Application of type I interferon signaling pathway inhibitors in the preparation of drugs for treating age-related cataracts

Abstract

This invention provides an application of type I interferon signaling pathway inhibitors in the preparation of drugs for treating age-related cataracts. By inhibiting type I interferon receptors, it can precisely intervene in the aging mechanism of lens epithelial cells, block the transmission of aging signals, and directly improve lens transparency, exhibiting higher therapeutic efficacy and targeting. The use of IFNAR inhibitors can effectively reverse the aging phenotype caused by STEAP3 deficiency, restore the proliferative capacity of lens epithelial cells, thereby maintaining lens transparency, significantly reducing surgical risks, and providing patients with an early intervention opportunity, delaying the onset and progression of cataracts. IFNAR inhibitors, through precise intervention in specific signaling pathways, have more significant therapeutic effects, and due to their targeting, have fewer side effects and are safer. They can not only improve existing cataracts but also play a preventive and delaying role in the early stages of cataracts. For patients with mild cataracts, the use of type I interferon receptor inhibitors can avoid premature surgical treatment, reducing patient dependence on surgery and also reducing the costs and risks associated with surgery.

Description

Technical Field

[0001] This invention relates to the field of biomedical technology, specifically to the application of type I interferon signaling pathway inhibitors in the preparation of drugs for treating age-related cataracts. Background Technology

[0002] Currently, the main treatment for age-related cataracts is surgical removal of the lens and implantation of an artificial lens. While this method effectively improves patients' vision, it still has some drawbacks, such as surgical risks, postoperative complications, and high treatment costs. Furthermore, there is a lack of drug treatments targeting the pathological mechanisms, especially in the early stages of cataracts. Traditional drug interventions mainly focus on anti-oxidation and anti-inflammation; however, these therapies do not directly address the root cause of cataracts—the aging of lens epithelial cells (LECs).

[0003] In recent years, research has revealed that cellular senescence is a crucial mechanism in many age-related diseases, including cataracts. Senescent cells activate chronic inflammation by secreting senescence-associated secretory phenotypes (SASPs), disrupting tissue homeostasis and promoting cataract development. Therefore, increasing research is focusing on preventing or treating cataracts by modulating cellular senescence mechanisms. In particular, abnormal activation of the type I interferon signaling pathway (IFN-I signaling) has been shown to play a key role in the aging process. Summary of the Invention

[0004] To address the shortcomings and deficiencies of existing technologies, this invention provides an application of type I interferon signaling pathway inhibitors in the preparation of drugs for treating age-related cataracts. By intervening in the type I interferon signaling pathway with IFNAR inhibitors (such as IFNAR1 and IFNAR2 inhibitors), the aging phenotype caused by STEAP3 deficiency can be effectively reversed, improving lens transparency and thus delaying or treating age-related cataracts. This discovery provides a novel target and strategy for the drug treatment of cataracts and has significant clinical potential.

[0005] The technical solution adopted in this invention is the application of type I interferon signaling pathway inhibitors in the preparation of drugs for treating age-related cataracts.

[0006] The type I interferon signaling pathway inhibitor is a type I interferon receptor inhibitor.

[0007] The type I interferon receptor inhibitors mentioned are IFNAR1 antagonists or IFNAR2 antagonists. These components can block the transmission of type I interferon signals and inhibit the aging phenomenon caused by STEAP3 deficiency.

[0008] The type I interferon receptor inhibitor is IFN alpha-IFNAR-IN-1 hydrochloride.

[0009] The type I interferon signaling pathway inhibitor is a small molecule IFNAR inhibitor.

[0010] The type I interferon signaling pathway inhibitor is an antibody drug that targets the type I interferon receptor.

[0011] The type I interferon signaling pathway inhibitor is a vector containing repressive genes that edit IFNAR1 and IFNAR2.

[0012] The concentration of the type I interferon receptor inhibitor is 2 μM-10 μM.

[0013] Drug dosage form: It can be topical eye drops, oral tablets or injections, depending on the patient's treatment needs and the bioavailability of the drug.

[0014] Excipients: Drugs may contain some common pharmaceutical excipients, such as stabilizers, humectants, and buffers, to ensure the stability and biocompatibility of the drug.

[0015] Preparation method:

[0016] Preparation of type I interferon receptor inhibitors: The preparation process of IFN alpha-IFNAR-IN-1 hydrochloride mainly includes the synthesis of IFN alpha-IFNAR-IN-1, reaction with hydrochloric acid to form the hydrochloride form, and subsequent crystallization, purification, and drying steps. These steps ensure that the final hydrochloride product has sufficient purity and stability, making it suitable for pharmaceutical applications.

[0017] Formulation preparation method: IFNAR inhibitors are mixed with excipients to prepare the desired dosage form (such as eye drops, tablets, or injections). For ophthalmic drugs, drug dispersions with appropriate particle sizes can be prepared by methods such as ultrasonic emulsification and solvent evaporation to ensure that the drug can quickly reach the eye and maintain an effective concentration.

[0018] Type I interferon signaling pathway inhibitors can also be: 1. Small Molecule IFNAR Inhibitors: In addition to recombinant protein formulations, small molecule compounds can also be developed as IFNAR inhibitors. Small molecule drugs have good penetration and are suitable for oral or injectable administration. The preparation methods for these small molecule inhibitors can involve high-throughput screening to identify potential inhibitors, followed by optimization, ultimately developing them into highly selective and efficient small molecule drugs.

[0019] 2. Targeted Antibody Therapies: Another alternative is to use monoclonal antibodies to target the type I interferon receptor. Antibody drugs can inhibit the activation of this signaling pathway by binding to the type I interferon receptor and blocking its binding to type I interferon.

[0020] 3. Gene Therapy: Gene therapy can also be considered, involving the introduction of the repressive genes for IFNAR1 and IFNAR2 into lens epithelial cells to achieve sustained inhibition of the type I interferon signaling pathway. This method requires stable gene expression using viral vectors or CRISPR-Cas9 technology.

[0021] The beneficial effects of this invention are as follows: This invention provides an application of type I interferon signaling pathway inhibitors in the preparation of drugs for treating age-related cataracts. By inhibiting type I interferon receptors, it can precisely intervene in the aging mechanism of lens epithelial cells, block the transmission of aging signals, and directly improve lens transparency, exhibiting higher therapeutic efficacy and targeting. Through the use of IFNAR inhibitors, the aging phenotype caused by STEAP3 deficiency can be effectively reversed, restoring the proliferative capacity of lens epithelial cells, thereby maintaining lens transparency. Compared with traditional surgical treatment methods, this provides a non-invasive, non-surgical treatment option, significantly reducing surgical risks and offering patients an opportunity for early intervention, delaying the occurrence and progression of cataracts. IFNAR inhibitors, through precise intervention in specific signaling pathways, have more significant therapeutic effects, and due to their targeting, have fewer side effects and are safer. It can not only improve existing cataracts but also play a preventive and delaying role in the early stages of cataracts. For patients with mild cataracts, the use of type I interferon receptor inhibitors can avoid premature surgical treatment, reducing patient dependence on surgery and also reducing the costs and risks associated with surgery. Attached Figure Description

[0022] Figure 1This study aimed to investigate the reversibility of STEAP3 knockdown-induced cellular senescence and cataract-like lesions by interferon receptor inhibition. The study included: A. RT-qPCR analysis of the knockdown efficiency of IFNAR1 in HLE-B3 cells using different siRNAs (Si IFNAR1-1, 2, 3) (n=3); B. RT-qPCR analysis of the knockdown efficiency of IFNAR2 in HLE-B3 cells using different siRNAs (Si IFNAR2-1, 2, 3) (n=3); C. RT-qPCR analysis of IFNAR1 and IFNAR2 expression in MOCK, Si NC, and Si STEAP3 HLE-B3 cells after co-transfection with highly efficient IFNAR siRNAs (n=3); D. RT-qPCR analysis of CCK-8 cell viability (left), P21 expression (middle), and relative P16 protein expression (right). The subjects were HLE-B3 cells transfected with Si STEAP3 and Si NC siRNAs. E. The transparency of the lens treated with H2O2 and different concentrations of IFNAR inhibitors was observed at 12 and 48 hours, indicating that IFNAR inhibition could reduce the severity of cataracts; F. Western blot analysis showed the expression level of p16, using β-actin as a loading control, revealing the effects of Si STEAP3, Si IFNARs, and IFNAR inhibitors at different concentrations (2 μM, 5 μM, 10 μM) on p16 protein expression. Statistical significance is defined as ns (no statistical significance). P<0.05, P<0.01, P<0.001, P<0.0001 is marked. Detailed Implementation

[0023] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. Based on the embodiments of the present invention, other embodiments obtained by those skilled in the art without creative effort are all within the scope of protection of the present invention.

[0024] Experimental Analysis Interference with IFNAR expression led to downregulation of IFNAR expression in HLE-B3. To interfere with IFNAR expression, HLE-B3 cells were transfected and divided into eight groups: MOCK group, Si NC group, Si IFNAR1-1 group, Si IFNAR1-2 group, Si IFNAR1-3 group, Si IFNAR2-1 group, Si IFNAR2-2 group, and SiIFNAR2-3 group. RNA samples were prepared from the eight groups, and RT-qPCR experiments were performed. The results showed that the mRNA expression levels of IFNAR1 and IFNAR2 in the Si RNA group were lower than those in the MOCK and NC groups. Figure 1 Based on interference efficiency, SiIFNAR1-3 and SiIFNAR2-1 groups were selected as the siRNAs used in this experiment to interfere with the expression of IFNAR1 and IFNAR2. Figure 1 C).

[0025] Inhibition of IFNARs can improve the proliferation activity of HLECs. To verify the potential role of IFN-I in HLEC senescence, we added Si STEAP3 to HLE-B3 cells 24 h after the addition of Si NC, Si IFNAR1 / 2, and different concentrations of IFNAR inhibitor (IFN alpha-IFNAR-IN-1 hydrochloride), resulting in six groups: MOCK group, Si STEAP3+Si NC group, Si STEAP3+Si IFNARs group, Si STEAP3+IFNARs inhibitor 2μM group, Si STEAP3+IFNARs inhibitor 5μM group, and Si STEAP3+IFNARs inhibitor 10μM group. All groups underwent medium changes at the same time after each reagent addition. Cell proliferation activity was assessed using the CCK8 assay, and the expression levels of p21 and p16 in the six groups were detected by qRT-PCR. The results showed that the proliferation capacity of STEAP3-deficient HLE-B3 cells was significantly restored after interferon receptor inhibition, and the expression of aging markers p16 and p21 was reduced. Figure 1 D and Figure 1 These data indicate that blocking type I interferon signaling can reverse STEAP3 deficiency-induced cellular senescence. In in vitro experiments, inhibiting IFNAR in a rabbit H2O2-induced cataract model by adding different concentrations of IFNAR inhibitors significantly improved lens transparency. Figure 1 E).

[0026] In summary: This invention provides a novel drug intervention strategy targeting the molecular mechanisms of age-related cataracts through the application of type I interferon receptor inhibitors. Compared with existing treatment methods, this invention has the following significant advantages: Precision treatment, more targeted: Existing technologies largely rely on antioxidant and anti-inflammatory drugs, which can provide some relief to senescent cells, but fail to directly address the fundamental mechanism of cataracts—the abnormal activation of the type I interferon signaling pathway. This invention, by inhibiting the type I interferon receptor (IFNAR), can precisely intervene in the aging mechanism of lens epithelial cells, blocking the transmission of aging signals and directly improving lens transparency, resulting in higher therapeutic efficacy and targeting.

[0027] Improves lens transparency and slows cataract progression: The use of IFNAR inhibitors can effectively reverse the aging phenotype caused by STEAP3 deficiency, restore the proliferative capacity of lens epithelial cells, and thus maintain lens transparency. Compared with traditional surgical treatments, this provides a non-invasive, non-surgical treatment option that can significantly reduce surgical risks and offer patients an opportunity for early intervention, delaying the onset and progression of cataracts.

[0028] Significant therapeutic effect with few side effects: Compared to existing antioxidant and anti-inflammatory drugs, IFNAR inhibitors have a more direct and effective effect. While existing drugs can alleviate age-related symptoms, their effects are often limited and they may cause certain side effects. In contrast, IFNAR inhibitors, by precisely intervening in specific signaling pathways, have a more significant therapeutic effect, and due to their targeted nature, they have fewer side effects and are safer.

[0029] Suitable for patients with early-stage cataracts, reducing reliance on surgery: The treatment method of this invention can not only improve existing cataracts, but also play a role in preventing and delaying the onset of cataracts in their early stages. For patients with mild cataracts, the use of type I interferon receptor inhibitors can avoid premature surgical treatment, reduce patients' dependence on surgery, and also reduce the costs and risks associated with surgery.

[0030] Treatment costs may be lower: The type I interferon receptor inhibitor treatment method proposed in this invention, if widely adopted, could significantly reduce costs compared to the high cost of surgical treatment, providing patients with an affordable treatment option. This would be particularly beneficial in low-income areas with limited medical resources, offering greater accessibility to the drug therapy.

[0031] Improve patients' quality of life and reduce postoperative complications: Compared to surgical treatment, the drug treatment method provided by this invention is non-invasive, avoiding complications such as infection, bleeding, and cataract recurrence that may occur with surgery. Furthermore, patients do not require prolonged recovery or complex postoperative care during treatment, which helps improve their quality of life.

[0032] Reduced environmental pollution: Traditional cataract treatment relies on surgery and the implantation of artificial lenses, which involves the disposal of medical waste. In contrast, drug therapy avoids the use of a large number of surgical instruments and the production of artificial lenses, thus reducing medical waste and environmental pollution to some extent, which aligns with the development trend of green medicine.

[0033] The specific embodiments described in this invention are merely illustrative of the spirit of the invention. Those skilled in the art to which this invention pertains can make various modifications or additions to the described specific embodiments or use similar methods to substitute them, without departing from the spirit of the invention or exceeding its defined scope. Although the invention has been detailed and described in the accompanying drawings and foregoing description, such descriptions are considered illustrative or exemplary rather than restrictive. It should be understood that changes and modifications can be made by those skilled in the art within the scope of the following claims.

Claims

1. Application of type I interferon signaling pathway inhibitors in the preparation of drugs for treating age-related cataracts.

2. The application according to claim 1, characterized in that, The type I interferon signaling pathway inhibitor is a type I interferon receptor inhibitor.

3. The application according to claim 2, characterized in that, The type I interferon receptor inhibitor is an IFNAR1 antagonist or an IFNAR2 antagonist.

4. The application according to claim 2, characterized in that, The type I interferon receptor inhibitor is IFNalpha-IFNAR-IN-1 hydrochloride.

5. The application according to claim 1, characterized in that, The type I interferon signaling pathway inhibitor is a small molecule IFNAR inhibitor.

6. The application according to claim 1, characterized in that, The type I interferon signaling pathway inhibitor is an antibody drug that targets the type I interferon receptor.

7. The application according to claim 1, characterized in that, The type I interferon signaling pathway inhibitor is a vector containing repressive genes that edit IFNAR1 and IFNAR2.

8. The application according to claim 2, characterized in that, The concentration of the type I interferon receptor inhibitor is 2 μM-10 μM.

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