Neuroregenerative gene therapy

December 16, 2020

Spinal cord injury (SCI) often causes disability and seriously compromises quality of life. While decades of research have made significant progress in axonal regeneration after SCI, most of the interventions have not been translated into clinical therapies. One of the major reasons for the difficulty of treatment for SCI might be due to the fact that many neurons are lost during the injury, leading to permanent loss of neural functions. In the current issue of Frontiers in Cell and Developmental Biology published on December 16th, 2020, a research team led by Prof. Gong Chen at Jinan University, Guangzhou, China, reported an innovative gene therapy approach to regenerate functional new neurons using local glial cells in the injured spinal cord, bringing new hope to millions of SCI patients worldwide.

Different from classical approaches on SCI, which are mostly focused on promoting axonal regeneration or engrafting external stem cells, Prof. Chen and his team exploit internal glial cells in the injured spinal cord and directly convert them into functional new neurons. Previously, Chen's team has published a series of articles demonstrating that overexpression of neural transcription factor NeuroD1 or NeuroD1 plus Dlx2 can convert reactive astrocytes into neurons in mouse models of Alzheimer's disease, ischemic stroke, or Huntington's disease. They have recently advanced this technology to non-human primates by demonstrating direct conversion of reactive astrocytes into neurons in the brains of rhesus macaque monkeys.

In this work, Prof. Chen and his team further extended their neuroregenerative technology from the brain to the spinal cord. They first demonstrate that overexpression of NeuroD1 in dividing reactive astrocytes through retrovirus can successfully convert astrocytes into neurons in the injured spinal cord. The advantage of using retrovirus is that they only express transgene such as NeuroD1 here in dividing glial cells, but not non-dividing neurons, eliminating the possibility of direct NeuroD1 expression in preexisting neurons. To increase the efficacy of neuronal conversion and pave the way for future translational application, Chen and team further developed adeno-associated viral system (AAV) to deliver NeuroD1 to both dividing and non-dividing astrocytes under the control of astrocytic promoter GFAP and confirmed direct astrocyte-to-neuron conversion in the spinal cord. AAV vector is commonly used for gene therapy because of its relatively low immunogenicity and high efficiency of spreading in various tissues including nervous tissue. Interestingly, Chen and team found that NeuroD1 alone generated mainly excitatory glutamatergic neurons, whereas addition of another transcription factor Dlx2 significantly increased the proportion of inhibitory GABAergic neurons, indicating that using different combinations of transcription factors can generate different subtypes of neurons.

Another important factor affecting neuronal fate after conversion is local environment. Chen's team designed a set of side-by-side comparison experiments by injecting the same NeuroD1 vector into the mouse cortex or spinal cord. After one month, they found that the neurons converted from cortical astrocytes showed cortical neuron markers but not spinal cord markers, whereas neurons converted from spinal astrocytes showed spinal neuron markers but not cortical markers, indicating the importance of local environment in shaping the neuronal fate after conversion.

Importantly, Chen and colleagues investigated the time window of neuronal conversion before and after glial scar formation following SCI. They tested the conversion efficiency of reactive astrocytes at 10 days versus those at 4 months following SCI, when glial scar has been well formed after injury. Chen's team demonstrated high efficiency of conversion not only at short-term but also after a long delay following injury. These studies provide the proof-of-concept that in vivo astrocyte-to-neuron conversion technology may be potentially developed into therapeutic interventions to regenerate functional new neurons in order to restore lost neural functions after SCI.
-end-
Besides Prof. Chen, contributors to this spinal cord repair work include Brendan Puls, Yan Ding, Fengyu Zhang, Mengjie Pan, Zhuofan Lei, Zifei Pei, Mei Jiang, Yuting Bai, Cody Forsyth, Morgan Metzger, Tanvi Rana, Lei Zhang, Xiaoyun Ding, Matthew Keefe, Alice Cai, Austin Redilla, Michael Lai, Kevin He, Hedong Li. This work was mainly supported by Charles. H. Smith Endowment Fund to Prof. Chen when he worked at Penn State.

Guangdong-Hongkong-Macau Institute of CNS Regeneration,Jinan University

Related Neurons Articles from Brightsurf:

Paying attention to the neurons behind our alertness
The neurons of layer 6 - the deepest layer of the cortex - were examined by researchers from the Okinawa Institute of Science and Technology Graduate University to uncover how they react to sensory stimulation in different behavioral states.

Trying to listen to the signal from neurons
Toyohashi University of Technology has developed a coaxial cable-inspired needle-electrode.

A mechanical way to stimulate neurons
Magnetic nanodiscs can be activated by an external magnetic field, providing a research tool for studying neural responses.

Extraordinary regeneration of neurons in zebrafish
Biologists from the University of Bayreuth have discovered a uniquely rapid form of regeneration in injured neurons and their function in the central nervous system of zebrafish.

Dopamine neurons mull over your options
Researchers at the University of Tsukuba have found that dopamine neurons in the brain can represent the decision-making process when making economic choices.

Neurons thrive even when malnourished
When animal, insect or human embryos grow in a malnourished environment, their developing nervous systems get first pick of any available nutrients so that new neurons can be made.

The first 3D map of the heart's neurons
An interdisciplinary research team establishes a new technological pipeline to build a 3D map of the neurons in the heart, revealing foundational insight into their role in heart attacks and other cardiac conditions.

Mapping the neurons of the rat heart in 3D
A team of researchers has developed a virtual 3D heart, digitally showcasing the heart's unique network of neurons for the first time.

How to put neurons into cages
Football-shaped microscale cages have been created using special laser technologies.

A molecule that directs neurons
A research team coordinated by the University of Trento studied a mass of brain cells, the habenula, linked to disorders like autism, schizophrenia and depression.

Read More: Neurons News and Neurons Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.