PTEN knockout using retrogradely transported AAVs restores locomotor abilities in both acute and chronic spinal cord injury.

bioRxiv preprint, 2023 · DOI: https://doi.org/10.1101/2023.04.17.537179 · Published: April 17, 2023

Spinal Cord Injury Regenerative Medicine Genetics

Simple Explanation

After a spinal cord injury (SCI), communication between the brain and the body is disrupted due to damaged nerve fibers (axons). The goal of regeneration strategies is to encourage these axons to regrow and reconnect. The researchers used a viral vector (AAV) to deliver a gene that knocks out PTEN, a protein that inhibits axon growth. This AAV was engineered to travel backward along axons, targeting many spinal-projecting neurons. The study found that knocking out PTEN improved motor function in mice with severe SCI, regardless of whether treatment was given soon after injury or months later. However, the benefits diminished over time, and there were signs of potential toxicity to certain neurons.

Study Duration

9 weeks (acute), 9 months (chronic)

Participants

C57BL/6 PTENFloxΔ/Δ mice

Evidence Level

Not specified

Key Findings

1
PTEN-KO using AAVrg’s improves locomotor outcomes in both acute and chronic SCI conditions, however, the effects are severity dependent.
2
PTEN-KO using AAVrg’s does increase axon growth into the lesions of acutely injured mice, demonstrating a growth effect on axons.
3
Observed a potential toxic response to prolonged PTEN-KO in motor neurons comprising the CST.

Research Summary

The study investigated the effects of PTEN knockout (PTEN-KO) using retrogradely transported adeno-associated viruses (AAVrg) on locomotor recovery in mice with acute and chronic spinal cord injury (SCI). A single injection of AAVrg to knockout PTEN in chronic SCI can effectively target both damaged and spared axons and restore locomotor functions in near-complete injury models. Long-term PTEN deletion may exert progressive neurotoxic effects on neurons in the motor cortex.

Practical Implications

Therapeutic Potential

AAVrg-mediated PTEN-KO holds promise for restoring motor functions in chronic SCI.

Toxicity Concerns

Long-term PTEN deletion may have neurotoxic effects, necessitating further research into optimizing delivery methods and managing potential complications.

Personalized Treatment

Responses to PTEN-KO are injury-severity dependent, suggesting that patient selection is crucial for optimizing therapeutic outcomes.

Study Limitations

1
PTEN-KO may silence the hSyn1 promoter which could affect synaptic strength for regeneration
2
Long-term growth via PTEN-KO may have adverse effects on neuronal health and viability of specific populations of neurons.
3
CST axons did not regenerate after PTEN-KO in either acute or chronic conditions.

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