Heparin mimetics: Novel non-anticoagulant compounds to promote CNS repair.

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Damage to the brain and spinal cord (together known as the central nervous system; CNS) is notoriously difficult to repair. In a disease such as multiple sclerosis damage occurs in which nerve processes lose their protective insulation wrapping (becoming "demyelinated", leading to faulty nerve signalling) and scarring forms in the tissue (called "astrogliosis", which prevents nerve regrowth). Current therapeutics tend to focus solely on altered immune responses, which cause damage, but not on other tissue changes. Repair is multifactorial and very complex, requiring a damping down of the immune response and scar tissue formation, as well as the promotion of re-insulation (myelination) and nerve outgrowth. Specialised sugar molecules that reside around the injury site, known as heparan sulphates (HS), carry out the regulation of many cellular functions required for repair. HS has varied patterns of sulphate groups on their surface, which by virtue of their number and position on the molecule can make neural cells carry out different types of functions. To study how HS works, we use chemical mimics of HS called heparin mimetics (mHeps). These mHeps are modified forms of the blood-thinning drug heparin but can be made chemically with altered amounts and positions of the sulphate groups. Using several assays in a Petri dish we have found that mHeps with a low number of sulphate groups promote remyelination, nerve process outgrowth and dampen down the scarring reactions. We also have some evidence that they can have a beneficial effect in animal models of disease, especially promoting remyelination, modulation of the immune response as well as general health (with less animal weight loss). For this reason, we now aim to carry out detailed experiments on the repair efficacy of a low sulphated mHep using an animal model of demyelination. We aim to:i) Confirm dosage, concentration and optimal molecular weight form of mHep7.ii) Confirm preliminary data that mHep7 (comparing two MW forms) can promote repair in two pre-clinical animal models classically used to study CNS injury.iii) Identify how the compounds work (ie. their mechanism-of-action), focusing on the immune response (which can enter the CNS and damage cells), weight gain (mHeps appear to promote CNS repair and animals appear healthier with less weight loss) and the integrity of the blood-brain barrier (BBB). The BBB prevents materials from the blood entering the brain. In disease, this can be leaky and allow the immune system to enter the brain, which can be harmful.Overall we aim to show that low sulphated mHeps are potential new drugs to promote CNS repair by having a multi-modal effect on several key cellular properties induced after injury/disease.