Therapeutically viable generation of neurons with antisense oligonucleotide suppression of PTB

Maimon, Roy; Chillón-Marinas, Carlos; Snethlage, Cedric E; Singhal, Sarthak; McAlonis-Downes, Melissa; Ling, Karen; Rigo, Frank; Bennett, C. Frank; Cruz, Sandrine Da; Hnasko, Thomas S.; Muotri, Alysson R.; Cleveland, Don W.

doi:10.1038/s41593-021-00864-y

Cited by 49 publications

(62 citation statements)

References 65 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since aging is the primary risk factor for most neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease, the possibility of modulating neural replacement in this context is currently a hot topic [ 53 ] that needs to be further investigated and also for nerve damage caused by injures or even for blindness [ 54 ]. Nonetheless, how aging can impact the feasibility of glia-to-neuron reprogramming is still largely unknown, although the Cleveland group paper [ 14 ] demonstrated that PTB reduction benefits glia-to-neuron conversion in aged mouse brains as well. The authors proposed the hypothesis that reducing the PTB-stimulated proliferation of radial glia-like cells triggered their conversion into new granule neurons in the aged rodent brain through what appears to be the typical process occurring in the hippocampus during development and in young adults.…”

Section: Discussionmentioning

confidence: 99%

“…Maimon and colleagues [ 14 ], with this mouse model, showed that PTB-ASO promoted the transdifferentiation of radial glia or astrocytes into neurons, and they also reproduced the PTB-ASO therapeutic approach in human organoids. Moreover, in non-engineered mice the PTB-ASO treatment was also clearly able to promote the formation of new immature (DCX+) neurons, which correlated with improved memory as assessed using the Barnes maze test.…”

Section: Ptb Silencing Approachesmentioning

confidence: 99%

“…This attempt was followed by a larger screening of 200 ASOs on the 4T1 mouse cell line, which led to the identification of two top candidates able to reduce Ptb expression [ 14 ]. The most promising ASO candidate showed molecular efficacy In Vitro on mouse astrocytes and human brain organoids from control subjects and in vivo with minimal animal toxicity, in healthy mice.…”

Section: Ptb Silencing Approachesmentioning

confidence: 99%

“…Recently, different groups have reported the successful direct conversion of fibroblasts and glia into neurons by reducing the expression of a single target, polypyrimidine tract-binding protein 1 (PTBP1, alias PTB) [ 13 , 14 ]. PTB was initially identified as a polypyrimidine tract-binding protein able to bind to heterogeneous nuclear RNA, placing it in a family of RNA-binding proteins (hnRNP I) [ 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Targeting PTB for Glia-to-Neuron Reprogramming In Vitro and In Vivo for Therapeutic Development in Neurological Diseases

et al. 2022

View full text Add to dashboard Cite

In vivo cell reprogramming of glial cells offers a promising way to generate new neurons in the adult mammalian nervous system. This approach might compensate for neuronal loss occurring in neurological disorders, but clinically viable tools are needed to advance this strategy from bench to bedside. Recently published work has described the successful neuronal conversion of glial cells through the repression of a single gene, polypyrimidine tract-binding protein 1 (Ptbp1), which encodes a key RNA-binding protein. Newly converted neurons not only express correct markers but they also functionally integrate into endogenous brain circuits and modify disease symptoms in in vivo models of neurodegenerative diseases. However, doubts about the nature of “converted” neurons, in particular in vivo, have been raised, based on concerns about tracking reporter genes in converted cells. More robust lineage tracing is needed to draw definitive conclusions about the reliability of this strategy. In vivo reprogramming and the possibility of implementing it with approaches that could be translated into the clinic with antisense oligonucleotides targeting a single gene like Ptbp1 are hot topics. They warrant further investigation with stringent methods and criteria of evaluation for the ultimate treatment of neurological diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Ptb Silencing Approachesmentioning

confidence: 99%

Section: Ptb Silencing Approachesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting PTB for Glia-to-Neuron Reprogramming In Vitro and In Vivo for Therapeutic Development in Neurological Diseases

et al. 2022

View full text Add to dashboard Cite

show abstract

“…It has recently been reported that nigral astrocytes can be transformed into DA-cells by injecting an antisense oligonucleotide against the RNAbinding protein PTB in the SN [202]. This injection increases the number of DA-cells in the nigra and re-innervates the striatum with new DAergic synapses, thus recovering the dopamine level of 6OHDA lesioned animals to 65% of the control levels [202][203][204][205]. These studies were performed in young animals and it is currently unknown whether the astrocytes of aged animals may be also reprogramed to neurons.…”

Section: The Global Activation Of the Neuroprotective Functions Of Astrocytesmentioning

confidence: 99%

Astrocytes, a Promising Opportunity to Control the Progress of Parkinson’s Disease

et al. 2021

View full text Add to dashboard Cite

At present, there is no efficient treatment to prevent the evolution of Parkinson’s disease (PD). PD is generated by the concurrent activity of multiple factors, which is a serious obstacle for the development of etio-pathogenic treatments. Astrocytes may act on most factors involved in PD and the promotion of their neuroprotection activity may be particularly suitable to prevent the onset and progression of this basal ganglia (BG) disorder. The main causes proposed for PD, the ability of astrocytes to control these causes, and the procedures that can be used to promote the neuroprotective action of astrocytes will be commented upon, here.

show abstract

Spatially Precise Genetic Engineering at the Electrode‐Tissue Interface

Xu,

Yang,

Ding

et al. 2024

Advanced Materials

View full text Add to dashboard Cite

The interface between electrodes and neural tissues plays a pivotal role in determining the efficacy and fidelity of neural activity recording and modulation. While considerable efforts have been made to improve the electrode‐tissue interface, the majority of studies have primarily concentrated on the development of biocompatible neural electrodes through abiotic materials and structural engineering. In this study, we present an approach that seamlessly integrates abiotic and biotic engineering principles into the electrode‐tissue interface. Specifically, we combine ultraflexible neural electrodes with short hairpin RNAs (shRNAs) designed to silence the expression of endogenous genes within neural tissues. Our system facilitates shRNA‐mediated knockdown of PTEN and PTBP1, two essential genes associated in neural survival/growth and neurogenesis, within specific cell populations located at the electrode‐tissue interface. Additionally, we demonstrate that the downregulation of PTEN in neurons can result in an enlargement of neuronal cell bodies at the electrode‐tissue interface. Furthermore, our system enables long‐term monitoring of neuronal activities following PTEN knockdown in a mouse model of Parkinson's disease and traumatic brain injury. Our system provides a versatile approach for genetically engineering the electrode‐tissue interface with unparalleled precision, paving the way for the development of regenerative electronics and next‐generation brain‐machine interfaces.This article is protected by copyright. All rights reserved

show abstract

Therapeutically viable generation of neurons with antisense oligonucleotide suppression of PTB

Cited by 49 publications

References 65 publications

Targeting PTB for Glia-to-Neuron Reprogramming In Vitro and In Vivo for Therapeutic Development in Neurological Diseases

Targeting PTB for Glia-to-Neuron Reprogramming In Vitro and In Vivo for Therapeutic Development in Neurological Diseases

Astrocytes, a Promising Opportunity to Control the Progress of Parkinson’s Disease

Spatially Precise Genetic Engineering at the Electrode‐Tissue Interface

Contact Info

Product

Resources

About