Immune-evasive gene switch enables regulated delivery of chondroitinase after spinal cord injury

Brain, 2018 · DOI: 10.1093/brain/awy158 · Published: June 14, 2018

Spinal Cord Injury Genetics Neuroplasticity

Simple Explanation

Spinal cord injuries often lead to permanent loss of function due to the formation of scar tissue that inhibits nerve regeneration. Chondroitinase ABC (ChABC) is an enzyme that can break down this scar tissue, promoting nerve regrowth and functional recovery. This study introduces a new gene therapy approach where the ChABC gene is delivered using a viral vector that can be switched on and off using a drug called doxycycline. This allows researchers to control when and for how long ChABC is produced in the injured spinal cord. The researchers found that short-term ChABC treatment improved some motor functions, while long-term treatment was needed for more complex tasks like skilled hand movements. This suggests that the timing of ChABC delivery is crucial for maximizing recovery after spinal cord injury.

Study Duration

8 Weeks

Participants

85 adult female Lister Hooded rats

Evidence Level

Not specified

Key Findings

1
A novel immune-evasive gene switch (dox-i-ChABC) enables regulated delivery of ChABC in the injured mammalian spinal cord.
2
Short-term dox-i-ChABC treatment is sufficient to promote improvement in sensory axon conduction and ladder walking performance.
3
Long-term dox-i-ChABC treatment leads to significantly improved skilled reaching and grasping function, correlating with increased vGlut1+ innervation in spinal cord grey matter.

Research Summary

This study introduces a novel immune-evasive gene switch (dox-i-ChABC) that enables regulated delivery of ChABC in the injured mammalian spinal cord, providing an experimental tool to control delivery and understand the role of timing in ChABC treatment. The study reveals that short-term ChABC gene therapy is sufficient to replicate prior reported functional improvements, while long term administration elicits additional recovery of skilled forelimb reaching and grasping behaviors and this is associated with vGlut1 + fibre remodelling in the spinal cord. The findings demonstrate temporally dependent, task-specific, functional effects where short term administration is sufficient to enable recovery of sensorimotor integration during walking and long term administration confers additional benefit to skilled reaching and grasping after cervical contusion injury.

Practical Implications

Clinical Translation

The development of a regulatable and immune-evasive ChABC gene therapy system represents a significant step towards clinical application for spinal cord injury treatment.

Therapeutic Timing

Understanding the temporal effects of ChABC delivery can optimize treatment strategies, potentially combining gene therapy with rehabilitation paradigms to maximize functional recovery.

Broader Applications

The immune-evasive gene regulation method may be expanded to other neurological disorders with an autoimmune or inflammatory component, such as multiple sclerosis or amyotrophic lateral sclerosis.

Study Limitations

1
Dox-i-ChABC has low-level basal ‘leaky’ transgene expression.
2
The study focused on female rats, and the results may not be generalizable to males.
3
Further studies are needed to characterize the specific spinal pathways involved in the recovery of skilled reaching performance.

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