Chondroitinase ABC

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Introduction

Chondroitinase ABC (ChABC) is a lyase from Proteus Vulgaris, responsible for the degradation of chondroitin sulfate and dermatan sulfate chains of proteoglycan molecules, and it also has hyaluronidase activity. At present, many research results show that ChABC can effectively treat spinal cord injury (SCI), and it has been widely used as a strategy to promote repair after SCI. Most of the therapeutic effects of ChABC can be attributed to its ability to degrade the sugar chains from a class of proteoglycan molecules (chondroitin sulphate proteoglycans). This enzyme can degrade molecules that inhibit nerve regeneration and break down the structure of the perineuronal nets (PNNs). This structure limits the plasticity of nerve cells, and their removal allows the establishment of new nerve connections, so this mechanism can be used to obtain therapeutic effects. Pre-clinical models also show that chondroitinase can also be effective in treating other diseases, such as peripheral nerve injury, Parkinson's disease, stroke, and certain types of cancer. The extensive therapeutic effect of chondroitinase reflects the complex role of chondroitin sulfate proteoglycan (its substrate) in health and disease, and has led to the further development of this enzyme as an effective therapy.

ChABC and SCI

Spinal cord injury (SCI) is a devastating disease, and effective treatments have not yet been developed. Patients with SCI may also experience sexual dysfunction, respiratory impairment, and neuropathic pain. The reason for these symptoms is that the central nervous system neurons cannot repair the damage after being injured. Some of them are caused by the existence of molecules that hinder repair in the environment of the damaged spinal cord. One of the major contributory factors is a class of molecules called CSPG. ChABC can break down such molecules to play a role in nerve regeneration and functional recovery. It also promotes plasticity, allows undamaged neurons to sprout and takes over the functions of damaged neurons. The beneficial effect of this enzyme has been confirmed in many related studies and several animal models. It is important that in addition to effective treatment of acute injuries, there are studies reporting its effectiveness against chronic injuries, which greatly increases the number and range of patients who may benefit. In early studies, first demonstrated that ChABC delivered to the cord via intrathecal injection can be used as a therapeutic strategy to promote nerve regeneration. However, due to the thermal instability of the enzyme, this method may require multiple injections for efficacy. Therefore, alternative strategies for enzyme delivery have been extensively investigated.

Figure 1. Schematic depicting the conditions in the spinal cord after injury and strategies developed for treating SCI (Zhao, R.R.; Fawcett, J.W. 2013)

Other therapeutic applications of ChABC

• ChABC and cancer

Takeuchi et al. published the first report on the treatment effect of ChABC in 1972, proving that ChABC inhibited the growth of Ehlrich ascites tumors. CSPG occupies the major part of the extracellular matrix stroma, which can regulate the proliferation and migration of solid tumors. In breast, prostate and lung cancer, the level of CSPG versican is increased, whilst brevican expression is up-regulated in gliomas. Another potential anti-tumor mechanism of ChABC is that it can promote the apoptosis of certain types of tumor cells (melanoma, pulmonary artery endothelial cells) by activating caspase-3. In addition, in experimental models of glioblastoma, ChABC can also enhance the spread of oncolytic viruses and make cells sensitive to tumor-targeting drugs (such as temozolomide).

• ChABC, myocardial infarction and stroke

In addition, recent studies have shown that this enzyme can effectively treat other diseases that prevent nerve repair (such as myocardial infarction and stroke). For stroke, the neuroprotective actions of ChABC can limit the primary and secondary damage, and can promote the plasticity of the brain and spinal cord. Crucially, ChABC is also effective in experimental models of chronic stroke. In order to improve the biological activity of the enzyme for stroke treatment, Hetiaratchi et al. doubled its half-life by site-directed mutagenesis (N1000 to G), and prevented the unfolding and aggregation of protein by PEGlylation.

• ChABC and fear memories

ChABC degrades PNNs, and these structures are necessary for fear learning and are important for protecting fear memories from erasure. Therefore, ChABC treatment may benefit patients suffering from phobias and anxiety disorders.

• ChABC and multiple sclerosis

ChABC may also be a potential treatment for multiple sclerosis, because there is strong evidence that CSPGs inhibit oligodendrocyte maturation and remyelination, and ChABC can promote remyelination.