An mRNA ‘vaccine’ for spinal cord regeneration
Description: Background: Spinal cord injury (SCI) results in permanent paralysis, for which we currently have no therapies to reverse. Our unpublished work demonstrated that one can restore neurological function by accelerating the formation of the blood-spinal cord barrier and astrocyte border after SCI, enabling an immediate neuroprotection of the surrounding neural tissue and descending projections. The consequence of this was the restoration of walking after severe SCI. However, to achieve this, we leveraged viral technology that has a complicated translational path to a human treatment. To address these challenges, we have now developed an mRNA-based gene therapy. Leveraging lipid nanoparticles for mRNA delivery (mRNA-LNPs), we draw inspiration from the rapidly advancing mRNA technology, exemplified by the development of COVID-19 vaccines mRNA-1273 and BNT162b2. Overall Goal and Aims: We have now developed rapidly expressing, clinically-relevant gene therapy that instead leverages mRNA-LNP technologies to overexpress relevant growth factors for spinal cord repair. Here, we propose to test the efficacy of this technology to promote biological repair and restoration of walking in a rodent model of incomplete spinal cord injury when delivered after the occurrence of SCI. To our knowledge, this would mark the first application of mRNA gene therapy in the central nervous system, particularly targeting a traumatic condition. This proposal represents a considerable deviation from the field, and a series of experiments that can be realistically achieved within the short timeframe of the SPARK program. Aim 1 | To determine whether the formation of the tripartite barrier can be accelerated with mRNA-LNP delivery of EGF, FGF2, and VEGF in mice with SCI. We will conduct extensive morphometric analyses on tissue from mice to quantify the effects of our repair intervention in a model of anatomically incomplete SCI in old mice. We predict that this targeted repair intervention will result in a reduction in blood-spinal cord barrier leakage, reduced peripheral immune invasion, a contraction of the astrocyte border, and an increase in spared neuronal tissue as well as descending projections.Aim 2 | To determine whether the delivery of mRNA-LNPs expressing EGF, FGF2, and VEGF improves the recovery of walking in mice with SCI compared to equivalent mice not treated with mRNA-LNPs. We will conduct extensive kinematic behavioral analyses on all mice. We predict that our mRNA-LNP repair intervention will improve recovery of walking following incomplete SCI.Significance: Although impressive regeneration of axons through a complete SCI has been observed, and can restore walking in paralyzed mice, this therapy is based on multiple research-grade viral vectors. The eventual translation of this work into large animal models and to humans will require 1) the development of clinically-ready delivery systems, and 2) a gene therapy approach that can lead to rapid gene expression. In the proposed work, we test a new clinically-ready mRNA-LNP approach that enables rapid expression dynamics and paves the way for human clinical trials. We therefore believe that this project has the potential to make a significant scientific contribution to the field of SCI, and to move us tangibly closer to altering the course of this catastrophic injury.
Amount: CHF 100,000
Funding type: grant
Funder scheme: Spark
Start date: 2024-11-01
End date: 2025-10-31
Investigator: Squair, Jordan
Institution: University of Lausanne – LA
Subfield: Molecular Biology
Domain: Life Sciences
Funded outputs count: 0
Funder award ID: 228646
OpenAlex ID: G6937573378