Vision loss can be a side effect of a major brain injury, such as a stroke. In this context, neurons aren’t able to regenerate, and the use of stem cell therapy to help these patients is a costly and difficult process, with limited success. Therefore, researchers, led by a team at Purdue University, have developed a novel method to use gene therapy to restore vision loss after a stroke in a mouse model.
Neuron loss after brain injury
Functional circuit impairment associated with neuronal loss is commonly seen in patients with brain injuries, such as strokes. Currently, it still remains a challenge to generate neurons in adults and functionally incorporate them into local brain circuits. Several strategies have shown the capability to induce neurogenesis, which have seen some result in behavioural recovery.
Recently, progress has been made in the use of gene therapies to reprogramme non-neuronal cells, such as fibroblasts, into neurons by expressing transcription factors. However, several questions remain unanswered as to the effectiveness of reprogramming non-neuronal cells in brain injuries.
The first question is whether such reprogrammed cells can become integrated into the functional circuits in the brain that have complex circuit structures. Additionally, there are questions surrounding whether reprogrammed cells gain the functional properties of a typical neuron and become part of the specific circuit. Moreover, it is not yet known how safe the process of converting non-neuronal cells into neurons is in patients. Do these cells remain as neurons, or do they gain other potentially aberrant cellular properties?
Answering these questions is crucial for the development of new regenerative therapies for brain injuries.
Gene therapy to restore vision after stroke in the mouse model
To try and answer some of these questions, the researchers behind this study, published in Frontiers in Cell and Developmental Biology, turned to the mouse visual cortex.
The team investigated the effect of Neuro-D1 mediated in vivo direct reprogramming on visual cortical circuit integration and functional recovery. The transcription factor NeuroD1 has previously been demonstrated to convert human embryonic stem cells and induce pluripotent stem cells into neurons in vitro.
Can gene therapy restore vision?
The researchers performed electrophysiological extracellular recordings and two-photon calcium imaging of reprogrammed cells in vivo. Following that, they mapped the synaptic connections formed onto these cells ex vivo. This enabled the researchers to identify that NeuroD1 reprogrammed neurons were integrated into the cortical microcircuit and acquired direct visual responses. Furthermore, following visual stimulation, the reprogrammed neurons demonstrated maturation of functional connectivity.
Talking about his work, the lead researcher behind this study, Professor Alexander Chubykin, said:
“We are directly reprogramming the local glial cells into neurons. We don’t have to implant new cells, so there’s no immunogenic rejection. This process is easier to do than stem cell therapy, and there’s less damage to the brain. We are helping the brain heal itself. We can see the connections between the old neurons and the newly reprogrammed neurons get re-established. We can watch the mice get their vision back.”
Implications and future work
Overall, these results have shown that NeuroD1-reprogrammed neurons can successfully develop and integrate into the visual cortical circuit, and lead to vision recovery after a stroke.
This research is particularly important because visual function is easier to accurately measure than motor skills. Therefore, perfecting and understanding this technique could lead to the development of a similar technique that would be able to re-establish motor function. In addition, this research helps to bridge the gap in our understanding between the basic interpretation of neurons and the function of organs.
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