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Application of Ptbp1 inhibitor in preventing and/or treating nervous system diseases related to functional neuron death

A neurological disease, neuron technology, applied in the field of biomedicine, can solve problems such as failure to prevent the development of the disease

Inactive Publication Date: 2021-03-09
CENT FOR EXCELLENCE IN BRAIN SCI & INTELLIGENCE TECH CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It should be pointed out that all these methods can only partially alleviate the disease, and cannot achieve the effect of preventing the development of the disease.

Method used

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  • Application of Ptbp1 inhibitor in preventing and/or treating nervous system diseases related to functional neuron death
  • Application of Ptbp1 inhibitor in preventing and/or treating nervous system diseases related to functional neuron death
  • Application of Ptbp1 inhibitor in preventing and/or treating nervous system diseases related to functional neuron death

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0304] Example 1 Using CasRx to specifically knock down Ptbp1 in vitro

[0305] To determine the efficiency of CasRx-mediated Ptbp1 knockdown, six gRNAs targeting Ptbp1 were first designed, and their inhibitory efficiencies were compared in cultured N2a cells and astrocytes ( figure 1 A and 1B). It was found that co-transfection of two gRNAs (combination of 5 and 6) targeting Ptbp1 exon IV and VII regions could achieve 87% ± 0.4% and 76% ± 4% in N2a cells and astrocytes, respectively. decreased (Figure 1C and 1D). RNA whole-transcriptome sequencing data further showed that this knockdown was very specific ( figure 1 E, 1F and 2A).

Embodiment 2

[0306] Example 2 Conversion of Müller glia to optic ganglion cells in the mature retina

[0307] Previous studies have found that knockdown of Ptbp1 by shRNA can convert cultured mouse fibroblasts and N2a cells into functional neurons, and next investigated whether Ptbp1 knockdown in the mature retina regenerates Müller glial cells in vivo. into optic ganglion cells. To specifically and permanently label retinal Müller glia, we injected AAV-GFAP-GFP-Cre into the eyes of Ai9 mice (Rosa-CAG-LSL-tdTomato-WPRE) to specifically induce tdTomato in Müller glia Expression in cells ( figure 2 B and 2C). We also constructed AAV-GFAP-CasRx-Ptbp1 (gRNA 5+6) driven by the Müller glial cell-specific promoter GFAP, hoping to specifically knock down Ptbp1 in Müller glial cells and we simultaneously constructed A control virus AAV-GFAP-CasRx not targeting Ptbp1 ( image 3 A and 2D). We first co-injected AAV-GFAP-CasRx-Ptbp1 and AAV-GFAP-Cre-GFP under the retina of Ai9 mice aged about 5 w...

Embodiment 3

[0308] Example 3 Conversion of MG to RGC in retinal injury mouse model

[0309] To explore whether MG-induced RGCs could replenish lost RGCs in a mouse model of retinal injury, we injected NMDA (200 mM) intravitreally into 4- to 8-week-old Ai9 mice, resulting in most Death of RGCs and reduction of inner plexiform layer (IPL) thickness. Two to three weeks after injection of NMDA, AAV-GFAP-CasRx-Ptbp1 plus AAV-GFAP-GFP-Cre or control AAV virus ( Figure 6 A and 6B). One month after AAV injection, we found that the number of Brn3a or Rbpms-positive cells in the optic ganglion cell layer was significantly increased in AAV-GFAP-CasRx-Ptbp1-injected retinas. Interestingly, most of these cells were positive for tdTomato. However, we did not find an increase in the optic ganglion cell layer injected with control AAV ( Figure 6 C-6F). To determine whether MG-induced RGCs are integrated into retinal circuits and have the ability to receive visual information, we performed extracel...

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Abstract

The invention relates to an application of a Ptbp1 inhibitor in preventing and / or treating nervous system diseases related to functional neuron death. Specifically, the invention provides an application of a Ptbp1 gene or RNA or an encoded protein inhibitor of the Ptbp1 gene or RNA in preparation of a composition or a preparation, wherein the composition or the preparation is used for preventing and / or treating nervous system diseases related to functional neuron death. By inhibiting the expression or activity of the Ptbp1 gene or RNA or encoded protein of the Ptbp1 gene or RNA of astrocytes in the brain, transdifferentiation and differentiation of the astrocytes to dopamine neurons can be effectively induced; and meanwhile, by inhibiting the expression or activity of the Ptbp1 gene or RNAor encoded protein of the Ptbp1 gene or RNA in Muller glial cells in the retina, transdifferentiation of Muller glial cells into optic ganglion cells can be effectively induced, so that nervous system diseases related to functional neuron death are prevented and / or treated.

Description

technical field [0001] The invention relates to the field of biomedicine. More specifically, the present invention relates to the use of Ptbp1 inhibitors in the prevention and / or treatment of neurological diseases related to functional neuron death. Background technique [0002] Parkinson's disease (PD) is a severe neurodegenerative disorder characterized by the loss of dopamine neurons in the substantia nigra of the midbrain. Previous studies have achieved direct reprogramming of astrocytes to dopamine neurons in vitro and in animal models by simultaneously overexpressing several transcription factors. However, Ptbp1-mediated neuronal reprogramming in vivo has not been reported so far. [0003] At present, the main treatment for Parkinson's disease is the medicine represented by levodopa preparation. At the same time, surgical treatment can also improve symptoms to a certain extent. It should be pointed out that all these means can only partially alleviate the condition...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61P25/00A61P25/16A61P25/02A61P25/28A61P25/18A61P25/24A61P25/14A61P27/02A61P27/06C12Q1/02
CPCA61K45/00A61P25/00A61P25/02A61P25/14A61P25/16A61P25/18A61P25/24A61P25/28A61P27/02A61P27/06G01N33/5008G01N2500/10A61K45/06A61K48/005C12N15/113C12N15/90C12N2750/14143C12N2310/20
Inventor 杨辉周海波
Owner CENT FOR EXCELLENCE IN BRAIN SCI & INTELLIGENCE TECH CHINESE ACAD OF SCI
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