea in the inner ear of mice on day 7 after birth.

[0025] Figure 2 is a schematic diagram of the comparison results between wild-type mice (WT) and Serpineb6 gene knockout mice (Serpine6 ko or Serpine6- / -), wherein Figure 2A shows a photograph of Serpine6 protein expression in both mice; Figure 2B shows the hearing assessment results (ABR threshold) in both mice; Figures 2C and 2D show a significant loss of hair cells after Serpinb6 knockout; Figure 2E shows the number of hair cells per unit area in both mice; and Figure 2F shows the changes in ciliary morphology in both mice;

[0026] Figure 3 shows photos showing obvious apoptosis of hair cells in Serpinb6 gene knockout mice.

[0027] Figure 4A is a photograph showing upregulated expression of GCH1 in Serpinb6 gene knockout mice; Figure 4B is the chemical structural formula of the GCH1 inhibitor (DAHP); Figure 4C is a schematic diagram showing the hearing assessment results of Serpinb6 gene knockout mice injected with DAHP, untreated Serpinb6 gene knockout mice, and wild-type mice.

[0028] FIG5A is a graph showing the knockdown efficiency of different GCH1-shRNAs; FIG5B is a graph showing that GCH1-shRNA-3 appropriately restores the hearing of Serpinb6 gene knockout mice.

[0029] FIG6 is a graph showing that GCH1 expression is upregulated in hair cells injured by neomycin and cisplatin. DETAILED DESCRIPTION

[0030] The present invention will be described clearly and completely below in conjunction with the embodiments and accompanying drawings of the present invention. Obviously, the embodiments described are only part of the embodiments of the present invention, rather than all of the embodiments. All other embodiments that can be obtained by a person of ordinary skill in the art based on the embodiments of the present invention fall within the scope of protection of the present invention.

[0031] As mentioned above, existing treatments for hearing loss primarily rely on medical devices, which are costly, have low yields, and are limited in their effectiveness for hereditary hearing loss, thus failing to meet the needs of the majority of hearing-impaired individuals. Therefore, there is an urgent need for alternative methods and medications for treating hearing loss that can effectively treat hereditary or acquired hearing loss without the need for medical devices.

[0032] During their research on deafness mouse models, the inventors unexpectedly discovered that GCH1 (GTP-dependent cyclohydrolase 1) expression is upregulated in various deafness mouse models. Inhibiting GCH1 can reduce and restore hearing loss, potentially treating hearing loss. Therefore, the inventors believe that GCH1 may be a therapeutic target for hereditary and acquired deafness. This led to the completion of the present invention.

[0033] Therefore, in a first aspect, the present invention provides the use of a GCH1 (GTP-dependent cyclohydrolase 1) inhibitor in the preparation of a medicament for preventing and / or treating hearing loss.

[0034] GCH1 (GTP-dependent cyclohydrolase 1) is a key enzyme in the tetrahydrobiopterin (BH4) biosynthesis pathway. It affects a range of pathophysiological phenomena in vivo by affecting the biosynthesis of biopterin, a molecule with antioxidant properties. However, no studies or reports have yet investigated the interaction between GCH1 and hearing loss.

[0035] In the present invention, "treatment" and "prevention" should be understood in their broadest sense, including alleviating the symptoms of a specific disease or preventing or reducing the risk of a specific disease. The term "treatment" is a therapeutic intervention performed on a subject (sick individual) to reduce or alleviate at least one symptom, severity or frequency of attacks of an existing disease in the subject, and does not necessarily mean that the subject receives treatment until complete recovery. Similarly, the term "prevention" refers to a preventive intervention performed on a subject (normal individual or susceptible individual) to reduce the severity of at least one symptom of the subject's onset or reduce the likelihood of symptom onset, and does not necessarily mean that the subject will not eventually suffer from the corresponding disease.

[0036] The compounds of the present invention and the methods thereof can be used to prevent and / or treat hearing loss. They can be used not only in the early stages of hearing loss to prevent the damage from expanding, but also for repairing hearing loss after hearing loss. They can also be used as a preventive treatment method before exposure to noise or drugs or after a period of exposure to noise or drugs.

[0037] In some embodiments, the GCH1 inhibitor is capable of inhibiting the expression, activity, and / or function of GCH1. In the present invention, the inhibition can be partial inhibition, i.e., reducing the expression, activity, and / or function of GCH1, or complete inhibition, i.e., completely eliminating the expression, activity, and / or function of GCH1. For example, compared to a control group, the GCH1 inhibitor can reduce the level of GCH1 in a subject or cell by 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, or 100%. The inhibitory effect of the GCH1 inhibitor on GCH1 includes, but is not limited to, inhibiting the transcription or expression of the GCH1 gene, reducing the level of GCH1 in a subject or cell, or reducing the activity or function of GCH1 in a subject or cell. The GCH1 inhibitor can inhibit GCH1 through different mechanisms or systems. For example, the inhibitory function of the GCH1 inhibitor can be the inhibition of expression levels at the GCH1 gene nucleic acid molecule level (e.g., mRNA level, DNA level) and / or protein molecule level. For another example, the GCH1 inhibitor can also be a substance that competes with GCH1. In addition, the GCH1 inhibitor can also inhibit GCH1 through gene editing systems (e.g., TALEN, ZFN, CRISPR-Cas system, DNA / RNA base editing system, etc.) or protein degradation systems (e.g., PROTAC).

[0038] In some embodiments, the GCH1 inhibitor inhibits GCH1 activity and / or function by participating in the endogenous feedback inhibition mechanism of GCH1. In the present invention, the inhibition of GCH1 by the GCH1 inhibitor may not be the result of direct interaction with GCH1, but rather inhibits GCH1 activity and / or function through the endogenous feedback inhibition mechanism.

[0039] In some embodiments, the GCH1 inhibitor is selected from a nucleic acid molecule, a protein molecule, or a compound. In the present invention, the nucleic acid molecule can be a substance used to knock out or knock down the expression of the GCH1 gene, including but not limited to short hairpin RNA (shRNA), small interfering RNA (siRNA), and / or antisense oligonucleotides (ASOs). The protein molecule can be a peptide or protein capable of binding to GCH1, such as an enzyme or antibody. The GCH1 inhibitor can also be a compound that inhibits the expression, activity, and / or function of GCH1, including but not limited to carbohydrates, lipids, and small molecule chemicals. In a preferred embodiment, the GCH1 inhibitor is DAHP (2,4-diamino-6-hydroxypyrimidine), the structure of which is shown in Figure 4B. It inhibits GCH1 by participating in the endogenous feedback inhibition system (Kolinsky, MA, & Gross, SS. (2004). The mechanism of potent GTP cyclohydrolase I inhibition by 2,4-diamino-6-hydroxypyrimidine. Journal of Biological Chemistry.). Without being limited to the above description, any other substance that can inhibit the expression, activity and / or function of GCH1 is within the scope of the present invention.

[0040] In some embodiments, the hearing loss is hereditary hearing loss or acquired hearing loss. In the experimental results of the present invention, GCH1 is significantly upregulated in both hereditary hearing loss and acquired hearing loss models. In some embodiments, the acquired hearing loss is hearing loss caused by drugs. The drugs include but are not limited to one or more of aminoglycoside ototoxic drugs, macrolide ototoxic drugs, and chemotherapy drugs. Specifically, the aminoglycoside ototoxic drugs are, for example, streptomycin, gentamicin, kanamycin, neomycin, tobramycin, and metronidazole; macrolide ototoxic drugs are, for example, erythromycin, roxithromycin, etc.; and chemotherapy drugs are, for example, cisplatin. In some embodiments, the hearing loss is hearing loss associated with abnormal expression of Serpinb6.

[0041] The GCH1 inhibitors or medicaments containing GCH1 inhibitors provided herein can be adapted for any form of administration, for example, oral or parenteral administration. As used herein, the pharmaceutical composition can be in the form of an injection, sterile powder for injection, tablet, pill, capsule, lozenge, elixir, powder, granule, syrup, solution, tincture, aerosol, powder spray, or suppository. Those skilled in the art can select an appropriate formulation based on the mode of administration. In some embodiments, the medicament is an injectable formulation.

[0042] In a second aspect, the present invention provides a pharmaceutical composition for preventing and / or treating hearing loss, wherein the pharmaceutical composition comprises the GCH1 inhibitor or a pharmaceutically acceptable salt, ester, isomer, prodrug, polymorph or solvate thereof for the use described in the first aspect of the present invention, and a pharmaceutically acceptable carrier.

[0043] As used herein, the term "pharmaceutically acceptable carrier" of the present invention refers to a conventional pharmaceutical carrier in the field of pharmaceutical formulations, selected from one or more of fillers, binders, disintegrants, lubricants, suspending agents, wetting agents, pigments, flavoring agents, solvents, and surfactants. The term "prodrug" refers to a substance that, when administered by an appropriate method, undergoes metabolism or chemical reactions in the human body to convert into the active GCH1 inhibitor or a pharmaceutically acceptable salt, ester, isomer, prodrug, polymorph, or solvate.

[0044] In a third aspect, the present invention provides a method for preventing and / or treating hearing loss, comprising inhibiting the expression, activity and / or function of GCH1 in a subject. In some embodiments, the expression, activity and / or function of GCH1 in a subject can be inhibited by administering a GCH1 inhibitor to the subject.

[0045] Those skilled in the art will understand that the above description related to the use of the first aspect of the present invention in preparing a medicament for preventing and / or treating hearing loss is applicable to the third aspect of the present invention and will not be repeated here.

[0046] The present invention will be described in more detail below in conjunction with the examples. The test methods in the following examples are conventional methods unless otherwise specified. The test materials used in the following examples are purchased from conventional reagent stores unless otherwise specified. It should be noted that the above summary of the invention and the detailed description below are only for the purpose of specifically illustrating the present invention and are not intended to limit the present invention in any way.

[0047] Example

[0048] Example 1 Spatiotemporal expression of SERPINB6 protein in the cochlea of ​​wild-type mice

[0049] 1.1 Detection of Serpinb6 expression in the cochlear basal membrane of normal mice

[0050] Protein and RNA were extracted from the cochlear basilar membrane tissue of wild-type mice and Serpinb6 knockout mice (i.e., mice with the Serpinb6 gene knocked out, Serpinb6 ko or Serpine6- / -) at P0, P7, P14, P21, and P30 (days after birth). Western Blot and RT-PCR were used to detect the presence and expression of the Serpinb6 gene in the cochlear basilar membrane of normal mice, while no Serpinb6 gene was detected in the Serpinb6 knockout mice (see Figure 2A).

[0051] 1.2 Precise localization of Serpinb6 expression in the basilar membrane of the normal mouse cochlea

[0052] Basement membrane sections and slides of wild-type mice and Serpinb6 knockout mice were prepared at different time points, and immunofluorescence staining was performed on the mouse basement membrane sections and slides using the hair cell marker myosin7a, the supporting cell marker Sox2, and SERPINB6 antibodies. The temporal and spatial expression and specific expression sites of SERPINB6 in the inner ear of wild-type mice at time points such as P0, P7, P14, P21, and P30 were revealed (see Figure 1), while no SERPINB6 expression was detected in the corresponding locations in Serpinb6 gene knockout mice at any time point.

[0053] Example 2 Analysis of auditory function and cochlear morphology in Serpinb6 knockout mice

[0054] 2.1 Auditory function assessment of Serpinb6 knockout mice

[0055] The auditory response threshold, latency, and interwave duration of Serpinb6 knockout mice and wild-type mice in the same litter were detected by ABR to determine the difference in auditory function of the mice as a whole. Specifically, short sounds (Click), especially short sounds of different audio frequencies (4KHz, 8KHz, 12KHz, 16KHz, 24KHz, 32KHz) were used as stimuli to detect the hearing threshold of mice to different audio frequencies, analyze the hearing sensitivity of mice, and judge whether the mice have normal auditory function from hair cells to cerebral cortex as a whole. Generally, the higher the ABR threshold, the more serious the hearing loss of Serpinb6 knockout mice. From the results shown in Figure 2B, it can be seen that the ABR threshold of Serpinb6 knockout mice is significantly increased relative to wild-type mice, indicating that the hearing function of Serpinb6 knockout mice has a significant loss.

[0056] 2.3 Detection of hair cell number in Serpinb6 knockout mice

[0057] Immunofluorescence staining was used to examine the number of surviving inner ear hair cells in Serpinb6 knockout mice at different time points, including P0, P7, P14, P21, and P30. The results shown in Figures 2E, 2C, and 2D indicate that compared with wild-type mice, the number of surviving inner ear hair cells in Serpinb6 knockout mice was significantly reduced at different locations, indicating that Serpinb6 gene deletion leads to significant apoptosis in mouse hair cells.

[0058] Example 3 GCH1 expression is upregulated in Serpinb6 knockout mice

[0059] Cochlear proteins were extracted from 21-day-old Serpinb6 knockout mice and their wild-type littermates, and GCH1 expression was examined by western blot. The results shown in Figure 4A show that GCH1 expression is significantly increased in the cochlear proteins of Serpinb6 knockout mice compared to wild-type mice.

[0060] Example 4 Therapeutic Effect of GCH1 Inhibitor in Serpinb6 Knockout Mice

[0061] To verify that elevated GCH1 expression is the primary cause of hair cell death and elevated hearing thresholds in mice, mice were subcutaneously injected with DAHP, a classic GCH1 inhibitor, to downregulate GCH1 expression. Audiometric testing was then performed to assess the role of this pathway in the inner ear. The results, shown in Figure 4C, show that compared to the PBS-injected control group (KO mice-PBS), the ABR thresholds of Serpib6 knockout mice were significantly lower after DAHP injection, indicating a significant improvement in hearing.

[0062] Example 5 Restoration of hearing in Serpinb6 knockout mice by knocking down GCH1 through shRNA

[0063] First, five shRNA sequences targeting GCH1 were designed, and their knockdown efficiency was verified in OC1 cells. The GCH1 sequence was retrieved from the NCBI database, and shRNA design was performed using the Thermo Fisher shared platform. shRNA plasmids were synthesized by GenScript Biotech. To verify the efficiency of the shRNA in the OC1 cell line, five shRNAs were transfected into six-well plates using Lip2000. RNA was extracted 48 hours later and reverse-transcribed into cDNA. QPCR was then performed to assess the knockdown efficiency of the shRNAs. The shRNA with the highest knockdown efficiency was identified, with GCH1-shRNA-3 exhibiting the highest knockdown efficiency, and this shRNA was used in subsequent experiments (as shown in Figure 5A). This shRNA was then packaged into AAV-ie-GCH1-shRNA. Virus injection was performed via the round window membrane in Serpinb6 knockout mice at P2, and audiological function was assessed at P30. The audiometry results showed that compared with the Serpinb6 knockout mice (Serpine6- / -) used as the control, the hearing of the Serpinb6 knockout mice injected with GCH1-shRNA was restored to a certain extent (as shown in Figure 5B).

[0064] Example 6 GCH1 expression is upregulated in hair cell lines with downregulation of Serpinb6 and drug damage

[0065] The OC1 cell line is a cellular tool used to simulate inner ear hair cells for in vitro research. An OC1 cell line expressing Serpinb6 was constructed using siRNA transfection. GCH1 expression was assessed by qPCR after Serpinb6 knockdown in the cell line. The results shown in Figure 6 show that GCH1 expression was significantly increased in the Serpinb6 knockdown OC1 cell line (OC1-Si-SB6) compared to the untreated OC1 cell line, consistent with in vivo results.

[0066] Neomycin and cisplatin are both drugs that have been reported to damage the OC1 cell line. Therefore, the inventors added neomycin and cisplatin to the OC1 cell culture process to damage it, and used QPCR to investigate the expression of GCH1 under drug damage conditions. OC1 cells were seeded in 6-well plates and drug damage was performed when the cell density approached 80-90%. The neomycin damage concentration was 0.5mM, the damage time was 24 hours, and a 24-hour recovery period was allowed before RNA extraction. The cisplatin damage concentration was 15μM, the damage time was 48 hours, and RNA was directly extracted after the end. The RNA was reverse transcribed into cDNA using a reverse transcription kit and then detected by QPCR. As can be seen from the results shown in Figure 6, after drug damage by neomycin and cisplatin, the expression of GCH1 in OC1 cells was upregulated, which is consistent with the expected results.

[0067] Example 7 Therapeutic Effects of GCH1 Inhibitors in Animal Models of Drug Injury

[0068] In addition, existing studies have shown that neomycin and cisplatin can not only damage OC1 cell lines in vitro, but also cause hair cell loss and decreased hearing thresholds in mice. Therefore, the inventors attempted to establish a neomycin and cisplatin damage model in mice.

[0069] First, neomycin modeling was performed. Wild-type mice were injected with neomycin at a dose of 200 mg / kg between P7 and P14. Audiological testing was performed at P30. ABR audiometry results showed that the mice had impaired hearing function, indicating that the neomycin modeling was successful. To explore the relationship between GCH1 and drug damage, wild-type mice were first injected with neomycin between P7 and P14. Then, GCH1-shRNA was delivered to the mouse cochlea using AAV at P15. The screening results of GCH1-shRNA are shown in Figure 6A. Mice were subjected to audiological function testing at P30. ABR audiometry results showed that GCH1-shRNA injection could partially restore the hearing damage caused by neomycin in mice.

[0070] Similarly, the inventors used cisplatin to model hearing loss in mice. Wild-type mice at P21 were injected with cisplatin at a concentration of 0.4 ml / 10 g by intraperitoneal injection for 7 consecutive days. Audiological function tests were performed on the 8th day. The ABR audiometry results showed that the mice had impaired hearing function, indicating that the hearing model of mice damaged by cisplatin was successful. Similarly, in order to explore the relationship between GCH1 and drug damage caused by cisplatin, the inventors delivered AAV-GCH1-shRNA to the cochlea of ​​mice. The specific implementation was as follows: cisplatin was injected starting at P21 for 7 consecutive days. On the 8th day, the mice were injected with the virus by semicircular canal injection. Then, the mice were subjected to audiological function tests at P45. The ABR audiometry results showed that AAV-GCH1-shRNA injection could partially restore the hearing damage caused by cisplatin in mice.

[0071] Table 1. Related sequence information

Claims

1. Use of a GCH1 inhibitor in the preparation of a medicament for preventing and / or treating hearing loss.

2. The use according to claim 1, wherein the GCH1 inhibitor is capable of inhibiting the expression, activity and / or function of GCH1.

3. The use according to claim 2, wherein the GCH1 inhibitor inhibits GCH1 activity and / or function by participating in the endogenous feedback inhibition mechanism of GCH1.

4. The use according to any one of claims 1 to 3, wherein the GCH1 inhibitor is selected from a nucleic acid molecule, a protein molecule or a compound.

5. The use according to claim 4, wherein the nucleic acid molecule is selected from substances for knocking out or knocking down the expression of the GCH1 gene, such as short hairpin RNA, small interfering RNA and / or antisense oligonucleotide.

6. The use according to claim 4, wherein the compound is DAHP.

7. The use according to any one of claims 1 to 6, wherein the hearing loss is hereditary hearing loss or acquired hearing loss such as hearing loss caused by drugs.

8. The use according to claim 7, wherein the hearing loss is hearing loss associated with abnormal expression of Serpinb6.

9. The use according to any one of claims 1 to 8, wherein the medicament is an injection preparation.

10. A pharmaceutical composition for preventing and / or treating hearing loss, wherein the pharmaceutical composition comprises the GCH1 inhibitor for use according to any one of claims 1 to 9 or a pharmaceutically acceptable salt, ester, isomer, prodrug, polymorph or solvate thereof, and a pharmaceutically acceptable carrier.

11. A method for preventing and / or treating hearing loss, the method comprising inhibiting the expression, activity and / or function of GCH1 in a subject, such as administering a GCH1 inhibitor to the subject.

12. The method of claim 11, wherein the GCH1 inhibitor is selected from nucleic acid molecules such as short hairpin RNA, small interfering RNA and / or antisense oligonucleotides, protein molecules or compounds.

13. The method of claim 12, wherein the compound is DAHP.

14. The method according to any one of claims 11 to 13, wherein the hearing loss is hereditary hearing loss or acquired hearing loss such as drug-induced hearing loss.

15. The method of claim 14, wherein the hearing loss is hearing loss associated with abnormal expression of Serpinb6.

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