Bacterial enzyme aids recovery

I have posted before on the Glial scar and an inhibitory component of this, chondroitin sulphate proteoglycans, or CSPGs. The Glial scar is a particular consequence of CNS injury but CSPGs are also found everywhere in the extra cellular matrix (ECM) of the central nervous system. CSPGs have many known and unknown functions. For example, they form lattice-like nets around synapses between cells to stabilise these signalling junctions. They are likely to influence how cells move around the CNS, thus playing an important part in repair by resident stem and precursor cells which need to migrate to the area in need of repair, and they may harbour important molecules that sustain cells. Recently, two putative receptors have been identified giving insight into how CSPGs might act at the molecular level.
The inhibitory aspects of CSPGs are most problematic. The bacterial enzyme chondroitinase ABC (ChABC) degrades CSPGs, and experimentally, it has been shown to have a number of reparative effects making it a very promising treatment option for SCI. Nevertheless, there are concerns relating to how we should deliver this bacterial protein in the clinic. For one, ChABC activity is short-lived and therefore repeated injections or delivery by intrathecal catheter is needed which is unattractive.

Gene therapy approaches may provide the answer. Modified viruses have long been used as a tool to carry inserted genes into cells, “infecting” them with a copy of the gene which in turn causes the cell to produce (express) the protein. Obviously, concerns surround gene therapy as well, but the prospect of only needing a single administration of a therapeutic viral vector which gives rise to long-term expression of the therapeutic gene is compelling.

A number of groups are looking at a gene therapy approach for the delivery of chondroitinase. K Bartus (#892.21) presented a poster in the last session of the SfN meeting which got much attention. The poster presented data on sustained and widespread degradation of CSPGs following a single early injection of a lentiviral vector carrying a gene of ChABC optimised for expression in mammalian cells. The treatment led to a dramatic reduction of lesion pathology: sparing of neuronal tissue and dramatic reduction in cavity volume. The treatment also significantly improved signal conduction across the injury site coupled with improved performance on a horizontal ladder test.

With such sustained and active remodelling of the CSPG content of the cord there was a worry that there might be adverse effects such as development of pain syndromes. The authors tested for this and found no evidence of heightened sensitivity in the treated group of animals. The injury site was heavily vascularised with many tissue bridges associated with numerous axons.

Perhaps the most striking aspect of this study was that it was done in a contusion injury model, the most clinically relevant model of injury.