Neuroregenerative gene therapy
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 function.
In the current issue ofFrontiers in Cell and Developmental Biologypublished 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.
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.
