Key Neurons for Spinal Cord Repair and Develop Gene Therapy

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Breakthrough in Overcoming Paralysis: Scientists Discover Key Neurons for Spinal Cord Repair and Develop Gene Therapy

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Breakthrough in Overcoming Paralysis: Scientists Discover Key Neurons for Spinal Cord Repair and Develop Gene Therapy

The spinal cord, responsible for transmitting brain signals throughout the body, plays a vital role. Spinal cord injuries (SCI) can significantly impact movement and sensation, often leading to paralysis.

While the spinal cord possesses some self-repair capabilities, especially in cases of partial damage, extensive, spontaneous motor function recovery occurs after the initial paralysis. However, in the case of complete spinal cord injuries, this natural repair doesn’t happen, making the treatment of such injuries a significant challenge in the medical field.

Recently, a research team from the École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland, the University of California, Los Angeles (UCLA), and Harvard Medical School published a study titled “Recovery of walking after paralysis by regenerating characterized neurons to their natural target region” in the prestigious academic journal Science.

The research identified key neurons involved in the natural repair of the spinal cord. By promoting axonal growth of these neurons and bridging the gap created by spinal cord injuries, they successfully reestablished connections with neurons in their natural projection areas, thereby restoring motor function affected by spinal cord injuries.

Even more excitingly, building on this discovery, the research team developed a gene therapy for treating complete spinal cord injuries in mice. This groundbreaking achievement significantly restored the walking ability of paralyzed mice, marking a milestone in the field of spinal cord injury repair.

In 2018, Grégoire Courtine from EPFL and Michael Sofroniew from the University of California, Los Angeles, collaborated to demonstrate that nerve fibers could regenerate in cases of anatomically complete spinal cord injuries. This study, published in the journal Nature, generated significant buzz in the scientific community and became one of the pivotal events in spinal cord injury research.

However, the researchers encountered a setback. Although they witnessed axons extending from one side of the spinal cord injury site to the other and successfully connecting neurons on both sides, the motor abilities of the paralyzed mice did not improve.

This “failure” just short of the finish line led Mark Anderson (the first author of the aforementioned Nature paper and the corresponding author of the Science paper) and his team to realize that merely promoting axonal growth was insufficient for restoring motor function. The new axons couldn’t connect to the correct location on the other side of the spinal cord injury site.

Mark Anderson’s primary research interest lies in uncovering the cellular and molecular mechanisms responsible for the regeneration failure of the central nervous system (CNS) after injury. He aims to apply this knowledge to develop cell type-specific repair strategies to reverse paralysis following spinal cord injuries (SCI) in humans.

For a long time, scientists observed an intriguing phenomenon regarding natural spinal cord repair: both humans and experimental animals experience spontaneous functional recovery to varying degrees during the first few months after spinal cord injuries. This phenomenon is linked to neurons in the mid-thoracic spinal cord.

In their latest study published in Science, the research team utilized fluorescent protein labeling and single-cell nuclear RNA sequencing (snRNA-seq) techniques to identify a subset of neurons involved in motor function recovery after incomplete spinal cord injuries. They found that in mice recovering motor function following spinal cord injury, a specific group of neurons exhibited upregulated gene expression related to dendritic spine morphology, synaptic enhancement processes, and cytoskeletal rearrangement, consistent with the gene expression pattern during natural spinal cord repair.

The research team named this subset of neurons “SCVsx2::Hoxa7:Zfhx3→lumbar,” referred to as SC neurons for brevity.

Further research revealed that among different neuron subsets in the mid-thoracic spinal cord, SC neurons exhibited the most significant transcriptional perturbations during spinal cord’s natural recovery. They also displayed anatomical features facilitating the transmission of nerve signals from the spinal cord’s upper region to motor neurons in the lumbar spinal cord.

Incorporating lessons learned from the Nature study’s “failure” five years ago, Mark Anderson and his team speculated that SC neurons must have a natural projection target on the other side of the spinal cord injury site. Only when their axons correctly connected to this area could true spinal cord repair and motor function restoration occur.

To facilitate long-distance and directional regeneration of SC neuron axons, the research team developed a gene therapy. They used lentiviral delivery to continuously provide neurotrophic factors (GDNF), guiding SC neuron axons to extensively regenerate on both segments and reestablish connections with neurons in their natural projection areas on the other side of the spinal cord injury site.

The researchers tested the effectiveness of SC neuron regeneration therapy on 30 mice with complete spinal cord injuries and hindlimb paralysis, divided into five groups of six mice each. After four weeks of treatment, substantial hindlimb motor function recovery was observed in 27 mice (90%). Although the recovery did not reach the level of normal mice, it matched the motor abilities of mice with incomplete spinal cord injuries that had undergone natural recovery.

In simpler terms, these mice experienced a reversal of their paralysis, akin to a human transitioning from complete immobility in a wheelchair to walking with crutches.

Dr. Jordan Squair, the lead author of the study, stated that these findings not only highlighted the specific neuron axons that must regenerate but also revealed that these axons must reconnect to their natural projection target areas to genuinely repair spinal cord injuries and restore motor function.

In summary, this research has pioneered a gene therapy for complete spinal cord injuries. It involves stimulating the growth of specific neurons (SC neurons), guiding their axons to connect with the natural projection target areas downstream of the spinal cord injury, and transmitting nerve signals to motor neurons. This approach dramatically restores the motor function of paralyzed mice.

It’s worth noting that Grégoire Courtine and his team, the co-corresponding authors of both papers, previously helped several completely paralyzed spinal cord injury patients regain independent mobility by implanting spinal cord stimulation electrodes.

To enhance effectiveness, the research team plans to combine gene therapy with spinal cord stimulation therapy. Gene therapy aims to regenerate relevant nerve axons, while spinal cord stimulation aims to maximize the capacity of these nerve fibers and the spinal cord downstream of the injury to produce movement. Although many obstacles must be overcome before this gene therapy can be applied to humans, scientists have taken the critical first step required for this remarkable achievement!

Breakthrough in Overcoming Paralysis: Scientists Discover Key Neurons for Spinal Cord Repair and Develop Gene Therapy

Paper Links:
1. www.science.org/doi/10.1126/science.adi6412
2. https://www.nature.com/articles/s41586-018-0467-6

(source:internet, reference only)

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