CN113274400A - Use of tetrahedral framework nucleic acids in medicaments for the treatment of multiple sclerosis - Google Patents
Use of tetrahedral framework nucleic acids in medicaments for the treatment of multiple sclerosis Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Abstract
The invention provides the use of a tetrahedral framework nucleic acid in a medicament for the treatment of demyelinating diseases, such as multiple sclerosis. The tetrahedral framework nucleic acid is formed by base complementary pairing of 4 single-stranded DNAs; the sequences of the 4 single-stranded DNAs are respectively selected from the sequences of SEQ ID NO. 1-4 one by one. The tetrahedral framework nucleic acid can restore the expression of myelin sheath related protein by inhibiting apoptosis of cells of the central nervous system, thereby accelerating remyelination and enriching the number of myelinated axons. Therefore, the tetrahedral framework nucleic acid can effectively treat demyelinating diseases, particularly multiple sclerosis, and has excellent clinical application prospect.
Description
Technical Field
The invention belongs to the field of biomedicine, and particularly relates to application of tetrahedral framework nucleic acid in a medicament for treating demyelinating diseases, such as multiple sclerosis.
Background
Demyelinating diseases are acquired diseases with different etiologies, different clinical manifestations and similar characteristics, and are characterized by the pathological changes of demyelination of nerve fibers while nerve cells remain relatively intact. Myelin sheath protects neurons and allows nerve impulses to be transmitted quickly over neurons, so that demyelination can affect nerve impulse transmission.
As a disease with acute attack or subacute damage to nerve center, multiple sclerosis occurs when ischemic degeneration secondary to damaged nerve is delayed in treatment. Multiple Sclerosis (MS) is one of the most common demyelinating diseases, having affected 200-300 million people worldwide, with a prevalence of about 50-300/10 ten thousand in different regions. Clinically, patients can have weakness, spasm, imbalance, fatigue, hypopsia, cognitive dysfunction and neuropathic pain, most of the patients have symptoms for the first time in 20-40 years, and the complications of MS cause continuous neurological disability, seriously affect the work and life of the patients, and bring huge economic and social burden. Histopathologically, MS lesions manifest as multiple demyelinating lesions, inflammatory infiltrates, axonal damage, and oligodendrocyte loss.
So far, no measures for effectively curing MS exist, early treatment is mostly treated by hormone and nutrition therapy, but the curative effect is difficult to control and solidify. Demyelination causes recurrence of axonal damage secondary to severe nerve function damage, and even further aggravation of nerve function symptoms. Three strategies for treating MS are mainly proposed at present, including anti-inflammatory immunosuppressive therapy, promoting remyelination and neuroprotection.
Most drugs act on the immune system, acting through immunosuppression or immunomodulation, and do not directly promote myelin repair, such as cyclophosphamide, interferon- β, glatiramer acetate, and mitoxantrone. The medicines can actually achieve better curative effect clinically, but the mechanism and the target of the medicine action are single, and no medicine can finally cure patients or can permanently inhibit the disease development. And because the medicament inhibits the immune system of the organism and attacks lymphocytes, the toxic and side effects of the medicament are enhanced.
By promoting remyelination, the remyelinated myelin protects neurons, transmits nerve impulses and can better promote disease repair. Remyelination has proven effective in acute animal models of MS, such as the monoclonal antibody opimicumab (with the target LINGO1), antimuscarinic drugs such as clemastine and erythropoietin, but the results in the early stages of these clinical trials are less than ideal.
Therefore, there is still a need to research a novel drug for treating demyelinating diseases such as MS by repairing remyelination and protecting the nerve function.
Disclosure of Invention
The invention provides application of tetrahedral framework nucleic acid in a medicament for treating demyelinating diseases, wherein the tetrahedral framework nucleic acid is formed by complementary base pairing of 4 single-stranded DNAs; the sequences of the 4 single-stranded DNAs are respectively selected from the sequences of SEQ ID NO. 1-4.
Further, the tetrahedral framework nucleic acid is prepared by the following method: 4 single-stranded DNAs of tetrahedral framework nucleic acid are placed at a temperature sufficient for denaturation and maintained for more than 10min, and then the temperature is reduced to 2-8 ℃ and maintained for more than 20 min.
Further, the tetrahedral framework nucleic acid is prepared by the following method: the 4 single strands of the DNA tetrahedron are placed at 95 ℃ for 10min, and then the temperature is reduced to 4 ℃ for more than 20 min.
Further, the above-mentioned drug is a drug for the treatment of demyelinating diseases, preferably a drug for the treatment of multiple sclerosis, acute disseminated encephalomyelitis, acute necrotizing hemorrhagic leukoencephalopathy or diffuse cerebral sclerosis, more preferably a drug for the treatment of multiple sclerosis.
Further, the above-mentioned drug is a drug for promoting remyelination.
Further, the above-mentioned drugs are drugs that promote an increase in the number of the marrow fibers and the thickness of the myelin sheath.
Further, the above-mentioned drug is a drug which increases the expression of MBP and/or MOG; preferably, the agent that increases MBP expression is an agent that upregulates the PI3K/AKT/m-TOR signaling pathway.
Further, the above-mentioned drugs are drugs for alleviating inflammatory reactions of the central nervous system.
Furthermore, the medicine is used for inhibiting the activation of microglia and inhibiting the abnormal proliferation of astrocytes.
The invention provides a new application of tetrahedral framework nucleic acid in a medicament for treating demyelinating diseases. The tetrahedral framework nucleic acid can restore the expression of myelin sheath related protein by inhibiting apoptosis of cells of the central nervous system, thereby accelerating remyelination and enriching the number of myelinated axons. In addition, tetrahedral framework nucleic acids are able to inhibit the abnormal activation and proliferation of microglia and astrocytes, thereby alleviating inflammatory responses. These phenomena are associated with upregulation of the phosphorylation of the PI3K-AKT-mTOR signaling pathway by tFNAs. Therefore, the tetrahedral framework nucleic acid can effectively treat demyelinating diseases (multiple sclerosis, acute disseminated encephalomyelitis, acute necrotizing hemorrhagic leukoencephalopathy, diffuse cerebral sclerosis and the like), particularly multiple sclerosis, and has excellent clinical application prospect.
The terms of the present invention: MBP: myelin basic protein; and (3) MOG: myelin oligodendrocyte glycoprotein.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Drawings
FIG. 1 is a PAGE electrophoresis of tetrahedral framework nucleic acids and their single strands.
FIG. 2 is a capillary electrophoresis image of tetrahedral framework nucleic acid and its single strands.
FIG. 3 is a particle size diagram of tetrahedral framework nucleic acids.
FIG. 4 is a Zeta potential diagram of tetrahedral framework nucleic acids.
FIG. 5 is a transmission electron microscope set of tetrahedral framework nucleic acids.
FIG. 6 is a graph of the mouse movement locus for each group of open field experiments.
FIG. 7 is an LFB staining pattern of the callose myelin sheath of each group.
FIG. 8 is a transmission electron micrograph of callus of each group.
FIG. 9 is an immunofluorescence map of callus MBP for each group.
FIG. 10 is MOG immunofluorescence chart of callus of each group.
FIG. 11 is an immunofluorescence chart of callus Iba1 of each group.
FIG. 12 is a GFAP immunofluorescence map of callus of each group.
FIG. 13 is a fluorescent image of callus TUNEL of each group.
FIG. 14 is a WB plot of MBP expression levels and associated pathway changes in brain tissues of each group.
Detailed Description
The raw materials and equipment used in the invention are known products and are obtained by purchasing commercial products.
Example 1 Synthesis of DNA tetrahedron
Four DNA single strands (S1, S2, S3, S4) were dissolved in TM Buffer (10mM Tris-HCl,50mM MgCl2, pH 8.0) to a final concentration of 1. mu.M, mixed well, rapidly heated to 95 ℃ for 10 minutes, then rapidly cooled to 4 ℃ for 20 minutes or more, and the tetrahedral framework nucleic acid was obtained.
The sequences of the four single strands are as follows:
the synthesized tetrahedral framework nucleic acid has the size of about 180KD as seen by PAGE gel electrophoresis (figure 1) and capillary electrophoresis (figure 2), and the tetrahedral framework nucleic acid is considered to be successfully synthesized. The tetrahedral particle size was about 10.15d.nm (FIG. 3) with a potential of-2.83 mV (FIG. 4). The tetrahedral structure of the features was seen under the mirror using transmission electron microscopy (fig. 5).
The beneficial effects of the present invention are demonstrated by the following experimental examples.
Experimental example 1 therapeutic Effect of tetrahedral framework nucleic acid on model of multiple sclerosis (demyelinating disease)
1. Experimental methods
Model animals: a MS model of demyelination is prepared by using Cuprizone (CPZ) to induce C57BL/6J mice, and the effect and the possible mechanism of promoting remyelination and repair of tetrahedral framework nucleic acid are explored. A total of 25C 57BL/6 male mice were collected at 6-8 weeks of age. The treatment group was divided into 8 normal groups, 9 control groups and 8 treatment groups. The normal group was fed with the normal feed daily, and the control group and the treatment group were fed with the mixed feed containing 0.2% CPZ daily. After feeding for 6 weeks, the treatment group and the control group were injected with 0.1mL of tetrahedral framework nucleic acid (1000nM) and physiological saline in the tail vein, respectively, and 4 times every other day.
And (3) relevant index detection: carrying out an open field experiment on a mouse the next day after dosing is finished, then taking a mouse callus, observing changes of myelin sheath in a corpus callosum region by using LFB myelin sheath staining, MBP and MOG immunofluorescence staining, observing various groups of ultrastructures by using a transmission electron microscope, observing changes of microglia and astrocytes in the corpus callosum region by using IBa1 and GFAP immunofluorescence staining, and detecting the apoptosis proportion in the corpus callosum by using a TUNEL method. WB detected MBP expression levels and PI3K-AKT-mTOR pathway changes in each group.
2. Results of the experiment
(1) Symptoms and signs of MS include limb weakness, paresthesia, ataxia, and the like, and paroxysmal symptoms also include spasticity, dysarthria, epilepsy, and painful discomfort, which severely affect the motor function of the patient. The invention discovers that the total movement course of a treatment group is increased compared with that of a control group through an open field experiment, proves that the spontaneous activity intensity and the movement function of a mouse are improved (figure 6), and shows that the tetrahedral framework nucleic acid can effectively improve the movement disorder symptoms of MS patients and has a treatment effect on MS diseases.
(2) Compared with the normal group, the phenomena of lightening blue staining and loose structure appear in the myelin LFB staining result of the corpus callosum area of the control group, and the remyelination process is accelerated because the myelin structure is obviously restored after the treatment by using the tetrahedral framework nucleic acid, which shows that the tetrahedral framework nucleic acid has the functions of protecting the myelin structure and promoting remyelination (figure 7).
(3) The transmission electron microscope shows that the corpus callosum of the control group has obvious myelin ultramicro structure damage and axon mitochondrial damage, more vacuoles and dissolution appear, and the number of myelinated axons is obviously reduced. While the number of remyelinated axons in the treated group was significantly increased and the integrity of the myelin sheet layer structure was increased, suggesting that tetrahedral framework nucleic acids contribute to the recovery of myelinated fiber number and myelin thickness, accelerating remyelination progression (fig. 8).
(4) The results of the callous immunofluorescence staining on the expression levels of the myelination indicators MBP and MOG respectively show that the fluorescence signals of the MBP and MOG in the mouse calluses are obviously weakened under the induction of CPZ, and the expression levels of the MBP and MOG in the state can be improved by the administration of the tetrahedral framework nucleic acid, which shows that the administration of the tetrahedral framework nucleic acid has obvious promotion effect on the regeneration and repair of the myelination (FIGS. 9 and 10).
(5) The proliferation of astrocytes and microglia in MS is currently considered to be one of the obstacles to remyelination repair because it is not only involved in the inflammatory and immune responses, but the simultaneous formation of glial scars also hinders the remyelination process. In contrast, the Iba1 (FIG. 11) and GFAP (FIG. 12) immunofluorescent staining in the experiment showed a decrease in both Iba1 and GFAP fluorescence intensity in the treated groups, indicating that the tetrahedral framework nucleic acids were able to inhibit astrocyte dysplasia and microglial activation, thereby alleviating the inflammatory response.
(6) TUNEL method showed lower levels of apoptosis were detected in the treatment group (figure 13), suggesting that tetrahedral framework nucleic acids can inhibit CPZ-induced apoptosis in callus.
(7) Brain tissue WB showed a significant increase in MBP expression in the treatment group, with activation of the PI3K-AKT-mTOR phosphorylation pathway (fig. 14), suggesting that tetrahedral framework nucleic acids were able to upregulate phosphorylation of the PI3K-AKT-mTOR signaling pathway, promoting MBP expression and thus remyelination repair.
In conclusion, the invention provides a new application of tetrahedral framework nucleic acid in a medicament for treating demyelinating diseases. The tetrahedral framework nucleic acid can restore the expression of myelin sheath related protein by inhibiting apoptosis of cells of the central nervous system, thereby accelerating remyelination and enriching the number of myelinated axons. In addition, tetrahedral framework nucleic acids are able to inhibit the abnormal activation and proliferation of microglia and astrocytes, thereby alleviating inflammatory responses. These phenomena may be associated with upregulation of the phosphorylation of the PI3K-AKT-mTOR signaling pathway by tFNAs. Therefore, the tetrahedral framework nucleic acid can effectively treat demyelinating diseases, particularly multiple sclerosis, and has excellent clinical application prospect.
SEQUENCE LISTING
<110> Sichuan university
<120> use of tetrahedral framework nucleic acid in medicine for treating multiple sclerosis
<130> GYKH1118-2021P0113224CC
<160> 4
<170> PatentIn version 3.5
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Claims (10)
1. Use of a tetrahedral framework nucleic acid in a medicament for the treatment of demyelinating diseases, wherein the tetrahedral framework nucleic acid is formed from 4 single-stranded DNAs through base complementary pairing; the sequences of the 4 single-stranded DNAs are respectively selected from the sequences of SEQ ID NO. 1-4.
2. The use of claim 1, wherein said tetrahedral framework nucleic acid is prepared by a method comprising: 4 single-stranded DNAs of tetrahedral framework nucleic acid are placed at a temperature sufficient for denaturation and maintained for more than 10min, and then the temperature is reduced to 2-8 ℃ and maintained for more than 20 min.
3. The use of claim 2, wherein said tetrahedral framework nucleic acid is prepared by a method comprising: the 4 single strands of the DNA tetrahedron are placed at 95 ℃ for 10min, and then the temperature is reduced to 4 ℃ for more than 20 min.
4. The use according to any one of claims 1 to 3, wherein the medicament is a medicament for the treatment of a demyelinating disease.
5. Use according to claim 4, wherein the medicament is a medicament for the treatment of multiple sclerosis, acute disseminated encephalomyelitis, acute necrotizing hemorrhagic leukoencephalopathy or diffuse cerebral sclerosis, preferably for the treatment of multiple sclerosis.
6. The use of any one of claims 5, wherein the medicament is a remyelination promoting medicament.
7. The use of claim 6, wherein the medicament is a medicament that promotes an increase in the number of myelin fibers and myelin sheath thickness.
8. Use according to claim 6 or 7, wherein the medicament is a medicament that increases expression of MBP and/or MOG; preferably, the agent that increases MBP expression is an agent that upregulates the PI3K/AKT/m-TOR signaling pathway.
9. Use according to claim 6 or 7, wherein the medicament is a medicament for alleviating an inflammatory response of the central nervous system.
10. The use of claim 9, wherein the medicament is a medicament for inhibiting microglial activation and inhibiting astrocyte dysplasia.
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Cited By (4)
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| CN114159458A (en) * | 2021-12-10 | 2022-03-11 | 四川大学 | Use of tetrahedral framework nucleic acid in medicine for treating epilepsy |
| CN114404608A (en) * | 2022-03-01 | 2022-04-29 | 四川大学 | Embedded siRNA-carrying tetrahedral framework nucleic acid and application thereof |
| CN114748604A (en) * | 2022-05-10 | 2022-07-15 | 四川大学 | Compound for bone marrow damage and/or inhibition |
| CN115006423A (en) * | 2022-06-28 | 2022-09-06 | 四川大学 | Application of tetrahedral framework nucleic acid in preparation of medicine for preventing and/or treating post-traumatic brain syndrome |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114404608B (en) * | 2022-03-01 | 2023-02-03 | 四川大学 | Embedded siRNA-carrying tetrahedral framework nucleic acid and application thereof |
| CN114748604A (en) * | 2022-05-10 | 2022-07-15 | 四川大学 | Compound for bone marrow damage and/or inhibition |
| CN114748604B (en) * | 2022-05-10 | 2023-04-07 | 四川大学 | Compound for bone marrow damage and/or inhibition |
| CN115006423A (en) * | 2022-06-28 | 2022-09-06 | 四川大学 | Application of tetrahedral framework nucleic acid in preparation of medicine for preventing and/or treating post-traumatic brain syndrome |
| CN115006423B (en) * | 2022-06-28 | 2023-07-18 | 四川大学 | Application of tetrahedral framework nucleic acid in preparation of medicine for preventing and/or treating brain trauma sequelae |
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