It is estimated that about 450,000 people live with a form of spinal cord injury (SCI) in the US, and about 17,000 new SCI cases are diagnosed each year primarily due to automobile accidents, falls or acts of violence1. SCIs are graded across 5 tiers that range from recovery of full mobility to complete paralysis. A significant number of spinal cord injuries are typically irreversible as the central nervous system does not have intrinsic repair capabilities and the pharmacoeconomic impact of SCIs is estimated to be about $9.7B1 largely due to the need for lifelong care and possible complications. Current treatments are limited to steroid treatment, surgery (if applicable) and physical therapy but in many cases, the paralysis and loss of sensation are not reversible resulting in a significant reduction in quality of life. Clearly, there is a need for novel therapies that can repair damaged neurons and reverse paralysis.
There has been active research to identify specific factors that can promote neuron repair after SCI. In one study reported in March 2021, researchers at UT Southwestern Medical Center showed that overexpression of the Sox2 protein increased neuron proliferation in mice that had damaged spinal cords. Interestingly, the new neurons formed connections with the existing neurons which suggests that the newly formed neurons could bridge the damage to the spinal cord2. Overexpression of Sox2 also resulted in the reduced formation of scar tissue which is known to impede functional repair of the damaged tissues3. Another study identified a critical subset of genes that are involved in neuron repair in zebrafish – a group at the University of Edinburgh used synthetic RNA Oligo CRISPR guide RNAs to knock down 350 genes and identified 4 key genes that prevented spinal cord repair including TGF-β14. Zebrafish are a good model to screen multiple genes using phenotypic readouts such as fluorescence.
Recently, an exciting study that used novel scaffolds to deliver target proteins has advanced the search for novel repair therapies for spinal cord injuries. Researchers at Northwestern University developed bioactive scaffolds that carry target proteins to the spinal cord injury site. The scaffold consists of supramolecular polymers that are injected as a liquid but then form a gel like mesh mimicking the extracellular matrix or ECM surrounding the spinal cord tissue. The polymer includes 2 modified peptide sequences to activate the transmembrane receptor β1-integrin and basic fibroblast growth factor 2 receptor (FGFR2). Activating β1-integrin reduces the formation of scar tissue while activating basic FGFR2 increasing angiogenesis5. The peptide sequences in the polymers were modified in the non-bioactive domains to increase motion in the nanofibrils. These signal molecules were shown to “dance” or move around in the nanofibril which enhanced interactions with cell surface receptors resulting in increased cellular signaling that leads to vascularization, neuronal regeneration and survival and most importantly, functional recovery5.
Mice who had been paralyzed to mimic spinal cord injury received one injection of the polymer liquid and were able to walk 4 weeks post injection. The modified peptides were shown to persist around the injury site for a significant amount of time to maximize therapeutic efficacy and then degraded after 12 weeks suggesting that this approach has minimal local or systemic toxicity5. Additionally, supramolecular polymers are connected via weak forces compared to conventional polymers that are connected by strong covalent bonds, so they are more dynamic and can be modified for different disease conditions. They are also biodegradable, which makes them ideal for injection into humans. While most of the studies were done in mice, the supramolecular polymers have been tested in an in vitro human cell culture system where it induced increased downstream signaling suggesting that human cells are responsive.
The Northwestern group hopes to start a clinical trial in 2022 after FDA review and the first data sets from the clinical trial will be the true test on whether the moving peptides in the supramolecular polymers can repair neuronal damage and reverse paralysis and loss of sensation.
References:
1https://www.aans.org/en/Patients/Neurosurgical-Conditions-and-Treatments/Spinal-Cord-Injury
3https://www.nature.com/articles/s41467-019-11707-7
4https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009515
