A Localized Materials-Based Strategy to Non-Virally Deliver Chondroitinase ABC mRNA Improves Hindlimb Function in a Rat Spinal Cord Injury Model

Adv. Healthcare Mater., 2022 · DOI: 10.1002/adhm.202200206 · Published: August 25, 2022

Simple Explanation

Spinal cord injuries often lead to the formation of glial scars that inhibit neuronal regeneration. This study explores the use of mineral-coated microparticles (MCMs) to deliver mRNA encoding Chondroitinase ABC (ChABC), an enzyme that degrades the glial scar. The mRNA delivery allows for the in situ production of ChABC, overcoming the protein's instability issues. The MCMs facilitate efficient, non-viral mRNA delivery directly to the spinal cord lesion. Results showed that this method reduces CSPGs (the main component of glial scars) and improves motor function recovery in rats seven weeks post-injury.

Study Duration

7 weeks

Participants

Sprague Dawley rats (female, ≈225 g)

Evidence Level

Not specified

Key Findings

1
MCM-mediated mRNA delivery is an efficient non-viral gene delivery method in primary neural cells in vitro and enabled localized transgene expression in the glial scar in vivo.
2
MCM-mediated delivery of mtChABC-encoding mRNA resulted in decreased CSPG presence in an in vitro model of astrogliosis.
3
MCM-mediated delivery of mtChABC-encoding mRNA resulted in improved functional recovery in an established rat SCI model.

Research Summary

The study addresses the challenge of delivering therapeutic proteins, specifically ChABC, to spinal cord injuries (SCIs) due to their instability. It explores a non-viral mRNA-based method using mineral-coated microparticles (MCMs) for localized delivery. In vitro experiments showed improved transfection efficiency and transgene expression in primary rat glial cells using MCMs and mRNA. The delivered mtChABC was active in degrading chondroitin sulfate proteoglycan (CSPG) in an astrogliosis model. In vivo experiments on a rat SCI model demonstrated that MCM-mediated delivery of mtChABC mRNA resulted in CSPG digestion, sprouting of serotonergic axons, and improved hind limb motor function.

Practical Implications

Localized Therapy

MCMs offer targeted delivery of mRNA to the spinal cord injury site, reducing the risk of systemic side effects.

Enhanced Protein Production

In situ mRNA translation ensures higher bioactivity of ChABC compared to recombinant protein delivery.

Non-Viral Delivery

The non-viral approach mitigates concerns associated with immunogenicity and insertional mutagenesis common in viral gene therapies.

Study Limitations

1
The study primarily focuses on a rat model, and further research is needed to validate these findings in larger animal models and eventually humans.
2
The long-term effects of MCM-mediated mRNA delivery and ChABC expression on spinal cord tissue were not extensively investigated.
3
The study did not directly compare dosage, duration, and biological activity between recombinant proteins and those produced in situ via non-viral mRNA delivery.

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