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Reprogramming of non-neuronal cells into neurons and methods and compositions to treat neurodegenerative diseases and disorders

A neuron cell, reprogramming technology, used in nervous system diseases, nervous system cells, cell culture active agents, etc.

Pending Publication Date: 2021-02-02
RGT UNIV OF CALIFORNIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Cell replacement has been used with great success in the treatment of hematopoietic disorders; however, in other diseases this approach has either shown limited efficacy or is associated with a risk of triggering an immune response and / or tumor formation

Method used

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  • Reprogramming of non-neuronal cells into neurons and methods and compositions to treat neurodegenerative diseases and disorders
  • Reprogramming of non-neuronal cells into neurons and methods and compositions to treat neurodegenerative diseases and disorders
  • Reprogramming of non-neuronal cells into neurons and methods and compositions to treat neurodegenerative diseases and disorders

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0218] Example 1. Expression of miR-9 and Brn2 in astrocytes.

[0219] Testing PTB / nPTB-regulated gene expression programs in mouse and human primary astrocytes. As shown in Figures 2C-2F, both miR-124 and miR-9 were highly expressed in neurons but not in fibroblasts. In human and mouse astrocytes, miR-124 was found to be present at low levels (Fig. 2C and 2D), which may explain the high REST levels in this non-neuronal cell type and suggest that astrocytes Tight PTB-regulated circuits in cells. However, unexpectedly, miR-9 was found to be highly expressed in both mouse and human astrocytes (Fig. 2E and 2F). Brn2 followed the same expression pattern as miR-9, being low in fibroblasts but high in both astrocytes and neurons (Fig. 2A and 2B). These observations are consistent with the idea that astrocytes and neurons may share a common ancestor.

Embodiment 2

[0220] Example 2. Knockdown of PTB in mouse and human astrocytes leads to nPTB induction followed by nPTB decline.

[0221] Recognizing in the present invention that astrocytes already express factors that may be important for neuronal maturation (such as miR-9 and Brn2), the possibility that miR-9 immediately counteracts nPTB induced by PTB knockdown was tested. In contrast to the PTB / nPTB expression profile in human fibroblasts, it was shown in mouse and human astrocytes that PTB knockdown resulted in nPTB induction followed by nPTB decline (Figures 3A and 3B). Thus, high levels of miR-9 could enhance the stable reprogramming of astrocytes to mature neurons by depleting PTB in astrocytes alone.

Embodiment 3

[0222] Example 3: Knockdown of PTB in vitro efficiently converts astrocytes into functional neurons.

[0223] To explore the possibility that downregulation of PTB would lead to efficient conversion of astrocytes into mature neurons, mouse astrocytes were isolated from the cerebral cortex of pups at postnatal day 4 to 5 (P4-5). were isolated and human fetal astrocytes were obtained from a commercial source (ScienCell). Cells from both sources expressed the expected astrocyte markers GFAP and ALDH1L1, and had no detectable contamination of neuronal cells, as indicated by the absence of markers for neuronal or neural crest progenitor cells ( Figure 4 ).

[0224] Mouse astrocytes were infected with a lentiviral vector expressing a small hairpin RNA (shPTB) against PTB. Four weeks after transduction, approximately 50% of shPTB-treated cells maintained in standard neuronal differentiation medium containing a panel of small molecules showed neuronal morphology and positive staini...

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Abstract

Provided herein is a method of reprogramming a non-neuronal cell to a neuron. Aspects of the present disclosure relate to using cell reprogramming agent suppresses the expression or activity of PTB toconvert a non-neuronal cell into a neuron. Also provided herein is a method of treating neurodegenerative disease by reprogramming non-neuronal cells in vivo to functional neurons.

Description

[0001] Cross References to Related Applications [0002] This application claims priority under 35 U.S.C §119 to Provisional Application Serial No. 62 / 656,322, filed April 11, 2018, and Provisional Application Serial No. 62 / 718,774, filed August 14, 2018, the disclosure of which provisional application Incorporated herein by reference. [0003] government license [0004] This invention was made with Government Support Nos. 5R01GM052872 and 5R01HG004659 from the National Institutes of Health. The government has certain rights in this invention. technical field [0005] The present invention relates to methods and compositions for differentiating non-neuronal cells into neuronal cells and methods of treating neurodegenerative diseases and disorders. [0006] Incorporated by reference into the sequence listing [0007] Attached to this file is a sequence listing titled "Sequence_ST25.txt", which was created on April 11, 2019, and has 1,595 bytes of data, machine-formatted on...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00A61P25/28C12N5/079C12N5/0793C12N15/11C12N15/113
CPCC12N15/113A61P25/28C12N2740/16043C12N2310/11C12N2310/315A61K48/00C12N15/11C12N5/0622A61K48/005A61P25/16C12N2501/999C12N5/0619C12N2310/14C12N2310/531
Inventor X·D·付H·钱
Owner RGT UNIV OF CALIFORNIA
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