CN115957311A - Application of histone methyltransferase EZH2 in medicine for promoting optic nerve remyelination - Google Patents
Application of histone methyltransferase EZH2 in medicine for promoting optic nerve remyelination Download PDFInfo
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Abstract
The invention provides an application of histone methyltransferase EZH2 in a medicine for promoting optic nerve remyelination, and relates to the technical field of biomedicine. The invention discloses the effect of EZH2 in the process of optic nerve myelination; through an Ezh2 gene conditional knockout mouse optic nerve injury model, AAV-EZH2, AAV-CNTF, montelukast and PLX3397 are combined to treat optic nerve pinches, and the result proves that EZH2 can be used as a new molecular target for central nervous system demyelination diseases. The EZH2 combination treatment scheme is used for promoting optic nerve remyelination and provides a new strategy for remyelination treatment after central nervous system demyelination.
Description
Technical Field
The invention relates to the technical field of biomedicine, in particular to a composition and application thereof in a medicine for promoting optic nerve remyelination.
Background
In recent years, the incidence of Central Nervous System (CNS) demyelinating diseases has been increasing year by year, and the disease is mainly a Multiple Sclerosis (MS) and inflammatory demyelination, and the common diseases mainly include Multiple Sclerosis (NMO) and Neuromyelitis Optica (NMO).
The main affected part of the CNS demyelinating disease is myelin, which is a biofilm and wraps axons, and has the functions of insulating and accelerating electric pulse conduction, ensuring neuronal metabolic supply and the like. Oligodendrocytes (OLs) are involved in axonal myelination in the CNS, ensuring saltatory neurotransmission. Myelin plays a crucial role in the developmental maturation of the CNS and plasticity of neural tissue. Failure of remyelination following either a myelination defect or injury can lead to various neurodevelopmental disorders, intellectual impairment, and autism spectrum disorders. At the same time, defects in myelin repair are also the basis for neurodegenerative diseases such as multiple sclerosis and leukodystrophy. The degree of myelin destruction and regeneration is closely related to the severity of the disease and the effectiveness of the treatment. At the present time, it is known that,
the treatment of CNS demyelinating diseases is one of the difficulties in the neuro-medical field, and better methods for treating and improving prognosis can be found by further deeply researching the pathology, physiology and pathogenesis of the CNS demyelinating diseases. The optic nerve, an important component of the CNS, has been the subject of significant investigation for CNS injury repair. Both optic neuritis and optic nerve injury produce typical demyelinating lesions clinically. Optic neuritis is an acute inflammation of the optic nerve characterized by sudden loss of central vision and eye movement pain. Often associated with MS, patients can fully restore vision, usually by treatment, but may also develop irreversible vision loss. Currently, clinical treatment is mainly focused on relieving neuroinflammation and reducing the incidence of demyelination, but does not cure radically.
Disclosure of Invention
The invention aims to solve the technical problem that clinical treatment in the prior art mainly focuses on relieving neuroinflammation and reducing the incidence rate of demyelination, but cannot radically cure the neuroinflammation and the demyelination.
In order to achieve the purpose, the invention adopts the following technical scheme:
use of EZH2 for the manufacture of a medicament for promoting myelin repair or for the treatment of CNS demyelinating diseases.
The application also provides a medicine for treating CNS demyelinating diseases, which comprises AAV-EZH2 and AAV-CNTF.
Preferably, when the medicament is used for early promotion of initial differentiation of OPCs, the medicament further comprises Montelukast.
Preferably, when the medicament is used for delaying the clearance of microglia and promoting the maturation of OLs, the medicament further comprises PLX3397.
The application confirms the function of the Ezh2 gene in the formation of optic nerve myelin sheath, and confirms the influence of the Ezh2 gene on the differentiation of oligodendrocyte precursor cells, myelination and other related functions; through an Ezh2 gene conditional knockout mouse optic nerve injury model, an oligodendrocyte cell and neuron co-culture model, the effect of the Ezh2 gene on the formation and maintenance process of central nervous system myelin sheaths and the influence of the Ezh2 gene on the functions of the oligodendrocyte proliferation, differentiation and myelination are clarified from the molecular level, the cell level, the tissue level and the overall level, and a new molecular target spot is provided for the demyelinating diseases of the central nervous system. The AAV-EZH2 combined treatment scheme is intended to promote optic nerve remyelination, and a new strategy is provided for remyelination treatment after central nervous system demyelination.
Drawings
FIG. 1 illustrates the principle of the EZH2 combination regimen of the present invention for promoting remyelination of optic nerves;
FIG. 2 shows 10 weeks old wild type and Ezh2 fl/fl Olig1-Cre mouse optic nerve anti-MBP (marker myelin sheath), GST pi (marker oligodendrocyte) and DAPI immunofluorescence staining results suggest Ezh2 fl/fl Olig1-Cre mice had optic nerve myelin development disturbance compared to control group;
FIG. 3 is a related drawing showing the following results in example 4 of the present invention, showing that the mouse was subjected to intravitreal injection of AAV-CNTF virus to prepare an optic nerve pinching model 14 days after the intravitreal injection of AAV-CNTF virus, that Montelukast and PLX3397 were continuously administered for 21 days after the optic nerve pinching to promote remyelination, that CTB555 neuroproberts were intravitreally injected for 19 days after the optic nerve pinching, that materials were taken 21 days after the optic nerve pinching, and that Langfield's knot immunofluorescent staining (Caspr, ankyrin-G) and TEM results suggest Ezh2 fl/fl Olig1-Cre mice had significantly reduced remyelination of optic nerves compared to the control group.
FIG. 4 is a related drawing in example 4 of the present invention, which is used to show that 14 days after the injection of AAV-CNTF or AAV-Control virus into the vitreous of mice and the preparation of optic nerve clamp wound model after the injection of AAV-EZH2 into the optic nerve, the combination treatment of Montelukast and PLX3397 was continuously administered 21 days after the optic nerve clamp wound to promote the regeneration of myelin sheath, the material was taken 21 days after the optic nerve clamp wound, and the statistics of transmission electron microscopy suggest that the proportion of optic nerve myelinated nerve fibers in the EZH2 combination treatment group is significantly increased compared with the Control group.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail with reference to specific embodiments.
Referring to FIG. 1, the present application provides the use of enhancer of Zeste Gene homolog 2 (Enhancerorf homogeneity 2, EZH2) in the preparation of a medicament for promoting myelin repair or for treating CNS demyelinating diseases.
Wherein, EZH2 is one of the core subunits of polycomb repressive complex 2 (PRC 2), has histone methyltransferase activity, and is responsible for catalyzing the trimethylation of lysine at 27 th position of histone H3 (H3K 27me 3).
The application also provides a medicine for treating CNS demyelinating diseases, which comprises AAV-EZH2 and AAV-CNTF.
When the drug is used to promote the initial differentiation of Oligodendrocyte Precursor Cells (OPCs) at an early stage, the drug further includes Montelukast.
When the drug is used for delaying the clearance of microglia and promoting the maturation of Oligodendrocytes (OLs), the drug further comprises PLX3397.
The present application is illustrated below with reference to specific examples:
example 1:
effect of EZH2 on optic nerve myelination:
specifically, a conditional knockout mouse (Ezh 2) specifically knocking out the Ezh2 gene in Oligodendrocytes (OLs) of the central nervous system (Ezh 2) has been obtained in this example, referring to FIG. 2, by specifically knocking out the Ezh2 gene (Ezh 2fl/fl; olig1-Cre mouse, abbreviated as Ezh2 cKO; see FIG. 2 for short) fl/fl Olig1-Cre, hereinafter referred to as Ezh2 cKO), found that the expression of myelin associated protein MBP in the optic nerve of the Ezh2 cKO mice was significantly reduced and the number of mature oligodendrocytes (GST pi-positive) was significantly reduced, compared to the wild-type mice. From the above results it follows: mutations in the Ezh2 gene in Oligodendrocytes (OLs) may result in the loss of cells of the mature OLs lineage, which in turn causes impairment of optic nerve myelin development.
Example 2:
loss of EZH2 function in optic nerve OLs leads to optic nerve remyelination disorders. The axogenesis-promoting treatment regimen AAV-CNTF was given 14 days before the pinch, and the Montelukast and PLX3397 combination treatment regimen was given daily within 21 days after the pinch. Ezh2 was suggested by immunofluorescent staining of Langfei junctions (Caspr, ankyrin-G) and transmission electron microscopy results fl/fl Olig1-Cre mice had significantly reduced remyelination of optic nerves compared to the control group.
Referring to FIG. 3, an optic nerve injury model was prepared 14 days after intravitreal injection of AAV-CNTF virus in mice, montelukast and PLX3397 were administered continuously for 21 days after optic nerve injury to promote remyelination, CTB555 neurotracer was injected intravitreally 19 days after optic nerve injury, materials were taken 21 days after optic nerve injury, and Langerhans' knot immunofluorescent staining (Caspr, ankyrin-G)) And the result of the transmission electron microscope suggests Ezh2 fl/fl Olig1-Cre mice had significantly reduced remyelination of optic nerves compared to the control group.
Example 3:
the effect of the AAV-EZH2 combination remyelination therapy on remyelination after optic nerve pinch is to promote remyelination after optic nerve pinch. The axotrophic regeneration treatment protocol AAV-CNTF and myelinating AAV-EZH2 were administered 14 days before the pinch, and the Montelukast and PLX3397 combination treatment protocol was administered daily for 21 days after the pinch. The adult mouse optic nerve overexpresses the Ezh2 gene in OLs by injecting adeno-associated virus, and the effect of the AAV-EZH2 combination treatment regimen on remyelination after optic nerve bruise is clarified by transmission electron microscopy.
Referring to fig. 4, an optic nerve pinch model was prepared 14 days after intravitreal injection of AAV-CNTF or AAV-Control virus and AAV-EZH2 in optic nerve in wild type mice, montelukast and PLX3397 were continuously administered for 21 days after the optic nerve pinch to promote myelination, materials were taken 21 days after the optic nerve pinch, and the transmission electron microscopy statistics suggested that the ratio of optic nerve myelinated nerve fibers in the EZH2 combination treatment group was significantly increased compared to each Control group.
Based on the above examples, EZH2, as a histone methyltransferase, affects myelin-associated protein expression and plays an important role in myelination, maintenance and remyelination of the central nervous system optic nerve.
Claims (4)
- Use of ezh2 for the preparation of a medicament for promoting optic nerve myelin repair or for the treatment of CNS demyelinating diseases.
- 2. A medicament for treating CNS demyelinating diseases, comprising: including AAV-EZH2 and AAV-CNTF.
- 3. A medicament for the treatment of CNS demyelinating diseases according to claim 2, characterized in that: when the drug is used to promote the initial differentiation of OPCs early, the drug also includes Montelukast.
- 4. A medicament for the treatment of CNS demyelinating diseases according to claim 2, wherein: when the medicament is used for delaying microglial clearance and promoting maturation of OLs, the medicament also comprises PLX3397.
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CN111705069A (en) * | 2020-06-19 | 2020-09-25 | 武汉纽福斯生物科技有限公司 | Multi-neurotrophic factor combined expression vector and application thereof |
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WO2021222507A1 (en) * | 2020-05-01 | 2021-11-04 | The Children's Medical Center Corporation | Compositions and methods of promoting myelination |
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WO2020263484A1 (en) * | 2019-06-28 | 2020-12-30 | Mayo Foundation For Medical Education And Research | Methods and materials for treating neuromyelitis optica spectrum diseases |
WO2021222507A1 (en) * | 2020-05-01 | 2021-11-04 | The Children's Medical Center Corporation | Compositions and methods of promoting myelination |
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