New potential for spinal cord repair using peptide-based hydrogels and Epac2 elevation to promote neurite and axonal outgrowth


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No cure for spinal cord injury (SCI) exists due to the complex nature of such an injury. Obstacles to SCI repair include a lack of intrinsic growth capacity of adult mammalian CNS neurons, cavity and glial scar formation, and inhibitory molecules expressed at SCI lesions including chondroitin sulphate proteoglycans (CSPGs) and Nogo. Multiple strategies have been developed to boost the intrinsic growth capacity of adult CNS neurons but without translational success.

In a recently accepted article in the Journal of Neuroscience a team of researchers at the University of Aberdeen’s Institute of Medical Sciences, led by Dr Wenlong Huang, describe a novel approach to SCI repair. Haung et al., hypothesise that activation of Epac2 (a downstream effector of cAMP) will enhance neurite outgrowth after injury and thereby facilitate repair. To do this they have utilised self-assembling peptide hydrogel technology from Biogelx to both bridge the injury site and act as a drug delivery depot to deliver an Epac2 agonist directly to the injury site.

Using in vitro assays, the Aberdeen team demonstrated for the first time that Epac2 activation using a specific soluble agonist (S-220) significantly enhanced neurite outgrowth of postnatal rat cortical neurons and importantly markedly overcame the inhibition by chondroitin sulphate proteoglycans and mature astrocytes on neuron growth, both of which are known to negatively impact repair. Their studies also demonstrated that Biogelx’s unfunctionalized hydrogel (Biogelx-S) and that functionalised with RGD both proved to be suitable for the culture of CNS neuronal cells, with significantly increased neurite outgrowth being observed for postnatal rat cortical neurons, DRG neurons, and DRG explants.

To demonstrate the novel potential of this hydrogel/Epac2 activation combination strategy in promoting axonal outgrowth, an ex vivorat model of SCI mimicking post-SCI environment in vivowas used. Delivering S-220 via Biogelx hydrogel significantly enhanced axonal outgrowth across the lesion gaps in the organotypic spinal cordsliceswere observed,compared with controls. Additionally, the researcher’s demonstrated in vivothat S-220, when delivered by the Biogelx hydrogels at 3 weeks after contusion SCI in male adult rats, resulted in significantly better locomotor performance for up to 4 weeks post-treatment. The data demonstrated a promising therapeutic potential of S-220 in SCI, via beneficial effects on neurons and glia post-injury to facilitate axonal outgrowth. The ability to achieve a gradual, sustained, local release, where the therapeutic agent can be delivered directly to the injury site in a minimally invasive manner using a peptide-based hydrogel as an injectable delivery depot, represents huge potential for clinical translation.

All in all, the reported work has the potential to offer a game changing strategy for the treatment of spinal cord injury. Not only does it demonstrate that Epac2 elevation directly enhances the intrinsic capacity of injured neurons to regrow, and overcomes the inhibitory environment, including the glial scar and microglia, to facilitate axonal outgrowth, but with the use of Biogelx’s peptide-based hydrogel as a delivery depot for sustained release of S-220, the study confers translational potential. It has been demonstrated that the hydrogel technology has excellent biocompatibility and supports excellent neurite outgrowth in vitroand axonal outgrowth in the ex vivomodel. Moreover, its stiffness can be tuned to be similar to CNS tissue properties, which has been highlighted as a key requirement for spinal cord repair.

 

Check out the full article here; https://www.jneurosci.org/content/early/2019/08/13/JNEUROSCI.0374-19.2019

Guijarro-Belmar, M. Viskontas, Y.Wei, X. Bo, D. Shewan, W. Huang, “Epac2 elevation reverses inhibition by chondroitin sulfate proteoglycans in vitro and transforms post-lesion inhibitory environment to promote axonal outgrowth in an ex vivo model of spinal cord injury”, J. Neurosci, 2019; 10.1523/JNEUROSCI.0374-19.2019

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